The Present Survival with CAD

Time 0
 Hospital Mortality Post MI
25

20

15

10
25% 11% 8%
5

0
1970 1990 1995
Follow-up 132 Grafts at 10 Years
Is This the Best We Can Do?

10 Years Later
Treatment Goals
in CAD Patients
• Identify and Treat
Unstable Life-Threatening
Coronary Lesions
• Antithrombotic Rx
• Prevent Ventricular
Dilation with ACE Rx
• Lower LDL
•the More the Better
•After Lifestyle
•smoking
•obesity
 Factors affecting therapy
of hyperlipidemia
Modifiable risk factors Other factors
Hypertension Family history of coronary
heart disease or peripheral
Cigarette smoking vascular disease

Diabetes mellitus Personal history of early onset

coronary heart disease
Obesity
Male sex
Alcohol intake


Dietary, Exercise & Lifestyle
Modifications
Passive smoking

The incidence of heart disease

among women with smoking
husbands was 14.9 times higher
than that of women with non
smoking husbands.
Nutritional Management
of Hypercholesterolemia
Obesity

• Not an independent factor

•Strong association with other

risk factors:
• increased blood pressure
• diabetes
• hypercholesterolemia
 Body weight deserves a
deliberate attention in any
effort to reduce
cardiovascular risk.
Relation of Body Mass Index,
(BMI) to Relative Mortality Risk

BMI Risk Odds

Ratio
20 - 30 Desirable 1.0

25 – 30 Mild 1.0 - 1.25

30 – 40 Moderate 1.25 – 2.5

40 High > 2.5

Body Weight
• Restoration of normal body weight is most
important.

• Several studies have shown that decreasing body

weight decreases the plasma lipids regardless of
the design of the diet:
• decreases LDL Chol
• decreases TG
• Increases HDL Chol
 Dietary Fats and Cholesterol
AHA Recommendations
AVERAGE
NORTH STEP ONE STEP TWO MONO
NUTRIENT
AMERICAN DIET DIET DIET
DIET
TOTAL FAT
35-40% <30% <30% 35-40%
(% total calories)
Saturated 13-40% <10% <7% 8-10%
Monounsatur
14-16% 10-15% 10-15% 17-19%
ated
Polyunsatura
7-10% 7-10% 1-% 10%
ted
CARBOHYDRATE 40-50% 50-60% 50-60% 40-50%
PROTEIN 15-20% 10-20% 10-20% 15-20%
CHOLESTEROL
350-450 <300 <200 <300
(mg/day)
CCCC recommendations:
Intervention by dietary modification plus exercise

Goals for dietary intervention:

Dietary component % of caloric intake

fat < 30%
saturated fatty acids < 10%
polyunsaturates < 10%
protein 10-15%

In Addition:

• <30% fat; alcohol, sugar, sodium restrictions

• Balance: carbohydrates, esp polysaccharides, and fibre
sources
• Physical activity for CV fitness
• For children, adjust for healthy weight
Strategies

• Most families have 10-15 recipes that

constitute their daily diet

• It is often more efficient to modify or

replace individual meals, taking into
account:
• preparation time
• cost
• taste
Cholesterol
• Cholesterol intake should be
less than 300 mg per day
Strategies

• Reduction of the major and obvious

sources of saturated fatty acid and
cholesterol.

• Substitute rather than delete.

FAT
• Saturated fat: Increases total Chol and LDL C
• Monounsaturated fat: neutral
• Polyunsaturated fat: decreases total Chol
and LDL C
• Subtracting a certain amount of
saturated fat has the same effect as
adding twice that amount of
polyunsaturated fat.
• Animal and vegetable fats do not make
a complete distinction:
• butter, coconut oil: Increase Chol
• corn oil, whale oil: decrease Chol
• Replace fat in the diet by carbohydrate.

• Carbohydrate has less calories than fat.

• Increase fiber gradually

• Increase fish intake to two to three
90 g servings per week.

• Avoid fish oil supplements.

