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THE POSITION OF STATINS
IN THE NEW GUIDELINE
Suroto
Dept of Neurology, Fac of Medicine,
Sebelas Maret University
Stroke Risk Factors—Overview
Unmodifiable Risk Factors
Age
Male sex
Race
Family history of stroke/coronary heart
disease
Modifiable Risk Factors
Smoking
Diet
Sedentary lifestyle
Alcohol/Drug abuse
Obesity
Carotid artery disease
Atrial fibrillation
Hypertension
Diabetes
Dyslipidemia
Goldstein LB et al. Stroke. 2001;32:280-299.
Treatment Options
Carotid endarterectomy
Antiplatelet therapy
Anticoagulation therapy
Antihypertensive therapy
Antidiabetic therapy
Lipid-lowering therapies
HISTORY
•Akira Endo and Masao Kuroda of Tokyo, Japan commenced
research into inhibitors of HMG CoA reductase in 1971.
•This team reasoned that certain microorganism may produce
inhibitors of the enzyme to defend themselves against other
organism.
•The first agent isolated was Mevastatin ( ML- 236 ).
•The pharmaceutical company, Merck & Co showed an interest in
the Japanese research in1976, and isolated Lovastatin(mevinolin,
MK803), the first commercially marketed statin.
•Dr Endo was awarded the 2006 Japan Prize for his work
on the development of statins.
Potential mechanisms of benefit of statins
Reduction in
chylomicron and
HMG Co A reductase
inhibitor
Statins*
VLDL remnants,
IDL, LDL-C
Pleitrophic effect
Lipid lowering effect
1.
2.
3.
Macrophages
Lumen
4.
Lipid
core
Smooth
muscle
cells
Anti-inflammatory effects
Decreased thrombosis
Restore endothelial
function
Maintain SMC function
Potential Time Course of Statin Effects in CAD / ACS
Vulnerable
Inflammation plaques
stabilized
reduced
Endothelial
function
restored
Hours-Days
* Time course established
LDL-C
lowered*
Ischemic
episodes
reduced
Cardiac
events
reduced*
Weeks-Months
Statin Evidence: Expanding Benefits
Acute coronary event
No history of CAD
Unstable CAD
Stable CAD
4 month
AFCAPS / TexCAPS/
WOSCOPS
MIRACL
t=0
CARE/LIPID
3 month
4S
6 month
HPS
ASCOT-LLA
Hypertension
Primary prevention
Secondary prevention
Statin in primary and secondary prevention trials ;
The lower the better
Secondary prevention
Primary prevention
25
20
With CHD
event (%)
4S-PBO
LIPID-PBO
4S-Rx
CARE-PBO
15
HPS-PBO
CARE-Rx
10
LIPID-Rx
HPS-Rx
TNT-PBO
WOS-Rx
WOS-PBO
TNT-Rx
5
AFCAPS-Rx
AFCAPS-PBO
0
50
PBO = Placebo
Rx = Treated
70
90
110
130
150
LDL-C (mg/dL)
170
190
210
NCEP - ATP Guidelines
The revised ATP-III was
based on the review of
five statin trials
conducted since the
release of ATP-III
Revised ATP-III
2004
ATP - III
2001
ATP - II
1993
ATP - I
1988
 LDL-C <70 mg/dL considered in extremely high risk patient.
 LDL-C lowering drug indicated in addition to TLC if LDL-C > 100 mg/dL
 The intensity of LDL-lowering drug tx in high – moderately high risk patients
must be sufficient to achieve at least 30-40% reduction in LDL levels
 se emphasis on 1st prevention
 inclusion of high risk groups for 2nd prevention
 new risk levels for major lipid measures ( LDL-C <100 mg/dL optimal level for all
adults; HDL-C > 40 mg/dL and TG < 150 mg/dL )
 Important secondary target were non-HDL-C in patient with TG > 200 mg/dL and
metabolic syndrome
 New category “CHD risk equivalent” in diabetes and patients with > 20% CHD 10
year risk equivalent.
