1. Dyslipidemia primary prevention
Dr.Azeez Alzafiri
fRCPC , ABIM , MRCP

2. 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

3. Disclosure :
No Financial Relatioships .

4. Cholesterol
Cholesterol is a fatty substance manufactured in the liver and is carried throughout the body in the bloodstream.

5. 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

6. EPIDEMIOLOGY IN KUWAIT:
A cross sectional study of almost 500 candidate here in Kuwait , College of basic education , age in to determine the prevalence of dyslipidemia in this age group showed that :
Prevelence of dyslipidemia was 10.5 %
Overweight 30.6 %
Obesity 19.8 %

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

10. Secondary Causes of Dyslipidemia :-
1. Hypothyroidism
2. Nephrotic syndrome
3. SLE, multiple myeloma
4. Steroids
5. Cholestatic diseases of the liver

11. 6. Chronic renal failure
7. Type 2 diabetes mellitus
8. Excessive alcohol intake
9. Estrogens, oral contraceptives, pregnancy
10. Antihypertensive medications ( thiazide diuretics )

12. Who should be screened ?
Adults who have a relative with ?
Hx suggestive of Familial Hypercholestrolemia :
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)
Elevated cholesterol levels (total, non- HDL ,LDL) consistent with FH .

13. 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.

14. 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.

16. What clinical findings that might be found in some patients with primary familial hyperlipidemias ?

17. Tendon Xanthomata

21. Eruptive Xanthomata

22. Palmar xanthomata

23. Eruptive Xanthomata

25. 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

26. ASCOT–LLA — The Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm
19,342 patients
Randomized
-blocker ± diuretic
CCB ± ACE inhibitor
TC >250 mg/dL (>6.5 mmol/L)
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.

27. ASCOT–LLA — The Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm
End Points
Primary
Combined nonfatal MI and fatal CHD
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
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

28. Cumulative Incidence (%)
Patients with Hypertension and Multiple Risk Factors – ASCOT-LLA Results
Incidence of non fatal MI and fatal CHD 1 2 3 4
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Atorvastatin 10 mg Number of events: 100
Placebo Number of events: 154
3.0%
36% Risk Reduction
Cumulative Incidence (%)
1.9%
HR = 0.64 (0.50–0.83)
P=0.0005
Sever PS, et al. for the ASCOT Investigators. Lancet

29. 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

30. CARDS — The Collaborative Atorvastatin Diabetes Study
Study Design
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 years
Double-blind period
Atorvastatin 10 mg/day
2838 patients
Placebo
Minimum 4-year follow-up
Completion date:
Terminated early due
to significant benefit observed
in atorvastatin arm
Primary end point:
Time to the occurrence of a major cardiovascular event

31. Cumulative Incidence (%)
Type 2 diabetes Patients – CARDS Results
Primary endpoint: Major Cardiovascular Events 15
Atorvastatin 10 mg Number of events: 83
Placebo Number of events: 127
37% Risk Reduction 10
Cumulative Incidence (%) 5
In patients with type 2 diabetes (CARDS), at the 10 mg dose of atorvastatin, we see that the primary endpoint of acute CHD events, coronary revascularization, or stroke was significantly lowered by 37% (relative risk reduction) compared with placebo.
The trial was stopped early by the DSMB.
HR = 0.63 (95% CI, 0.48–0.83)
P=0.001 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 .

32. 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 % .

34. AFCAPS/TexCAPS: (Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels.
Design:
Randomized, double-blind, placebo-controlled trial
Setting:
Outpatient clinics in Texas
Participants:
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

35. Primary Endpoint ~ First Acute Major Coronary Event*
0.06
*Includes unstable angina,
fatal and non-fatal MI &
sudden cardiac death
0.05
Placebo
37% Risk Reduction
(p < 0.001)
0.04
Cumulative Incidence
0.03
Lovastatin
0.02
0.01
0.00 1 2 3 4 5
5+ Years
# At Risk
Years of Follow-up
Lovastatin
N=3304
N=3270
N=3228
N=3184
N=3134
N=1688
Placebo
N=3301
N=3251
N=3211
N=3159
N=3092
N=1644

36. 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 ).

37. 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 MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
Rosuvastatin 20 mg (N=8901)
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL (3.36 mmol/L)
hsCRP >2 mg/L
Placebo (N=8901)
4-week run-in
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

38. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Ridker - 162
HR 0.56, 95% CI
P <
Placebo 251 / 8901
0.08
Number Needed to Treat (NNT5) = 25
- 44 %
0.06
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901
0.02
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,631
8,412
6,540
3,893
1,958
1,353
983
544
157
Placebo
8,901
8,621
8,353
6,508
3,872
1,963
1,333
955
534
174

39. JUPITER TRIAL : Justification for the Use of statin in primary Prevention : Intervention Trial Evaluating Rosuvastatin )

40. 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 , ESC Score , Framingham risk scores ( AACE 2017)

41. 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)

42. 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)

43. 10 years risk: developing a heart attack or die from coronary disease in the next 10 years.

44. 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%

45. 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 %

46. 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

48. Intensity of Statin Therapy

49. 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) (< 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)

50. Statin therapy is recommended as the primary pharmacologic agent to achieve target LDL goals.
Ezetimibe may be considered as monotherapy, especially in statin- intolerant pts. ( IMPROVE IT Trial ) 2ndry prevention
Also can be used in combination with statins to further reduce both LDL and ASCVD.

51. 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

52. 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.

53. Reassess lipid status 6 weeks after therapy initiation.
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 :-
Deterioration of diabetes control.
Use of a new drug known to affect lipid levels.
Progression of atherothrombotic disease.
Development of a new risk factor.

54. 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.

55. 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 :

56. 1- Treat those with an estimated 10-year CVD risk ≥7.5
percent with moderate-to-high intensity statin therapy

57. 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

58. 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

59. 4- For adults with an LDL-C ≥190 mg/dL (4
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

60. 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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