1. Dyslipidemia Management with
Better CVD Risk Prevention
Dr Sukartono Toposubroto SpPD
RSI Pekajangan Pekalongan
Round Tabel Discussion
RSI Pekajangan
2. Dyslipidaemia and CVD Risk
Most cardiovascular events and deaths attributable to
raised blood pressure and dyslipidaemia occur among
patients with blood pressure and lipid concentrations
deemed normal.
Intervention studies have confirmed the cardiovascular
benefits of statins in primary prevention, secondary
prevention and acute coronary syndromes across a wide
age range and among patients with total cholesterol
concentrations much lower than average.
The lowering of cholesterol concentrations in individuals at
high risk of cardiovascular disease improves outcome.
4. What is Dyslipidaemia?
Dyslipidemias are disorders of lipoprotein
metabolism
Including lipoprotein overproduction &
deficiency
They may manifest as one or more of the
following: Elevated total cholesterol, low-density
lipoprotein cholesterol (LDL), &
triglyceride levels or as decreased high-density
lipoprotein cholesterol (HDL) level
7. How to Assess Risk?
• Assess risk factors:
CHD or CHD risk equivalent (regardless of number
of risk factors) using NCEP ATP III definition of CHD
& CHD risk equivalent
≥ 2 risk factors with no CHD & no CHD risk
equivalent using NECP ATP III major risk factors that
modify LDL goals
• If ≥ 2 risk factors & no CHD or CHD risk equivalent:
Assess global CHD risk by Framingham Point Score
8. CHD & CHD Risk Equivalent
Clinical CHD Carotid artery
disease
Peripheral
arterial
disease
Abnormal
aortic
aneurysm
DM
Myocardial ischemia
(angina)
Stroke history Claudication Present Present
Myocardial infarction Transient
ischemic
attack history
ABI > 0.9
Coronary
angiography &/or
stent replacement
Carotid
stenosis >
50%
CABG
Prior unstable angina
Any of these present?
Yes -------------------------------------------- CHD or CHD risk
equivalent
No ----- See if the patient has major risk factors that
modify LDL goals
NCEP ATP III Definition of CHD & CHD Risk Equivalent
9. Major Risk Factors That Modify LDL Goals
Positive risk factors (↑ risk) Negative risk factors (↓ risk)
Age: Male ≥ 45 yr
High HDL (≥ 60 mg/dl)
Female ≥ 55 yr
Family history of premature CHD
(definite MI or sudden death before
55 yr in father or other male first
degree relative OR before 65 yr in
mother or other female relative)
Check if your patient has ≥ 2 risk factors
Current cigarette smoking
Hypertension (≥ 140/90 mm Hg or on
antihypertensive drugs)
Low HDL (< 40 mg/dl)
NCEP ATP III Major Risk Factors That Modify LDL Goals
10. Framingham Point Score
When to use it?
• If the patient has CHD or CHD risk equivalent
• ≥ 2 risk factors & no CHD or CHD risk equivalent
• < 2 risk factors
NO
Yes
NO
11. Framingham Point Score
• It defines the 10 year risk of
developing CHD
• Framingham Point Score Male
• Framingham Point Score Female
12.
13.
14.
15.
16. How to Assess:
Your patient must fall in one of 3 categories:
• If the patient has CHD or CHD risk equivalent
• ≥ 2 risk factors & no CHD or CHD risk equivalent
• < 2 risk factors No need to use
Framingham score
because these patients
already have ≥ 20% risk
of CHD in 10 years
without any calculation
Use to Framingham score
to assess their 10 year
risk
No need to use
Framingham score
because they already have
low risk for CHD
17. Classification of Lipid Levels
Total cholesterol mg/dl LDL cholesterol mg/dl
< 200 Desirable < 100 Optimal
200-239 Border line
high 100-129
Near
optima/Above
optimal
≥ 240 High
130-159 Borderline
high
160-189 High
≥ 190 Very high
NCEP ATP III Classification of Blood Lipids
18. Classification of Lipid Levels
Triglycerides mg/dl HDL cholesterol mg/dl
< 150 Normal
< 40 Low
150-199 Border line
high
200-400 High
≥ 60 High
≥ 500 Very high
NCEP ATP III Classification of Blood Lipids
20. Non Lipid Risk Factors for CHD
Modifiable Risk Factors Non Modifiable Risk Factors
Hypertension Age
Cigarette smoking Male
Thrombogenic/ hemostatic state Family history of premature
CHD
Diabetes
Obesity
Physical inactivity
Atherogenic Diet
22. Therapeutic Life Style Changes
Nutrient Recommended intake
Total fat 25-35% of total calories
Saturated fate < 7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Carbohydrates 50-60% of total calories
Fiber 20-30 g/day
Cholesterol < 200 mg/day
Protein 15% of total calories
23. Therapeutic Life Style Changes
Other life style changes include:
• Weight reduction specially in overweight
patients (reduce 10% in the first 6 months)
• Increase physical activity
• Smoking cessation
31. ATORVASTATIN :: PPrriimmaarryy PPrreevveennttiioonn
Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering
Arm (ASCOT-LLA)
10,305 patients with HTN randomized to atorvastatin (10 mg) or
4
3
2
1
0
Atorvastatin 90 mg/dl*
Placebo 126 mg/dl*
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
CHD=Coronary heart disease, RR=Relative risk
Sever PS et al. Lancet. 2003;361:1149-1158
P=0.0005
Cumulative incidence of
MI and fatal CHD (%)
Follow-up (yr)
36% RRR
*Post-treatment LDL-C level
placebo for 5 years
Statins provide significant benefit in moderate- to high-risk
individuals by lowering LDL-C levels below current goals
ATORWIN 10 & 20
32. AATTOORRVVAASSTTAATTIINN :: SSeeccoonnddaarryy PPrreevveennttiioonn
Myocardial Ischemia Reduction with Aggressive Cholesterol
3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16
15
10
5
0
Lowering (MIRACL) Trial
17.4%
14.8%
RR=0.84, P=0.048
Combined cardiovascular
event rate (%)*
Atorvastatin
Placebo
0 4 8 12 16
Weeks
*Includes death, MI resuscitated cardiac arrest,
recurrent symptomatic myocardial ischemia requiring
emergency rehospitalization.