 Global risk score based on Framingham Heart Study used for calculation of 10 year risk
 LDL-C target < 100 mg/dL
 Focus on 2nd Prevention
 Introduction of HDL-C as CHD risk ( <35 mg/dL )
TG level<200 mg/dL was normal
 LDL-C target < 130 mg/dL
 Focus on 1st Prevention
TLC : Therapeutic Lifestyle
Changes
Comparison of Major Features of ATP II and ATP III
ATP II
ATP III
< 100 mg/dL
<70mg/dL in very high
LDL-C target for CHD or
CHD Risk Equivalent :
 100 mg/dL
LDL-C level in very high
cholesterol :
 220 mg/dL
 190 mg/dL
Categorically low HDL-C :
< 35 mg/dL
< 40 mg/dL
Triglycerides :
< 200 mg/dL
< 150 mg/dL
Diabetes :
Completion of Framingham
Risk Assessment :
Risk Factor
CHD Equivalent
Recommended lipid
profile :
risk patients ( revised )
No
Total-C and HDL-C
Yes
Total-C, HDL-C,
LDL-C, and TG
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 1993;269:3015.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
ESC/EAS Guidelines
ESC/EAS Guidelines for the management of dyslipidaemias
Intervention strategies as a function of total CV risk and LDL-C level
<1
No lipid intervention
No lipid intervention
Lifestyle intervention
Lifestyle intervention
Lifestyle intervention,
consider drug if
uncontrlled
>1 to <5
Lifestyle intervention
Lifestyle intervention
Lifestyle intervention,
consider drug if
uncontrlled
Lifestyle intervention,
consider drug if
uncontrlled
Lifestyle intervention,
consider drug if
uncontrlled
>5 to <10,
or high risk
Lifestyle
intervention,
consider drug
Lifestyle
intervention,
consider drug
Lifestyle intervention,
and immediate drug
intervention
Lifestyle intervention,
and immediate drug
intervention
Lifestyle intervention,
and immediate drug
intervention
>10 or very
high risk
Lifestyle
intervention,
consider drug
Lifestyle intervention,
and immediate drug
intervention
Lifestyle intervention,
and immediate drug
intervention
Lifestyle intervention,
and immediate drug
intervention
Lifestyle intervention,
and immediate drug
intervention
ESC/EAS : European Society of Cardiology /European Atherosclerosis Society
European Heart Journal (2011) 32, 1769–1818
+
5
SCORE
1
15% and over
10-14%
Age
2
5-9%
3-4%
2%
1%
< 1%
10-year risk of
fatal CVD in
populations at
high CVD risk
3
Total
cardiovascular risk
estimation
European Heart Journal (2011) 32, 1769–1818
4
Risk will be higher than calculated in patients with
additional conditions such as:
o Diabetes
o Evidence of subclinical atherosclerosis
(CalciumScore, Carotid Screening)
o Familial premature atherosclerotic disease
o Chronic Kidney Disease
o Increased Lp (a), AboB/ApoB1 ratio, low HDL-C, high TC
• In patients at very high CV risk : established CVD, type 2
diabetes or type 1 diabetes with target organ damage, moderate
to severe CKD or a SCORE level ≥10 %
the LDL-C goal is <1.8 mmol/L(<~70 mg/ dL) and/or a ≥ 50 %
LDL-C reduction when target level cannot be reached.
• In patients at high CV risk : markedly elevated single risk
factors, a SCORE level ≥5 - <10%
the LDL-Cgoal <2.5 mmol/L (<~100 mg/dL).
• In patients at moderate risk : SCORE level >1 to ≤5%
the LDL-C goal <3.0 mmol/L (<~115 mg/dL).
If drug treatment is indicated to decrease LDL-C, a statin is
recommended, up to the highest tolerable dose, to reach
the target level.
2013 ACC/AHA Guideline
2013 ACC/AHA Guideline on the Treatment of
Blood Cholesterol to Reduce Atherosclerotic
Cardiovascular Risk in Adults
November 12, 2013
 First new guidelines since ATP III guideline update in
2004
 The most important statements or changes presented in
these guidelines
•
•
•
•
No longer have therapeutic targets
New risk calculator
Use medications proven to reduce risk, ie statins
Avoid medications or supplements that may lower the
cholesterol number, but have no data to decrease CV
risk
Circulation,published online November 12, 2013
Overview of the Expert Panel’s guideline
What has changed compared
to ATP-III guideline?
