ALL YOU NEED TO KNOW ABOUT LIPIDS BUT WERE AFRAID TO ASK! Dr. Pat Twomey, Consultant Chemical Pathologist The Ipswich Hospital
Jan 02, 2016
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 ADJUSTEDFOR I.Q.
THE BRITISH ISLES ADJUSTEDFOR I.Q.
1. Pharmaceutical Companies
DISCLOSURE1
• Shares – None
• Advisory Boards
– AstraZeneca
– Novartis
• Presentations
– Abbot
– AstraZeneca
– Bayer
– Fournier
– Glaxo Smith Kline
– Merck
– MSD
– Novartis
– Pfizer
– Roche
– Takeda
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
TurbidityNADHAbsorbance
340 415 450 510 570 600 700 800
Icterus Hemolysis
Wavelength (nm)
CVD Risk factors
• What are they?
Serum Cholesterol Levels in Men*Framingham Heart Study
% P
op
ula
tio
n
0
10
20
30
40
*During first 16 years of study: Entry ages 30–40 yearsAdapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A.
MINo MI
150 200 250 300 350 400 450
Serum cholesterol
3.9(mg/dl)
(mmol/L)5.2 6.5 7.8 9.1 10.3 11.6
Increased HDL and Reduced CHD Incidence
Framingham Study
Rel
ativ
e ri
sk o
f C
HD
Adapted from Kannel WB. Status of risk factors and their consideration in antihypertensive therapy. Am J Cardiol 1987;59:80A-90A.
0
1
2
3 LDL 220 mg/dl
LDL 160 mg/dl
LDL 100 mg/dl
(mmol/L)
(5.7)
(4.1)
(2.6)
HDL
250.65
350.90
(mg/dl)(mmol/L)
451.16
551.42
651.68
751.94
852.20
0
1
2
3
4
Copenhagen Male StudyRelative Risk for Ischemic Heart Disease (IHD) during8 Years according to Level of Fasting Triglycerides
Rel
ativ
e ri
sk o
f IH
D
Adapted from Jeppesen J et al Circulation 1998;97:1029-1036.
1.01.5
2.2
TG level (thirds)
0.88(0.44–1.09)
78
1.33(1.10–1.59)
117
2.45(1.60–22.4)
217
(mmol/L)
(mg/dl)
P <.05
P <.001
Adjusted for:AgeLDL-CHDL-CAlcohol useTobaccoPhysical activityBMISBP/DBPHTNNIDDMGlycosuriaLow 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
Courtesy of HB Brewer Jr, MD
SR-BI
Liver
LRPLDLr
VLDL
CholesterolPool
CD36SR-A
LDLIDL
LPL
LPLE
E
BB
B
HLC-IIC-II
Chylomicron Remnant
Chylomicron
Intestine
E
B
B
LPL
ABC1
Arterial WallMacrophage
CETP LipidsA-I
A-ILCAT
HDL
NascentHDL
Oxidation
KidneyHDL-R
C-II
Lipoprotein Treatment Priorities
• Total cholesterol (LDL cholesterol)
• HDL cholesterol
• Triglycerides
UKPDS: Major Identified Risk Factors
Adapted from Turner RC et al BMJ 1998;316:823-828.
• LDL cholesterol
• Diastolic blood pressure
• Smoking
• HDL cholesterol
• HbA1C
Joint British Recommendations Dec 1998
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’
Number of individuals needed to be treated (NNT) to prevent a coronary event versus underlying CHD risk*
0 1 2 3 4 5 6
Primaryprevention(high risk)
Primaryprevention
Secondaryprevention
WOSCOPS all
WOSCOPShigh risk
4 S
% CHD event rate/year
NN
T
50
40
30
20
10
0
*Data taken from several recent clinical trials.
CHD Mortality in Type 2 Diabetics
Adapted from Haffner SM et al (East-West Study in Finland) New Engl J Med 1998;339:229-234.
% S
urv
ival
100
80
60
40
20
0
Non-diabetic, no MI (n=1304)Type 2, no MI (n=890)Non-diabetic, MI (n=69)
Type 2, MI (n=169)
0 1 2 3 4 5 6 7 8
Years
2o causes of dyslipidaemia
• Obesity
• Diabetes Mellitus
• Alcohol abuse
• Liver disease
• Renal disease
• Hypothyroidism
• Medication
Why rule out 2o 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
70
40
20
0
10 13 26 35 50 60
% LDL-C reduction
% R
edu
ctio
n in
ris
k o
fca
rdia
c e
nd
po
ints LRC-CPPT (cholestyramine)
CARE (pravastatin)
WOSCOPS (pravastatin)
4S (simvastatin)
?
?
What Is an Appropriate Therapeutic Target for LDL Cholesterol?
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
Joint British Recommendations Dec 1998
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’
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
Risk ratio and 95% CISTATIN PLACEBOBaselinefeature (10269) (10267) STATIN better STATIN worse
LDL (mmol/l)
Het = 3.0
< 3.0 (116 mg/dl) 602 761
3.0 < 3.5 483 655
3.5 (135 mg/dl) 957 1190
Total cholesterol (mmol/l)
Het = 0.5
<5.0 (193 mg/dl) 361 476
5.0 < 6.0 746 965
6.0 (232 mg/dl) 935 1165
ALL PATIENTS 2042 2606(19.9%) (25.4%)
24% SE 2.6reduction(2P<0.00001)
0.4 0.6 0.8 1.0 1.2 1.4MRC/BHF Heart Protection Study. Lancet 2002;360:7-22.
