Download mmol/L

ALL YOU NEED TO KNOW ABOUT
LIPIDS BUT WERE AFRAID TO
ASK!
Dr. Pat Twomey,
Consultant Chemical Pathologist
The Ipswich Hospital
CHEMICAL PATHOLOGIST
• Clinical activity
– Currently
• Lipid/Cardiovascular Risk Clinic
• Nutrition
• Obesity
• Metabolic
– Previously
• Diabetes Clinics
• Endocrinology Clinics
CHEMICAL PATHOLOGIST
• Laboratory Interpretation
– GMS2 and training changes increase this
• Laboratory Management
– Utilisation of laboratory tests
– Laboratory organisation
– Quality
• Research (if I am lucky)
CHEMICAL PATHOLOGIST
• Trained in
– Cork
– Dublin
– Edinburgh
THE STONE OF ELOQUENCE
• Blarney Castle is famous for its
stone, which is traditionally
believed to have the power to
bestow eloquence on all those
who kiss it.
THE BRITISH ISLES
THE BRITISH
ISLES ADJUSTED
FOR I.Q.
THE BRITISH
ISLES ADJUSTED
FOR I.Q.
1
DISCLOSURE
•
Shares – None
•
Advisory Boards
•
–
AstraZeneca
–
Novartis
Presentations
–
Abbot
–
AstraZeneca
–
Bayer
–
Fournier
–
Glaxo Smith Kline
–
Merck
–
MSD
–
Novartis
–
Pfizer
–
Roche
–
Takeda
1. Pharmaceutical Companies
THE STONE OF ELOQUENCE
• Blarney Castle is famous for its stone,
which is traditionally believed to have the
power to bestow eloquence on all those
who kiss it.
• Questions at anytime.
Lipids
• What are they?
• Name some lipids?
• Why are they important?
Turbidity
• What is it?
• What causes it?
• What wavelengths are involved?
• Are all assays affected at these
wavelengths?
Interfering spectra
NADH
Absorbance
Turbidity
Icterus
340
415
450
510
570
600
700
Hemolysis
800
Wavelength (nm)
CVD Risk factors
• What are they?
Serum Cholesterol Levels in Men*
Framingham Heart Study
% Population
40
MI
No MI
30
20
10
0
150
200
250
300
350
400
3.9
5.2
6.5
7.8
9.1
10.3
Serum cholesterol
*During first 16 years of study: Entry ages 30–40 years
Adapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A.
(mg/dl)
11.6 (mmol/L)
450
Increased HDL and Reduced CHD Incidence
Framingham Study
(mmol/L)
Relative risk of CHD
3
LDL 220 mg/dl
LDL 160 mg/dl
LDL 100 mg/dl
(5.7)
(4.1)
(2.6)
2
1
0
25
0.65
35
0.90
45
1.16
55
1.42
65
1.68
75
1.94
85
2.20
(mg/dl)
(mmol/L)
HDL
Adapted from Kannel WB. Status of risk factors and their consideration in antihypertensive therapy. Am J Cardiol 1987;59:80A-90A.
Copenhagen Male Study
Relative risk of IHD
Relative Risk for Ischemic Heart Disease (IHD) during
8 Years according to Level of Fasting Triglycerides
4
3
P <.001
2
P <.05
2.2
1.5
1
1.0
0
(mmol/L)
0.88
(0.44–1.09)
(mg/dl)
78
1.33
(1.10–1.59)
117
TG level (thirds)
Adapted from Jeppesen J et al Circulation 1998;97:1029-1036.
2.45
(1.60–22.4)
217
Adjusted for:
Age
LDL-C
HDL-C
Alcohol use
Tobacco
Physical activity
BMI
SBP/DBP
HTN
NIDDM
Glycosuria
Low social class
Lipoproteins
• Name as many lipoproteins as
you can?
Lipoproteins
• LDL
• HDL
• Chylomicrons
• Chylomicron remnants
• VLDL
• IDL (VLDL remnants)
• Lp (a)
Lipoproteins
• Where do they come from?
HDL Metabolism and Atherosclerosis
Chylomicron
Chylomicron
Remnant
Intestine
LPL
B
E
LPL
HL
E
LRP
E
LPL
Oxidation
IDL
LDLr
LDL
VLDL
SR-BI
CETP
Cholesterol
Pool
Lipids
A-I
Liver
LCAT
A-I
HDL-R
Kidney
Nascent
HDL
HDL
Courtesy of HB Brewer Jr, MD
CD36
SR-A
ABC1
Arterial Wall
Macrophage
Lipoprotein Treatment Priorities
• Total cholesterol (LDL
cholesterol)
• HDL cholesterol
• Triglycerides
UKPDS: Major Identified Risk Factors
• LDL cholesterol
• Diastolic blood pressure
• Smoking
• HDL cholesterol
• HbA1C
Adapted from Turner RC et al BMJ 1998;316:823-828.
