Download Dyslipidemia primary prevention

Dyslipidemia primary
prevention
DR.AZEEZ ALZAFIRI
FRCPC , ABIM , MRCP
Objectives

Epidemiology of Dyslipidemia

Who should be screened ?

Clinical Manifestation of Familial Hypercholestrolemia

Evidence behind Primary prevention of ASCVD

Risk Scores and stratifications of risk of ASCVD

Intensity of Therapy

Goals of Treatment of dyslipidemia

Summary of ACC/AHA guidelines in primary prevention
Disclosure :
No
Financial Relatioships .
Cholesterol
Cholesterol is a fatty
substance manufactured
in the liver and is carried
throughout the body in
the bloodstream.
Prevalence:

About 50% of U.S. adults have an elevated total
cholesterol level

Majority of patients with atherosclerosis have some
form of dyslipidemia

70-80% of individuals with dyslipidemia do not meet
LDL cholesterol targets despite lipid therapy
EPIDEMIOLOGY IN KUWAIT:

A cross sectional study of almost 500 candidate here in Kuwait ,
College of basic education , age 17- 24 in 2010 to determine the
prevalence of dyslipidemia in this age group showed that :

Prevelence of dyslipidemia was 10.5 %

Overweight 30.6 %

Obesity 19.8 %
Atherosclerosis:

Leading cause of morbidity and mortality in the
U.S.

Accounts for more than 1/3 of all deaths each
year

About 13 million Americans have coronary heart
disease (CHD)

Dyslipidemia is the most prevalent and
important modifiable risk factor for
atherosclerosis
 Secondary
Causes of Dyslipidemia :-
1. Hypothyroidism
2. Nephrotic syndrome
3. SLE, multiple myeloma
4. Steroids
5. Cholestatic diseases of the liver
6. Chronic renal failure
7. Type 2 diabetes mellitus
8. Excessive alcohol intake
9. Estrogens, oral contraceptives, pregnancy
10. Antihypertensive medications ( thiazide diuretics )
 Who
should be screened ?
Adults who have a relative with ?
Hx suggestive of Familial
Hypercholestrolemia :
1. Premature ASCVD (definite MI or
sudden death before age 55 years in
male first-degree relative, or before
age 65 years in female first-degree
relative)
2. Elevated cholesterol levels (total, nonHDL ,LDL) consistent with FH .
 Adults
With Diabetes :
Annually screen all adults with DM type 1
or 2 for dyslipidemia.
 Young
Adults
Evaluate all adults 20 years of age or
older for dyslipidemia every 5 years.
 Middle-Aged
Adults (between 45-65y)
In the absence of ASCVD risk factor , at
least once every 1 to 2 years. More
frequent lipid testing when multiple risk
factors are present.
 Older
Adults (Older Than 65 Years) :
Annually screen older for dyslipidemia.
Screening for this group is based on age
and risk, but not gender; therefore, older
women should be screened in the same
way as older men.
 Children
:
In children at risk for FH (e.g., family history of
premature cardiovascular disease),
screening should be at 3 years, between 9
and 11 years, and at age of 18.
 What
clinical findings that might be
found in some patients with primary
familial hyperlipidemias ?
Tendon Xanthomata
Eruptive Xanthomata
Palmar xanthomata
Eruptive Xanthomata
Based on what evidence treatment of patients who have risk factors
of ASCVD might lead decrease their risk of getting ASCVD?