2
2
2
2
Lipid Lowering and Recent Statin Trials
• MIRACL
• REVERSAL
• PROVE IT – TIMI 22
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
MIRACL: Addressed a Research Gap
Acute coronaryevent
MIRACL
4S
AFCAPS / TexCAPS/WOSCOPS
CARE/LIPID
4 moNo history of CAD Unstable CAD
Randomization:24–96 h
3 mo
t=0
6 mo
Randomization:CARE - 3–20 moLIPID - 3–36 mo
Randomization:>6 mo
Stable CAD
Primary prevention Secondary prevention
Schwartz GG et al. JAMA 2001; 285(13)1711-1718
Hospitalisationfor
unstable anginaor non-Q-wave
MI
Placebo
Atorvastatin 80
mg
n=3,086Randomised
24-96 hoursafter
admission
16 weeks
Assessments conducted at weeks 0, 2, 6 and 16
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.
Schwartz GG et al. JAMA 2001; 285(13)1711-1718
Baseline End of studyMean of both groups % Change Atorvastatin vs. placebo
mmol/L
Total cholesterol 5.3 -34%
LDL cholesterol 3.2 -52% (1.9mmol/L)
HDL cholesterol 1.2 +1.6%
Triglycerides 2.0 -25%
Lipids at Randomisation and Study End
Schwartz GG et al. JAMA 2001; 285(13)1711-1718
Relative Risk = 0.84(0.70-1.00), p=0.048
Atorvastatin
Placebo
0
5
10
15
0 4 8 12 16Time since randomisation (weeks)
Cumulative incidence (%)
Time to first occurrence of:
Death Nonfatal MI Resuscitated cardiac arrest Worsening angina with
objective evidence of ischaemia requiring rehospitalisation
17.4%
14.8%
Relative Event Rate Reduction in Primary Endpoint
Nissen SE et al. JAMA 2004; 291(9)1071-1080
REVERSAL
657 CHD Patients
Atorvastatin 80mg Pravastatin 40mg
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
253 patients with IVUS at baseline and 18 months
249 patients with IVUS at baseline and 18 months
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?REVERSAL: Why was IVUS used?REVERSAL: Why was IVUS used?
Angiogram IVUS Image
Nissen SE et al. JAMA 2004; 291(9)1071-1080
% Change from Baseline in Lipid Parameters
*P<.001
-40
-30
-20
-10
0
10
Atorvastatin
-50
Cha
nge
from
bas
elin
e (%
)Total cholesterol LDL-cholesterol
-25.2
-18.4
5.6
-6.8
-46.3*
-34.1*
2.9
-20.0*
Triglycerides HDL-cholesterol
Pravastatin
2.04mmol/L
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Percent Change in Total Atheroma Volume
* vs baseline† between groups
p = 0.02†
3.5
3
2.5
2
1.5
1
0.5
0
-0.5
-1
2.7
-0.4
Progression (p=0.001*)
No change (p=0.98*)
% Change in Total Atheroma
Volume
Pravastatin Atorvastatin
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Comparative Adverse Events
Pravastatin
(n=327)
Atorvastatin
(n=327)
Death 1 (0.3%) 1 (0.3%)
Myocardial Infarction 7 (2.1%) 4 (1.2%)
Stroke 1 (0.3%) 1 (0.3%)
A L T > 3 x U L N 5/316 (1.6%) 7/311 (2.3%)
A S T > 3 x U L N 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
Cannon CP et al. NEJM 2004; 350(9):15
PROVE IT – TIMI 22 Rationale
• 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?
(Pravastatin Or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction 22)
Cannon CP et al. NEJM 2004; 350(9):15
PROVE IT – TIMI 22: Study Design4,162 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)
•Primary Endpoint: Death, MI, Documented UA requiring hospitalisation,Revascularisation (>30 days after randomisation), and Stroke
•Randomised, double blind study•349 sites in 8 countries
•Designed as a non - inferiority trial
Cannon CP et al. NEJM 2004; 350(9):15
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
STEMI/NSTEMI/UA (%) 36/36/29 33/37/30
Prior Statin Use (%) 26 25
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)
(at 1 year)
72%
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
0
20
40
60
80
100
120
Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final
LDL-C (mg/dL)
Pravastatin 40mg
Atorvastatin 80mg P<0.001
Median LDL-C achieved2.5mmol/L
1.6mmol/L
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
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)
0
5
10
15
20
25
30
0 3 6 9 12 15 18 21 24 27 30
Pravastatin 40mg(26.3%)
Atorvastatin 80mg(22.4%)
16% RRR (5-26)(P = 0.005)
% withEvent
Months of Follow-up
Criteria for equivalence were not met
Atorvastatin 80mg was superior to Pravastatin 40mg
Cannon CP et al. NEJM 2004; 350(9):15
Tolerability and Safety Profile
Atorvastatin80mg (2099)
Pravastatin40mg (2063)
P-value
Discontinuation for AE, patient preference or other reasons
30.4% 33.0% 0.11
Discontinuation for Myalgia/CK
elevation3.3% 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
How low should we go?