Schwartz GG et al. JAMA 2001;285:1711-1718
weeks
Acute intensive treatment significantly reduces event rates
ATORWIN 10 & 20
33. AATTOORRVVAASSTTAATTIINN:: SSeeccoonnddaarryy PPrreevveennttiioonn
Pravastatin or Atorvastatin Evaluation and Infection Therapy
4,162 pts with an ACS randomized to atorvastatin (80 mg) or
pravastatin (40 mg) for 24 months
3 6 9 12 15 18 21 24 27 30
Follow-up (months)
30
25
20
15
10
5
0
P =0.005
Recurrent MI, cardiac death,
UA, revascularization, or stroke
16% RRR
(PROVE-IT)—TIMI 22 Study
Atorvastatin
Pravastatin
Acute intensive treatment significantly reduces event rates
ACS=Acute coronary syndrome, CV=Cardiovascular,
MI=Myocardial infarction, UA=Unstable angina
Cannon CP et al. NEJM 2004;350:1495-1504
ATORWIN 10 & 20
34. AATTOORRVVAASSTTAATTIINN:: SSeeccoonnddaarryy PPrreevveennttiioonn
10,001 patients with stable CHD randomized to atorvastatin (80 mg) or
atorvastatin (10 mg) for 4.9 years
Years
Major CV Event* (%)
P<0.001
0 1 2 3 4 5 6
22% RRR
Treating to New Targets (TNT) Trial
Atorvastatin (10 mg)
Atorvastatin (80 mg)
0.15
0.10
0.05
0.00
High-dose statins provide benefit in chronic CHD
CHD=Coronary heart disease, CV=Cardiovascular,
MI=Myocardial infarction, RRR=Relative risk reduction
*Includes CHD death, nonfatal MI, resuscitation
after cardiac arrest, or stroke
LaRosa JC et al. NEJM 2005;352:1425-35
ATORWIN 10 & 20
35. AATTOORRVVAASSTTAATTIINN:: SSeeccoonnddaarryy PPrreevveennttiioonn
Incremental Decrease in End Points Through Aggressive Lipid
Lowering (IDEAL) Trial
8,888 patients with a history of acute MI randomized to atorvastatin (80 mg)
Cumulative Hazard
(%)
12
8
or simvastatin (20 mg) for 5 years
Simvastatin (20 mg)
Atorvastatin (80 mg)
0 1 2 3 4 5
Years Since Randomization
4
HR=0.89, P=0.07
High-dose statins provide a strong trend towards benefit
HR=Hazard ratio, MI=Myocardial infarction
*Includes coronary death, hospitalization for nonfatal
acute MI, or cardiac arrest with resuscitation
Pedersen et al. JAMA 2005;294:2437-2445
after a MI
ATORWIN 10 & 20
36. ACS Patients: Major Coronary Events
MI + CHD Death + Resuscitated Cardiac Arrest
Incremental Decrease in End Points Through Aggressive Lipid
Lowering (IDEAL) Trial
Simvastatin
Atorvastatin
Years Since Randomization
Cumulative Hazard (%)
0 1 2 3 4 5
20
16
12
8
4
0
34% RRR
HR = .66 (95% CI = 0.46, 0.95), P=.02
Pedersen, Olsson, Cater et al. WCC, 2006
ATORWIN 10 & 20
37. SUMMARY
– Lower is better
• LDL
• CRP
• Triglycerides
(and probably) higher is
better for HDL
– LDL cholesterol as a primary target of therapy
– Studies showed that Atorvastatin proof was in
better CVD risk prevention
– ATORWIN as new Atorvastatin can be as a
new choice with high quality product, right
dose and right price
Atorvastatin inhibit the HMG-CoA Reductase enzyme which leads to a reduction in hepatic intracellular cholesterol.