Trials of Primary prevention of ASCVD :

1-ASCOT TRIAL

2-CARDS TRIAL

3- WOSCOPS TRIAL

4- AFcaps/TEXcaps

5-JUPITER TRIAL

ASCOT–LLA — The Anglo-Scandinavian Cardiac
Outcomes Trial–Lipid-Lowering Arm
19,342 patients
Randomized
-blocker ± diuretic
TC >250 mg/dL
(>6.5 mmol/L)
CCB ± ACE inhibitor
2532 TC 250 mg/dL
(6.5 mmol/L)
TC >250 mg/dL
(>6.5 mmol/L)
Randomized
Open lipid lowering
1258
Atorvastatin 10 mg
1274
Placebo
Open lipid lowering
Primary end point: Composite of fatal CHD and nonfatal MI
Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm.
Modified from Sever PS et al. J Hypertens.
ASCOT–LLA — The Anglo-Scandinavian
Cardiac Outcomes Trial–Lipid-Lowering
Arm
End Points
Primary
•
Combined nonfatal MI and
fatal CHD
Secondary
 All-cause mortality and
cardiovascular mortality
 Fatal and nonfatal stroke
 Fatal and nonfatal heart failure
 Total coronary events
 Total cardiovascular events and
procedures
 Primary end point excluding
silent MI
Tertiary
•
•
•
•
•
•
•
•
Development of renal
impairment
Development of diabetes
Silent MI
Unstable angina
Chronic stable angina
PAD
Life-threatening arrhythmias
Synergistic effects of amlodipine
with atorvastatin on study
end points
Patients with Hypertension and Multiple Risk Factors – ASCOT-LLA Results
Incidence of non fatal MI and fatal CHD
Cumulative Incidence (%)
4
Atorvastatin 10 mg
Number of events:
100
Placebo
Number of events:
154
3.0%
3
36% Risk
Reduction
2
1.9%
1
HR = 0.64 (0.50–0.83)
P=0.0005
0
0.0
0.5
1.0
Sever PS, et al. for the ASCOT Investigators. Lancet
1.5
2.0
Years
2.5
3.0
3.5
CARDS — The Collaborative Atorvastatin Diabetes
Study
Study Objective:

To investigate whether treatment with atorvastatin 10 mg versus
placebo reduces the incidence of major cardiovascular events or
revascularization procedures in patients with type 2 diabetes
without established CHD
CARDS — The Collaborative Atorvastatin Diabetes Study
Study Design
Double-blind period
Patient population:

Enrolled at 132 sites in
the UK and Ireland

Type 2 diabetes with no
previous MI or CHD

≥1 other CHD risk factor
plus LDL-C  160
mg/dL(4.1 mmol/L)

Aged 40-75 years
Atorvastatin 10 mg/day
2838
patients
Primary end point:
 Time to the occurrence of a major
cardiovascular event
Placebo
Minimum 4-year follow-up
Completion date:
 Terminated early due
to significant benefit observed
in atorvastatin arm
Type 2 diabetes Patients – CARDS Results
Primary endpoint: Major Cardiovascular Events
Cumulative Incidence (%)
15
Atorvastatin 10 mg
Number of events:
83
Placebo
Number of events:
127
37% Risk
Reduction
10
5
HR = 0.63 (95% CI, 0.48–0.83)
P=0.001
0
0
1
2
3
4
4.75
Years
* Primary endpoint: acute coronary heart disease events (myocardial infarction including silent infarction, unstable angina, acute
coronary heart disease death, resuscitated cardiac arrest), coronary revascularization procedures, or stroke.
Colhoun HM, et al. for the CARDS Investigators. Lancet .
WOSCOPS TRIAL
The West of Scotland Coronary Prevention Study
(WOSCOPS) , 6959 patients with average TC of 7
mmol/L and LDL average of 4 mmol/L .
This study showed that cholesterol lowering with
pravastatin reduced both the number of nonfatal
myocardial infarctions and coronary heart disease
(CHD) mortality in middle-aged men by 32 % .
AFCAPS/TexCAPS:
(Primary Prevention of Acute Coronary Events with
Lovastatin in Men and Women with Average
Cholesterol Levels.