Cost Effectiveness
• ‘in determining health policy, cost
effectiveness rather than the cost of
drugs is of pivotal importance. It is
clear that treatment of the elderly and
those at highest risk is more cost
effective’
Joint British Recommendations Dec 1998
Number of individuals needed to be treated (NNT) to
prevent a coronary event versus underlying CHD risk*
50
WOSCOPS all
NNT
40
30
WOSCOPS
high risk
20
4S
10
Primary
prevention
0
0
1
Primary
prevention
(high risk)
2
3
Secondary
prevention
4
% CHD event rate/year
*Data taken from several recent clinical trials.
5
6
CHD Mortality in Type 2 Diabetics
100
Non-diabetic, no MI (n=1304)
Type 2, no MI (n=890)
Non-diabetic, MI (n=69)
% Survival
80
60
Type 2, MI (n=169)
40
20
0
0
1
2
3
4
5
6
7
8
Years
Adapted from Haffner SM et al (East-West Study in Finland) New Engl J Med 1998;339:229-234.
o
2 causes of dyslipidaemia
• Obesity
• Diabetes Mellitus
• Alcohol abuse
• Liver disease
• Renal disease
• Hypothyroidism
• Medication
o
Why rule out 2 causes?
• Good medicine - treat the
cause, not the resulting
condition
• Increased side effects, e.g.,
hypothyroidism and statins
How low should we go?
Lipid Management in Clinical Practice
What Is an Appropriate Therapeutic Target for LDL Cholesterol?
% Reduction in risk of
cardiac endpoints
0
20
LRC-CPPT (cholestyramine)
CARE (pravastatin)
WOSCOPS (pravastatin)
40
4S (simvastatin)
?
70
?
10
13
26
35
50
60
% LDL-C reduction
LRC-CPPT = Lipid Research Clinics–Coronary Primary Prevention Trial; CARE = Cholesterol and Recurrent Events;
WOSCOPS = West of Scotland Coronary Prevention Study; 4S = Scandinavian Simvastatin Survival Study
Lipids
• ‘at least to an LDL cholesterol less
than 3.0 mmol/L (total cholesterol less
than 5.0 mmol/L)’ in established CHD
• ‘Patients who fail to reach this target
should be referred to a specialist
clinic’
Joint British Recommendations Dec 1998
Lipids - rechecking
• 3 months after dietary advice
• 4 - 6 weeks after drug
initiation/change in dosage
QUESTIONS
• Do high risk populations achieve similar
benefit irrespective of starting cholesterol
(or LDL-C) concentrations?
• Is there benefit from starting statins
immediately post-event rather than waiting
until 3-6 months as in 4S, CARE etc.?
• Do high risk populations achieve extra
benefit from intensive cholesterol (or LDL-C)
lowering?
HPS: VASCULAR EVENT by PRIOR LIPID LEVELS
Baseline
feature
STATIN
(10269)
PLACEBO
(10267)
Risk ratio and 95% CI
STATIN better STATIN worse
LDL (mmol/l)
< 3.0 (116 mg/dl)
602
761
 3.0 < 3.5
483
655
 3.5 (135 mg/dl)
957
1190
<5.0 (193 mg/dl)
361
476
 5.0 < 6.0
746
965
 6.0 (232 mg/dl)
935
1165
Het c 2 = 3.0
2
Total cholesterol (mmol/l)
ALL PATIENTS
2042
(19.9%)
Het c 2 = 0.5
2
2606
(25.4%)
MRC/BHF Heart Protection Study. Lancet 2002;360:7-22.
24% SE 2.6
reduction
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
Lipid Lowering and Recent Statin Trials
• MIRACL
• REVERSAL
• PROVE IT – TIMI 22
MIRACL: Addressed a Research Gap
Acute coronary
event
No history of CAD
Unstable CAD
Stable CAD
4 mo
AFCAPS / TexCAPS/
WOSCOPS
MIRACL
t=0
CARE/LIPID
3 mo
4S
6 mo
Randomization:
24–96 h
Primary prevention
Randomization:
CARE - 3–20 mo
LIPID - 3–36 mo
Secondary prevention
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
Randomization:
>6 mo
MIRACL - Study Design
Study Hypothesis: Lipid lowering with atorvastatin 80mg started within 24 - 96 hours of hospitalisation
following diagnosis of unstable angina or non-Q-wave acute MI, reduces early recurrent ischaemic events.