 Initiate either moderate-intensity or high-intensity statin
therapy for patients who fall into the four categories
 Unlike ATP-III, Do not titrate to a specific LDL cholesterol
target
 Measure lipids during follow-ups to assess adherence to
treatment, not to achieve a specific LDL target
Four Major Statin Benefit Groups
1) Individuals with clinical ASCVD
2) Individuals with LDL >190
3) Individuals with Diabetes, 40-75 yo with LDL 70189 and without clinical ASCVD
4) Individuals without clinical ASCVD or Diabetes,
with LDL 70-189 and estimated 10-year ASCVD
risk >7.5%
ASCVD : AtheroSclerotic CardioVascular Disease
Age < 75y
Yes
Adults age > 21y and
Yes
A candidate for Statin Tx
Clinical
ASCVD
Yes
No
Cardiovascular
risk
calculator
No
LDL-C >
190 mg/dL
High-intensity statin
(Moderate-intensity if not candidate
for high intensity Statin)
Age > 75y or if not candidate
for high intensity Statin
Moderate-intensity statin
Yes
High-intensity statin
(Moderate-intensity if not
candidate for high intensity
Statin)
No
Yes
Moderate-intensity statin
Moderate-intensity statin
Diabetes
Age 40-75 y
Yes
No
Cardiovascular
risk
calculator
Estimated 10-y ASCVD risk >7.5%
High intensity statin
Estimate 10-y ASCVD risk
With Pooled Cohort Equation
 > 7.5% estimated
10-y ASCVD risk
Age 40-75 y
Yes
Moderate-to- high intensity
statin
Intensity of Statin Therapy
High-Moderate-and Low-Intensity Statin Therapy (Used in the RCTs reviewed
by the Expert Panel)
High-Intensity
Statin Therapy
Moderate-Intensity
Statin Therapy
Low-Intensity
Statin Therapy
Daily dose lowers LDL-C on
average, by approximately
> 50%
Daily dose lowers LDL-C on
average, by approximately
30% to 50%
Daily dose lowers LDL-C on
average, by < 30%
Atorvastatin ( 40 )- 80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg*
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
RCT : Randomized Control Trials
Circulation,published online November 12, 2013
Risk Assessment :
http://my.americanheart.org/cvriskcalculator
1.
Sex
M or F
2.
Age
Years ( 40-79 )
3.
Race
4.
Total Cholesterol
mg/dL ( 130 - 320 )
5.
HDL-Cholesterol
mg/dL ( 20 – 100 )
6.
Systolic blood pressure
mmHg ( 90 – 200 )
7.
Treatment for High blood pressure
Y ( Yes ) or N ( No )
8.
Diabetes
Y ( Yes ) or N ( No )
9.
Smoker
Y ( Yes ) or N ( No )
AA ( Afro american ) or WH ( White or others )
Risk Assessment :
Your 10 year ASCVD
Risk (%)
10 year ASCVD Risk (%) for
someone with optimal risk factor (
Col E )
Your lifetime ASCVD
Risk (%)
Lifetime ASCVD Risk (%) for
someone with optimal risk factor (
Col E )
This calculator only provides 10-year
risk estimates for individuals 40-79
years of age
STATIN Safety recommendations (1)
 Select the appropriate dose
 If high or moderate intensity statin not tolerated, use
the maximum tolerated dose instead
 Conditions that could predispose patients to statin side
effect:
• Impaired renal or hepatic function
•
•
•
•
•
History of previous statin intolerance or muscle disorder
Age >75
Unexplained ALT elevation > 3x ULN
History of hemorrhagic stroke
Asian ancestry
STATIN Safety recommendations (2)
 Check baseline ALT prior initiating the statin (Grade B)
 Check LFTs if patient develops Symptoms of hepatic
dysfunction (Grade E)
 If 2 consecutive LDL <40, Consider decreasing the
statin dose (Grade C, weak recommendation)
 It may be harmful to initiate simvastatin 80mg, or
increase the dose of simvastatin to 80mg (Grade B)
Case 1
50 year old white female
•
•
•
•
•
•
Total cholesterol 180
HDL: 50
SBP: 130
taking anti-hypertension meds
+ diabetic
+ smoker
Calculated 10 yr ASCVD: 9.1%
Your 10 year ASCVD
Risk (%)
9.1
10 year ASCVD Risk (%) for
someone with optimal risk
factor ( Col E )
0.8
Your lifetime ASCVD
Risk (%)
50.0
Lifetime ASCVD Risk (%) for
someone with optimal risk
factor ( Col E )
8.0
Your 10 year
ASCVD Risk
(%)
10 year ASCVD
Risk (%) for
someone with
optimal risk
factor ( Col E )
Your Lifetime
ASCVD Risk
(%)
Lifetime
ASCVD Risk
(%) for
someone with
optimal risk
factor ( Col E )
Age < 75y
Yes
Adults age > 21y and
Yes
A candidate for Statin Tx
Clinical
ASCVD
Yes
No
LDL-C >
190 mg/dL
High-intensity statin
(Moderate-intensity if not candidate
for high intensity Statin)
Age > 75y or if not candidate
for high intensity Statin
Moderate-intensity statin
Yes
High-intensity statin
(Moderate-intensity if not
candidate for high intensity
Statin)
No
Yes
Moderate-intensity statin