Design:


Setting:


Outpatient clinics in Texas
Participants:


Randomized, double-blind, placebo-controlled trial
5608 men and 997 women with at baseline, average TC (221
mg/dL (5.7 mmol/L) and LDL-C (150 mg/dL(3.8 mmol/L) and
below-average HDL-C (37 mg/dL(0.95 mmol/L)
Intervention:

Lovastatin (20-40 mg daily - to achieve an LDL-C of < 110
mg/dL(2.8 mmol/l) or placebo in addition to a low-saturated fat,
low-cholesterol diet.
JAMA
Primary Endpoint ~ First Acute Major Coronary Event*
Cumulative Incidence
0.06
*Includes unstable angina,
fatal and non-fatal MI &
sudden cardiac death
Placebo
0.05
37% Risk Reduction
(p < 0.001)
0.04
0.03
Lovastatin
0.02
0.01
0.00
# At Risk
Lovastatin
Placebo
0
1
2
N=3304
N=3301
N=3270
N=3251
N=3228
N=3211
3
4
5
N=3184
N=3159
N=3134
N=3092
N=1688
N=1644
Years of Follow-up
5+ Years

It has been observed within AFCAPS/TexCAPS that
among those with low LDL but high hsCRP, vascular
event rates were just as high as rates among study
participants with overt hyperlipidemia, and that statin
therapy significantly reduced events in this subgroup
.

This observation has lead to another landmark
trial ( Jupiter Trial ).
JUPITER
Trial Design
Ridker - 162
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
17,802 participants from 216 countries
No Prior CVD or DM
Rosuvastatin 20 mg (N=8901)
Men >50, Women >60
LDL <130 mg/dL (3.36 mmol/L)
4-week
hsCRP >2 mg/L
run-in
Placebo (N=8901)
MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
JUPITER
Ridker - 162
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
0.08
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Placebo 251 / 8901
0.04
0.06
- 44 %
Rosuvastatin 142 / 8901
0.00
0.02
Cumulative Incidence
Number Needed to Treat (NNT5) = 25
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,631
8,621
8,412
8,353
6,540
6,508
3,893
3,872
1,958
1,963
1,353
1,333
983
955
544
534
157
174
JUPITER TRIAL :
Justification for the Use of statin in primary
Prevention : Intervention Trial Evaluating
Rosuvastatin )
RISK SCORES

What are the risk scores widely adopted when
deciding whom to treat and which LDL target ?

The most important of which include ACC/AHA
risk score 2013 , ESC Score 2016 , Framingham
risk scores ( AACE 2017)
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CA0B0334
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ACC/AHA RISK SCORE

Prediction variables used in ACC/AHA pooled cohort hard CVD risk
calculator :

●Age

●Gender

●Total cholesterol (mg/dL)

●HDL cholesterol (mg/dL)

●Systolic blood pressure (mmHg)

●Blood pressure treatment (yes or no)

●Diabetes mellitus (yes or no)

●Current smoking (yes or no)
FRAMINGHAM RISK SCORE
Prediction variables used in Framingham General CVD risk score :

●Age

●Gender

●Total cholesterol

●HDL cholesterol

●Systolic blood pressure (mmHg)

●Blood pressure treatment (yes or no)

●Diabetes mellitus (yes or no)

●Current smoking (yes or no)

Example #1 :

65 gentleman who smokes with TC = 5.5 mmol/L , HDL = 0.8 mmol/L
with no other risk factors .

What is his ACC/AHA risk score and what is his FRAMINGHAM risk
score ?

ACC score = 21.3%

FRAMINGHAM Score =41.8%

Example # 2
Same patient ( Age 30 , TC = 5.5 mmol/L , HDL = 0.8 mmol/L with
smoking and no other risk factor )
What is his ACC risk score and what is his FRAMINGHAM risk Score )
ACC SCORE = 3.8 %
FRAMINGHAM SCORE = 4.95 %

ESC SCORE 2016 ( Has been devided into high risk score countries
and low risk score countries )

It measures the 10 year risk of Fatal CVD in high risk regions Vs Low
risk regions based on those variables :