Hospitalisation
for
unstable angina
or non-Q-wave MI
n=3,086
Randomised
24-96 hours
after admission
Placebo
Atorvastatin 80 mg
16 weeks
Assessments conducted at
weeks 0, 2, 6 and 16
Schwartz GG et al. JAMA 2001; 285(13)1711-1718
Lipids at Randomisation and Study End
Baseline
Mean of both groups
mmol/L
End of study
% Change Atorvastatin vs. placebo
Total cholesterol
5.3
-34%
LDL cholesterol
3.2
-52% (1.9mmol/L)
HDL cholesterol
1.2
+1.6%
Triglycerides
2.0
-25%
Schwartz GG et al. JAMA 2001; 285(13)1711-1718
Relative Event Rate Reduction in Primary Endpoint
Cumulative incidence (%)
Placebo
15
17.4%
14.8%
Atorvastatin
10
Time to first occurrence of:
 Death
 Nonfatal MI
 Resuscitated cardiac arrest
 Worsening angina with objective
5
Relative Risk = 0.84
(0.70-1.00), p=0.048
evidence of ischaemia requiring
rehospitalisation
0
0
4
8
12
Time since randomisation (weeks)
Schwartz GG et al. JAMA 2001; 285(13)1711-1718
16
REVERSAL
657 CHD Patients
Atorvastatin 80mg
253 patients
with IVUS at
baseline and 18
months
Pravastatin 40mg
249 patients
with IVUS at
baseline and 18
months
 Randomised, double blind multicentre trial performed at 34 community and tertiary
care centres in the United States
 Primary endpoint: % change in Coronary Plaque Volume by IVUS
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Patient Population
• Inclusion criteria:
– Patients aged 30-75 years requiring diagnostic coronary angiography
for a clinical indication
– LDL-cholesterol between 3.2 mmol/L and 5.4 mmol/L
• Angiographic inclusion criteria:
– Angiographic evidence of CHD defined as ≥ 1 lesion with ≥ 20% reduction
in lumen diameter in any coronary artery
– ≤ 50% reduction in lumen diameter of the left main coronary artery
– The vessel undergoing IVUS evaluation (the ‘target’ vessel) should have ≤
50% stenosis throughout a segment of minimum length of 30 mm
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Intravascular Ultrasound (IVUS)
REVERSAL: Why was IVUS used?
Angiogram
IVUS Image
Nissen SE et al. JAMA 2004; 291(9)1071-1080
% Change from Baseline in Lipid Parameters
Total cholesterol
LDL-cholesterol
Triglycerides
Change from baseline (%)
10
HDL-cholesterol
5.6
2.9
0
-6.8
-10
-20
-18.4
-20.0*
Pravastatin
-25.2
-30
Atorvastatin
-34.1*
-40
-50
-46.3*
2.04mmol/L
*P<.001
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Percent Change in Total Atheroma Volume
3.5
3
% Change in Total
Atheroma Volume
2.5
Progression (p=0.001*)
2.7
p = 0.02†
2
1.5
1
0.5
0
-0.5
-1
* vs baseline
† between groups
-0.4
No change (p=0.98*)
Pravastatin
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Atorvastatin
Comparative Adverse Events
Pravastatin
Atorvastatin
(n=327)
(n=327)
Death
1 (0.3%)
1 (0.3%)
Myocardial Infarction
7 (2.1%)
4 (1.2%)
Stroke
1 (0.3%)
1 (0.3%)
ALT>3xULN
5/316 (1.6%)
7/311 (2.3%)
AST>3xULN
2/316 (0.6%)
2/311 (0.6%)
C K > 10 x U L N
0/316 (0.0%)
0/311 (0.0%)
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Study Limitations
• The REVERSAL study was not powered to assess
differences in clinical events
• Morbidity and mortality endpoints are always the preferred
efficacy measures in clinical trials
• However, comparison of two statins in a conventional
events trial would require approximately 10,000 patients
and 5-6 years follow-up
• Furthermore, previous trials have demonstrated a
relationship between atherosclerosis progression and
vascular events
Nissen SE et al. JAMA 2004; 291(9)1071-1080
PROVE IT – TIMI 22 Rationale
(Pravastatin Or Atorvastatin Evaluation and Infection
Therapy - Thrombolysis in Myocardial Infarction 22)
• Are statins effective in reducing cardiac events
when started early after an acute coronary
syndrome (ACS)?