Moderate-intensity statin
Diabetes
Age 40-75 y
Yes
No
Cardiovascular
risk
calculator
Estimated 10-y ASCVD risk >7.5%
High-intensity statin
Estimate 10-y ASCVD risk
With Pooled Cohort Equation
 > 7.5% estimated
10-y ASCVD risk
Age 40-75 y
Yes
Moderate-to- high intensity
statin
High-Intensity
Statin Therapy
Moderate-Intensity
Statin Therapy
Low-Intensity
Statin Therapy
Daily dose lowers LDL-C on
average, by approximately
> 50%
Daily dose lowers LDL-C on
average, by approximately
30% to 50%
Daily dose lowers LDL-C on
average, by < 30%
Atorvastatin ( 40 )- 80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg*
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
Case 2
•
•
•
•
•
•
48 year white female
Total cholesterol 180
HDL: 55
SBP: 130
Not taking anti-hypertension meds
+ diabetic
Non-smoker
Calculated 10 yr risk ASCVD : 1.8%
Your 10 year ASCVD
Risk (%)
1.8
10 year ASCVD Risk (%) for
someone with optimal risk
factor ( Col E )
0.7
Your lifetime ASCVD
Risk (%)
39.0
Lifetime ASCVD Risk (%) for
someone with optimal risk
factor ( Col E )
8.0
Your 10 year
ASCVD Risk
(%)
10 year ASCVD
Risk (%) for
someone with
optimal risk
factor ( Col E )
Your Lifetime
ASCVD Risk
(%)
Lifetime
ASCVD Risk
(%) for
someone with
optimal risk
factor ( Col E )
Age < 75y
Yes
Adults age > 21y and
Yes
A candidate for Statin Tx
Clinical
ASCVD
Yes
No
LDL-C >
190 mg/dL
High-intensity statin
(Moderate-intensity if not candidate
for high intensity Statin)
Age > 75y or if not candidate
for high intensity Statin
Moderate-intensity statin
Yes
High-intensity statin
(Moderate-intensity if not
candidate for high intensity
Statin)
No
Yes
Moderate-intensity statin
Moderate-intensity statin
Diabetes
Age 40-75 y
Yes
No
Cardiovascular
risk
calculator
Estimated 10-y ASCVD risk >7.5%
High intensity statin
Estimate 10-y ASCVD risk
With Pooled Cohort Equation
 > 7.5% estimated
10-y ASCVD risk
Age 40-75 y
Yes
Moderate-to- high intensity
statin
High-Intensity
Statin Therapy
Moderate-Intensity
Statin Therapy
Low-Intensity
Statin Therapy
Daily dose lowers LDL-C on
average, by approximately
> 50%
Daily dose lowers LDL-C on
average, by approximately
30% to 50%
Daily dose lowers LDL-C on
average, by < 30%
Atorvastatin ( 40 )- 80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg*
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
Case 3
•
•
•
•
•
22 year white male
LDL- cholesterol 195
SBP: 120
Not taking anti-hypertension meds
Non-diabetic
Non-smoker
Age < 75y
Yes
Adults age > 21y and
Yes
A candidate for Statin Tx
Clinical
ASCVD
Yes
No
Cardiovascular
risk
calculator
No
LDL-C >
190 mg/dL
High-intensity statin
(Moderate-intensity if not candidate
for high intensity Statin)
Age > 75y or if not candidate
for high intensity Statin
Moderate-intensity statin
Yes
High-intensity statin
(Moderate-intensity if not
candidate for high intensity
Statin)
No
Yes
Moderate-intensity statin
Moderate-intensity statin
Diabetes
Age 40-75 y
Yes
No
Estimated 10-y ASCVD risk >7.5%
High intensity statin
Estimate 10-y ASCVD risk
With Pooled Cohort Equation
 > 7.5% estimated
10-y ASCVD risk
Age 40-75 y
Yes
Moderate-to- high intensity
statin
High-Intensity
Statin Therapy
Moderate-Intensity
Statin Therapy
Low-Intensity
Statin Therapy
Daily dose lowers LDL-C on
average, by approximately
> 50%
Daily dose lowers LDL-C on
average, by approximately
30% to 50%
Daily dose lowers LDL-C on
average, by < 30%
Atorvastatin ( 40 )- 80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg*
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
Summary
 The statins (or HMG-CoA reductase inhibitors) form a class of
Hypolipidemic drugs used to lower cholesterol levels in people
with or at risk of Cardiovascular disease.
 Based on clinical trials (RCT), the National Cholesterol Education
Program / Adult Treatment Panel (NCEP-ATP) had developed
guidelines, focus on aggressively lowering LDL-cholesterol.
 The statins continue to play an important role in both the primary and
secondary prevention of ASCVD.
 End of 2013 the ACC and AHA , collaborate with the National Heart,
Lung, and Blood Institute (NHLBI) develop new clinical practice
guidelines for assessment of CV risk, lifestyle modifications to
reduce CV risk, and management of blood cholesterol.
 This guideline focuses on treatments to reduce ASCVD events.
ASCVD : AtheroSclerotic CardioVascular Disease
RCT : Randomized Control Trial