A healthy diet, that includes increased amounts of whole grains, fiber, fruits, vegetables, soy protein, and stanol esters, can significantly reduce levels of LDL-C.
Atorvastatin inhibit the HMG-CoA Reductase enzyme which leads to a reduction in hepatic intracellular cholesterol.
ACSCOT-LLA was a substudy of the ASCOT trial and sought to assess the benefits of cholesterol reduction in the primary prevention of coronary heart disease in hypertensive patients not deemed hypercholesterolemic (total non-fasting cholesterol &lt;250mg/dl) by conventional means. All patients had to have at least three other cardiovascular risk factors making this a moderate to high risk population.
Patients were randomized to treatment with atorvastatin (10 mg) or placebo. The primary endpoint was non-fatal MI and fatal CHD by an intention to treat analysis. The study was stopped after 3.3 years due to a significant reduction in the primary endpoint in the atorvastatin arm compared to placebo, hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005. Importantly, differences were noted in the first year of treatment and the LDL-C levels attained were lower than current goals. There was no significant difference in death between the two arms.
The MIRACL trial was the first large scale study to evaluate the effects of acute intensive statin therapy in the secondary prevention setting. Compared to placebo, treatment with atorvastatin (80 mg) within 96 hours of an acute coronary syndrome resulted in a 16% relative risk reduction in the primary end point (death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or objective evidence of recurrent symptomatic myocardial ischemia requiring emergency rehospitalization) in the first 16 weeks of treatment.
There were no significant differences in the risk of death, nonfatal myocardial infarction, or cardiac arrest in the two arms of the study. The difference in the primary endpoint was driven by a lower risk of symptomatic ischemia requiring emergency rehospitalization (6.2% vs. 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =0.02). Treatment with atorvastatin resulted in a mean decrease in LDL-C from 124 mg/dL to 72 mg/dL. There was a significant increase in hepatic transaminases &gt;3x the upper limit of normal with atorvastatin as compared to placebo (2.5% vs 0.6%; P&lt;.001).
PROVE IT-TIMI 22 was designed to assess the effects of early statin therapy in individuals with an acute coronary syndrome. In a head-to-head comparison of statin regimens, patients were randomized to a high dose potent statin (atorvastatin 80 mg) or a moderate dose less potent statin (pravastatin 40 mg) over a mean follow-up of 24 months to determine if intensive statin therapy was associated with a lower event rate. Use of atorvastatin and pravastatin resulted in on-treatment mean LDL-C levels of 62 mg/dL and 95 mg/dL, respectively.
The primary end point (a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, recurrent revascularization, or stroke) occurred in 22.4% of individuals on atorvastatin vs. 26.3% of individuals on pravastatin, p=0.005. This effect of intensive statin therapy set a new benchmark for aggressive early LDL-C lowering in acute coronary syndromes.
Following the Heart Protection Study, the TNT study sought to determine whether high dose statin therapy provided additional cardiovascular benefit among individuals with chronic coronary heart disease. All patients entered an open-label eight week period with low dose atorvastatin (10 mg), those who experienced a statin related side effect or did not achieve an LDL-C level &lt;130 mg/dL were excluded prior to randomization.
High dose atorvastatin (80 mg) resulted in a significant 22% relative risk reduction in the primary composite endpoint (death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke) as compared to low dose atorvastatin (10 mg). Paralleling the reduction in the composite primary endpoint was a decrease in the LDL-C levels to 77 mg/dL and 101 mg/dl in the high and low dose atorvastatin arms, respectively. There were no differences in overall mortality.
These results add to the body of data obtained in the PROVE IT-TIMI 22 and HPS trials, demonstrating a benefit with lower LDL-C levels in individuals with coronary heart disease.
The Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study evaluated the effect of intensive vs. moderate lipid lowering therapy in patients with a history of MI. Patients were randomized to receive atorvastatin (80 mg) or simvastatin (20 mg) over a mean period of 5 years.
The primary endpoint was occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. There was no significant difference in the primary endpoint (HR 0.89, 95% CI, 0.78-1.01, p=0.07), despite an LDL-C difference of 23 mg/dL (81 mg/dL vs. 104 mg/dl in the atorvastatin vs. simvastatin treatment groups, respectively). There was, however, a significant reduction in nonfatal MI (6.0% vs. 7.2% respectively, p=0.02), major cardiovascular events, and any coronary event. There was no difference in mortality endpoints between the two groups.
Importantly, the primary endpoint did not include stroke. When stroke was added to the primary end point, however, the relative risk reduction was similar to that seen in the TNT study.