• Do the benefits of “intensive” LDL-C lowering to
~1.8mmol/L with 80mg atorvastatin achieve a
greater reduction in clinical events than
“standard” LDL-C lowering to ~2.6mmol/L with
40mg pravastatin?
Cannon CP et al. NEJM 2004; 350(9):15
PROVE IT – TIMI 22: Study Design
4,162 patients with an Acute
Coronary Syndrome < 10
days
ASA + Standard Medical
Therapy
Intensive Therapy
(Atorvastatin 80 mg)
Standard Therapy
(Pravastatin 40 mg)
2x2 Factorial: Gatifloxacin
vs. placebo
Duration: Mean 2 year
follow-up
(> 925 events)
Cannon CP et al. NEJM 2004; 350(9):15
•Randomised, double blind study
•349 sites in 8 countries
•Designed as a non inferiority trial
•Primary Endpoint: Death,
MI, Documented UA
requiring hospitalisation,
Revascularisation (>30 days
after randomisation), and
Stroke
Patient Population
Inclusion Criteria:
• Hospitalisation for acute MI or high-risk unstable
angina within the last 10 days
• Total cholesterol < 6.2mmol/L (< 5.2mmol/L if on
lipid lowering therapy)
• Stabilised (i.e.without ischemia, CHF, post PCI if
planned)
Cannon CP et al. NEJM 2004; 350(9):15
Baseline Characteristics
Atorvastatin
80mg
(2099)
Pravastatin 40
mg
(2063)
Mean Age (years)
58
58
Male/Female (%)
78/22
78/22
History of Hypertension (%)
51
49
Current Smoker (%)
36
37
History of Diabetes (%)
18
18
Prior MI (%)
18
19
36/36/29
33/37/30
26
25
STEMI/NSTEMI/UA (%)
Prior Statin Use (%)
Cannon CP et al. NEJM 2004; 350(9):15
Concomitant Therapies
PCI for initial ACS pre-randomisation
69%
Aspirin
93%
Warfarin
8%
Clopidogrel/ticlopidine (initial)
72%
(at 1 year)
20%
B-blockers
85%
ACE Inhibitors
69%
AII receptor blockers
14%
Statin Therapy
25%
Cannon CP et al. NEJM 2004; 350(9):15
Baseline Lipid Levels
Median Values*
Atorvastatin
80mg
(2099)
Pravastatin
40 mg
(2063)
Total Cholesterol (mmol/L)
4.7
4.7
LDL Cholesterol (mmol/L)
2.7
2.7
Triglycerides (mmol/L)
1.8
1.7
HDL Cholesterol (mmol/L)
1.0
1.0
* 25% of patients receiving statin therapy prior to randomisation
Cannon CP et al. NEJM 2004; 350(9):15
Changes from (Post-ACS) Baseline in Median LDL-C
120
Pravastatin 40mg
Median LDL-C achieved
100
80
2.5mmol/L
1.6mmol/L
Atorvastatin
80mg
LDL-C
(mg/dL)
P<0.001
60
Note: Changes in LDL-C may
differ from prior trials:
•25% of patients on statins prior to
ACS event and no washout period
•LDL-C is transiently lowered by
the acute coronary event itself
40
20
0
Rand.
30 Days
4 Mos.
8 Mos.
16 Mos.
Final
Cannon CP et al. NEJM 2004; 350(9):15
Benefits of Intensive Lipid Lowering on
All-Cause Death or Major CV Events (Primary Endpoint at 2 Years)
30
25
Pravastatin 40mg
(26.3%)
Criteria for
equivalence were
not met
20
% with
Event
Atorvastatin 80mg
(22.4%)
15
Atorvastatin 80mg
was superior to
Pravastatin 40mg
10
5
16% RRR (5-26)
(P = 0.005)
0
0
3
6
9
12
15
18
21
24
Months of Follow-up
Cannon CP et al. NEJM 2004; 350(9):15
27
30
Tolerability and Safety Profile
Atorvastatin
80mg (2099)
Pravastatin
40mg (2063)
P-value
Discontinuation
for AE, patient
preference or
other reasons
30.4%
33.0%
0.11
Discontinuation
for Myalgia/CK
elevation
3.3%
2.7%
0.23
Rhabdomyolysis
0%
0%
N/A
ALT ≥3 ULN
3.3%
1.1%
<0.001
Dose halving for
AE or raised ALT
1.9%
1.4%
0.20
Cannon CP et al. NEJM 2004; 350(9):15
How low should we go?