1-Age

2-Systolic blood pressure

3-Gender

4-Total Cholesterol

5-smoking status
Intensity of Statin Therapy
Treatment Goals for Patients at Risk for
Atherosclerotic Cardiovascular Disease
 TC
<200 (mg/dL) (< 5.1 mmol/L)


LDL <130 (low risk) ( < 3.36 mmol/L)
<100 (moderate to high risk) (< 2.58
mmol/L)
<70 (very high risk) (< 1.8 mmol/L)
<55 (extreme risk) (< 1.4 mmol/L)

TG
<150 (mg/dL) ( < 1.69 mmol/L)

HDL
> 40 (mg/dL) ( >1 mmol/L)
 Statin
therapy is recommended as the
primary pharmacologic agent to
achieve target LDL goals.
 Ezetimibe
may be considered as
monotherapy, especially in statinintolerant pts. ( IMPROVE IT Trial ) 2ndry
prevention
Also can be used in combination with
statins to further reduce both LDL and
ASCVD.
PCSK9 Inhibitors in primary
prevention :

PCSK9 inhibitors — Proprotein convertase subtilisin kexin 9 (PCSK9)
inhibitors have not been adequately evaluated in primary
prevention in patients without familial hypercholesterolemia.

Their effects in secondary prevention suggest that they could be
expected to reduce CV outcomes to a similar degree as is seen with
statin therapy .( Fourier Trial on Evolucomab ) -- 2ndry prevention

However, their cost, the requirement for injections, and the lack of
long-term safety data would make them an option only in the
highest-risk primary prevention patients who are unable to tolerate
statin therapy
 Fibrates
should be used to treat
severe hypertriglyceridemia.
 Omega-3
oil should be used to treat
severe hypertriglyceridemia
(TG >500 mg/dL) ( > 5.6 mmol/L)
 Combination
therapy should be
considered when LDL level is
markedly increased and
monotherapy does not achieve
therapeutic goal.

When to follow up ?
Reassess lipid status 6 weeks after therapy
initiation.
 While on stable lipid therapy, individuals should
be tested at 6- to 12-month intervals.
 More frequent evaluation is recommended in
situations such as :1. Deterioration of diabetes control.
2. Use of a new drug known to affect lipid
levels.
3. Progression of atherothrombotic disease.
4. Development of a new risk factor.

 Liver
transaminase levels should be
measured before and 3 months after
treatment initiation because most
liver abnormalities occur within 3
months of treatment initiation.
 Creatine
kinase levels should be
assessed and the statin
discontinued when an individual
reports significant myalgias or
muscle weakness.
The American College of Cardiology/American Heart
Association (ACC/AHA) makes the following
recommendations :
For adults ages 40 to 75 without known
cardiovascular disease (CVD) and low-density
lipoprotein cholesterol (LDL-C) between 70 mg/dL
(1.81 mmol/L) and 189 mg/dL (4.90 mmol/L) based on
risk calculation using the ACC/AHA calculator :
1- Treat those with an estimated 10-year CVD risk ≥7.5
percent with moderate-to-high intensity statin therapy
2- In those without diabetes:
• It is reasonable to offer treatment with
moderate intensity statin therapy to those
with an estimated 10-year CVD risk
between 5.0 and 7.5 percent
3- In those with diabetes:
-Treat with at least moderate statin therapy
-High-intensity statin therapy is reasonable in those
with an estimated 10-year CVD risk ≥7.5
4- For adults with an LDL-C ≥190 mg/dL (4.92
mmol/L) the ACC/AHA recommends
treatment with high-intensity statin therapy
and consideration of use of nonstatin drugs
to further reduce the LDL-C
Debates about Treatment to Target?
Major difficulties: (ACC/AHA Explanation)
•
•
•
•
Current RCT data do not indicate what the target
should be
Unknown magnitude of additional ASCVD risk
reduction with one target compared to another
Unknown rate of additional adverse effects from
multidrug therapy used to achieve a specific goal
Therefore, unknown net benefit from treat-to-target
approach
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