New Targets
• LDL cholesterol <2.0 mmol/L
• Total cholesterol <4.0 mmol/L)
Joint British Recommendations Dec 1998
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’
Overview of Early Secondary Prevention Trials
–9–6
–15
–10
–29
–13
–35
–23
-40
-30
-20
-10
0
Pe
rcen
tag
e C
ha
ng
e
Total-C* CHD events*
CDP: clofibraten=8341; P=NS
CDP: niacinn =8341; P=NS
Stockholm: clofibrate + niacinn =555; P=NS
POSCH: partial ileal bypassn =838; P<0.001
CDP, Coronary Drug Projects; NS, not significant; POSCH, Program on Surgical Control of the Hyperlipidaemias. *Net difference between treatment and control groups (P values are for events). Kwiterovich PO. Am J Cardiol 1998;82(12A):3U–17U.
Joint British Recommendations Dec 1998
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’
Am J Cardiol 1997; 80: 166-167
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%
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
0 -10 20 -30 -50 -60-5 -15 -25 -35 -45 -55
20mg
‡
40mg
‡
80mg‡
-40
20mg
40mg
80mg
LDL-C: Mean change (%) from baseline at week 6
20mg‡
40mg‡
40mg‡ ‡
20mg
Jones PH for the STELLAR Study Group. JACC 2003;41:in press.
rosuvastatin
simvastatin
atorvastatin
10mg
10mg
10mg
10mg
pravastatin
p<0.002 vs. rosuvastatin 10mg ‡ p<0,002 vs, rosuvastatin 20mg p<0.002 vs. rosuvastatin 40mg
Serum Cholesterol Levels in Men*Framingham Heart Study
% P
op
ula
tio
n
0
10
20
30
40
*During first 16 years of study: Entry ages 30–40 yearsAdapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A.
MINo MI
150 200 250 300 350 400 450
Serum cholesterol
3.9(mg/dl)
(mmol/L)5.2 6.5 7.8 9.1 10.3 11.6
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 7% 5% 8.6%
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
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
Persistent ALT >3 × ULN (%)
Rosuvastatin (10–40 mg)
Atorvastatin (10–80 mg)
Fluvastatin (20–80 mg)
Simvastatin (40–80 mg)
Persistent ALT >3 Persistent ALT >3 ×× ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction
Muscle Problems
• Myo-, from Greek: of muscle
• Myopathy: muscle pathology
• Myalgia: muscle pain
• Myositis: muscle inflammation
• Rhabdomyolysis skeletal muscle breakdown
BNF March 2001 p125
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
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.
BNF March 2001 p125
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
CK >10 × ULN frequency by % LDL-C reduction
0.00.0
0.50.5
1.01.0
1.51.5
2.02.0
2.52.5
3.03.0
2020 3030 4040 5050 6060 7070
% LDL-C reduction% LDL-C reduction
% C
K >
10
× U
LN
% C
K >
10
× U
LN
Rosuvastatin (10–40mg)Pravastatin (40–80mg)
Cerivastatin (0.2–0.8mg) Atorvastatin (10–80mg)
Simvastatin (40–80mg) (40–80mg)
Brewer HB. Brewer HB. Am J CardiolAm J Cardiol 2003;92(Suppl):23K–29K 2003;92(Suppl):23K–29K
Risk:Benefit – MuscleRisk:Benefit – Muscle
Cumulative post-marketing reporting rate of rhabdomyolysis for rosuvastatin
Reporting rate <1:10,000 = very rare (CIOMS)
Patients = new and switched prescriptions
Update: 08 December 2004
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
04-Jun-2003
30-Jul-2003
24-Sep-2003
19-Nov-2003
14-Jan-2004
10-Mar-2004
05-May-2004
30-Jun-2004
25-Aug-2004
20-Oct-2004
01-Dec-2004
Week starting
Reporting rate per
10,000 patients
Reporting rate - ALL
Reporting rate - ACC/AHA criteria
90
Reporting rates of rhabdomyolysiswith lipid-modifying therapy
Semiannual Reporting Rates for All Reports of Rhabdomyolysis
US Cases*
0
20
40
60
80
100
120
03/99-08/99
09/99-02/00
03/00-08/00
09/00-02/01
03/01-08/01
09/01-02/02
03/02-08/02
09/02-02/03
03/03-08/03
06/03-11/03
12/03-05/04
06/04-11/04
Cerivastatin
Fluvastatin
Atorvastatin
Pravastatin
Simvastatin
Ezetimibe
Rosuvastatin
Reporting Rate Per
1,000,000 US Prescriptions **
Rosuvastatin†
Worldwide Cases‡
Reporting Rate Per 1,000,000
CRESTOR Prescriptions Worldwide‡
80
0
100
120
60
40
20
*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.
‡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.
Update: 08 December 2004
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