New Targets
• LDL cholesterol <2.0 mmol/L
• Total cholesterol <4.0 mmol/L)
What class of drugs?
• ‘The best evidence of cholesterol
lowering in secondary prevention
comes from randomised
controlled trials using statins;
these drugs are thus the preferred
class for CHD patients’
Joint British Recommendations Dec 1998
Overview of Early Secondary Prevention Trials
Total-C*
CHD events*
0
CDP: clofibrate
n=8341; P=NS
Percentage Change
–6
-10
-20
–9
–10
–13
–15
CDP: niacin
n =8341; P=NS
–23
Stockholm: clofibrate + niacin
n =555; P=NS
–29
-30
–35
-40
POSCH: partial ileal bypass
n =838; P<0.001
CDP, Coronary Drug Projects; NS, not significant; POSCH, Program on Surgical Control of the Hyperlipidaemias.
difference between treatment and control groups (P values are for events). Kwiterovich PO. Am J Cardiol 1998;82(12A):3U–17U.
*Net
What class of drugs?
• ‘Generally a statin should be
the initial choice of therapy in
combined hyperlipidaemia,
certainly when the triglycerides
are less than 5.0 mmol/L’
Joint British Recommendations Dec 1998
Rule of 5 & Rule of 7
•
A doubling of each statin lowers
Total cholesterol an additional 5%
• A doubling of each statin lowers
LDL cholesterol an additional 7%
Am J Cardiol 1997; 80: 166-167
Treating to Target
• Patient with CHD or with CHD risk over 10 years
> 30% with LDL cholesterol of 4.0 mmol/L
– Target LDL cholesterol
< 3.0 mmol/L
– Desired LDL cholesterol reduction
25 %
• Choose a drug that can achieve the target
• Note cost and evidence
LDL-C reduction and statins
LDL-C: Mean change (%) from baseline at week 6
0
-5
-10
-15
20
-25
-30
-35
-40
-45
10
mg
20
mg
10
mg

20
mg
40
mg
‡
‡
10
mg
20
mg
40
mg
mg

‡
‡ 
‡
10
mg
20
mg
40
mg

‡
‡ 
 p<0.002 vs. rosuvastatin 10mg
-50
‡ p<0,002 vs, rosuvastatin 20mg
80
mg
-55
40
mg
-60
rosuvastatin
atorvastatin
80
simvastatin
pravastatin
 p<0.002 vs. rosuvastatin 40mg
Jones PH for the STELLAR Study Group. JACC 2003;41:in press.
Serum Cholesterol Levels in Men*
Framingham Heart Study
% Population
40
MI
No MI
30
20
10
0
150
200
250
300
350
400
3.9
5.2
6.5
7.8
9.1
10.3
Serum cholesterol
*During first 16 years of study: Entry ages 30–40 years
Adapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A.
(mg/dl)
11.6 (mmol/L)
450
RIGHT SKEWED DISTRIBUTION
PROBLEMS WITH TREATMENT TO TARGET
• Bias
– Analytical
– Biological
• Variation
– Analytical
– Biological
• Combination of both
BIAS
ANALYTICAL BIAS
•Cholesterol
–Probably minimal
•Blood Pressure
–Potentially large
THE NORMAL DISTRIBUTION
TOTAL VARIATION
Biological Analytical Total
Cholesterol 6.5%
2.5%
6.9%
SBP
5%
8.6%
7%
Effect of Variation
• Cholesterol (mmol/L)
– Mean
5.0
– Upper 95% confidence interval
5.7
– Lower 95% confidence interval
4.3
TREATMENT TO TARGET
• Populations are made up of individuals
• If an individuals cholesterol has an average of 5.0
mmol/L, then 50% of the time it is above 5.0 mmol/L
• To be sure that 60% of CHD patients have a
cholesterol <5.0 mmol/l means that a lower target
cholesterol will be necessary to achieve this
• The mean - 2.8 x CVtotal is the value to ensure that a
patient is always (100%) below the target
• This value is c4.0 mmol/L
TREATMENT TO TARGET
• If you set a target cholesterol of 4.0 mmol/L for 60%
of your patients, then you should achieve the
contract target
• This allows lee-way for those with diabetes, mixed
dyslipidaemia/resistance to therapy, etc.
• Alternatively, you can set a higher target for >60%
of your patients
• This target MUST be <5.0 mmol/L to achieve the
contract target in practice
RIGHT SKEWED DISTRIBUTION
Raised ALT
• ALT NOT liver function tests
• Stop if consistently above 3 times upper
reference limit (111 U/L in Ipswich)
• Suggest measure ALT only to KEEP IT
SIMPLE
• BNF states assessment only for first year
Risk:Benefit – Liver
Persistent ALT >3 × ULN (%)
Persistent ALT >3 × ULN: Frequency by LDL-C Reduction
Rosuvastatin (10–40 mg)
Atorvastatin (10–80 mg)
Simvastatin (40–80 mg)
3.0
Fluvastatin (20–80 mg)
2.5
2.0
1.5
1.0
0.5
0.0
20
30
40
LDL-C reduction (%)
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
50
60
70
Muscle Problems
• Myo-,
from Greek: of muscle
• Myopathy:
muscle pathology
• Myalgia:
muscle pain
• Myositis:
muscle inflammation
• Rhabdomyolysis
skeletal muscle breakdown
Muscle Problems
• ‘Should a patient complain of muscle ache or
other minor muscle related problems, it is
recommended that a Creatine Kinase (CK) level be
analysed. A pre-treatment baseline level is
important for comparison purposes’
• Patient should NOT be started on a statin if the
pre-treatment CK level is >5 times normal (> 1,000
U/l in men, > 750 U/l in women)
BNF March 2001 p125
Muscle Problems
• ‘If the creatine kinase concentration is
markedly elevated (>10 times upper limit of
normal), and myopathy is suspected or
diagnosed, treatment should be
discontinued’
• Monitoring of creatine kinase is required if
patients of lipid-lowering medications have
muscle symptoms
BNF March 2001 p125
Muscle Problems
• Myositis, defined as muscle inflammation with
CK levels 10 times normal (> 2,000 U/l in men,
>1,500 U/l in women), is rarely reported.
• It is important to note that the CK level returns
to normal within 48 hours of discontinuing lipid
lowering medication.
Muscle Problems
• Rhabdomyolysis associated with lipid
lowering drugs is rare (1 case in every
100,000 treatment years) but may be
increased in those with renal impairment
and possibly those with hypothyroidism
• Concomitant treatment with cyclosporin or
in combined statin and fibrate therapy may
be associated with increased risk of serious
muscle toxicity
BNF March 2001 p125
Risk:Benefit – Muscle
CK >10 × ULN frequency by % LDL-C reduction
3.0
% CK > 10 × ULN
2.5
Cerivastatin (0.2–0.8mg)
Atorvastatin (10–80mg)
Pravastatin (40–80mg)
Rosuvastatin (10–40mg)
Simvastatin (40–80mg)
2.0
1.5
1.0
0.5
0.0
20
30
40
50
% LDL-C reduction
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
60
70
Cumulative post-marketing reporting rate of
rhabdomyolysis for rosuvastatin
Patients = new and switched prescriptions
Reporting rate <1:10,000 = very rare (CIOMS)
Reporting rate per
10,000 patients
1.0
0.9
0.8
Reporting rate - ALL
Reporting rate - ACC/AHA criteria
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Week starting
Update: 08 December 2004
Reporting rates of rhabdomyolysis
with lipid-modifying therapy
Semiannual Reporting Rates for All Reports of Rhabdomyolysis
Worldwide Cases‡
Cerivastatin
120
†
Rosuvastatin
Fluvastatin
100
100
Atorvastatin
Pravastatin
80
120
80
Simvastatin
60
Ezetimibe
60
Rosuvastatin
40
40
20
20
0
0
03/9908/99
09/9902/00
03/0008/00
09/0002/01
03/0108/01
09/0102/02
*All spontaneous reports including expedited, periodic and direct reports. **US
reporting rate for all statins and ezetimibe based on FDA Adverse Events Reporting
System made available through Freedom of Information Act divided by US
prescribing data supplied by IMS through August 2003.
†Cerivastatin reports received after September 1, 2001, are excluded.
Update: 08 December 2004
03/0208/02
09/0202/03
03/0308/03
06/0311/03
12/0305/04
Reporting Rate Per 1,000,000
CRESTOR Prescriptions Worldwide‡
Reporting Rate Per
1,000,000 US Prescriptions **
US Cases*
06/0411/04
‡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 November 2004. Total prescriptions based on IMS data
from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions
based on actual sales calculations.
90
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