 Maximum Potential of Dietary Changes to
Reduce Serum Cholesterol
Dietary Change ↓ in Serum Cholesterol
(%)
↓ saturated fat 15
from 14 to 7% of total calories
↑ polyunsaturated fat 5
from 7 to 10% of total calories
↓ cholesterol 7
from 500 to 250 mg/day
↑ fibre (especially soluble) 8
from 20 to 40 mg/day
Total maximum potential effect of dietary 35%
changes:

Average effect of dietary changes:

1.1 – 1.4 mmol/L decrease in serum cholesterol level
 Dietary Modification
Hepatic over production
Chylomicron
is a major cause of
Intestine
increased plasma lipids
LPL
Liver VLDL
Reduce excess dietary fat
Remnant
& excess caloric load &
LPL
HDL3 Remnant this will reduce hepatic
LCAT HPL
(IDL) production & reduce
HPL
HDL2 LDL
obesity
  hypertension
 diabetes
 Diet modification remains a
principal therapy for people with
elevated blood lipid levels.
• Lower LDL – the More the Better
 SUGGESTED APPROACH BASED ON LIPID
LEVELS AND RISK FACTORS (RF)
LIPID DIET DIET, and then
PROFILE THERAPY MEDICATION
if total Chol if LDL Chol if LDL Chol GOAL

< 35 yr., no RF > 6.2 > 4.1 > 5.7 4.1

> 35 yr., no RF > 6.2 > 4.1 > 4.9 4.1

> 2 Risk Factors > 5.2 > 3.4 > 4.1 3.4

With CHD >0 > 2.5 > 3.4 2.6

+ DRUGS
Lipid-lowering agents

1. HMG-CoA reductase inhibitors: Inhibit hepatic

cholesterol production

2. Bile acid resins: Bind cholesterol in gut

3. Fibric acid derivatives: ↑ cholesterol excretion in

bile

4. Probucol: ↑ LDL-C breakdown and may inhibit

LDL-C oxidation

5. Nicotinic acid: ↓ production of VLDL-C

Mechanism of action of Bile Acid Sequestrants

LDL
LDL
LDL

IIMG CoA IIMG CoA

Cholesterol Cholesterol

Bile Acids Bile Acids

Resins
 Bile acid Sequestrants in
Primary Hypercholesterolaemia
Diet Diet +
only Cholestyramine (16g/day)
Serum Concentration (mmol/l)

Total Cholesterol
LDL-Cholesterol
HDL-Cholesterol
Triglyceride
8.9
7.2
6.8

5.0

1.4 1.5
1.1 1.2
% Change - 23 - 30.5 + 9.1 + 7.0
HMG CoA Reductase Inhibitors
Prevastatin
Mevastatin Lovastatin Simvastatin CS 514,
HMG COA (compactin) (mevinolin) (Synvinolin) SQ 31000

Rate
limiting Fluvastatin
control of (Fluindostatin,
cholesterol SRI 62320)
synthesis
(secreted
in lipoproteins) (Lactone form) (Lactone form) (Lactone form)

Statins are pharmacologic targets to

 Reduce hepatic production
 Peripheral catabolism
 Treatment of hypercholesterolemia
8
Cholesterol
(mmol/l)
6

Weeks on treatment 0 4 8 12 16 20 24
Total LDL HDL
Effect of statin treatment (20 mg/day) on total, LDL and HDL
cholesterol concentrations (means +- s.e.m., n=10) in patients
with high plasma cholesterol.
HMG-CoA Reductase Inhibitors
Contraindications
• Active liver disease
• Pregnancy and lactation
• Hypersensitivity

Relative Contraindications
• Childhood
• Concurrent use of cyclosporine, erythromycin, (fibrates, niacin)

Side effects
• ↑ Serum transaminases
• ↑ CK
• Myopathies
• Abdominal pain, diarrhea, constipation
• Headaches
Primary Prevention Trials
Trials of Diet
•LA Veterans Study
•Oslo Primary Prevention Study
•Multiple Risk Factor Intervention Trial (MRFIT)

Trials of Drugs
•WHO Cooperative Trial of Clofibrate
•Lipid Research Clinics
Coronary Primary Prevention Trial (LRC-CPPT)
•Helsinki Heart Study
OSLO Primary Prevention Trial

325
TC (mg/dl)

300

275

0 1 2 3 4 5
Years
Treatment Group N = 604 Controls N = 628
 OSLO Primary Prevention Trial
Number of episodes Change Relative
to Controls
Coronary 19 - 47.2%
Heart Disease 36*

All Cardiovascular 22 - 43.6%

Disease 39*

Sudden 3 - 72.7%
Death 11

Total CVD Death 8 - 46.7%

(inc. Stroke) 15

Total 16 - 33.3%
Deaths 24

Treatment Group N = 604 Controls N = 628 * P < 0.05

 Conclusions from Primary
Prevention Studies

1) Elevated blood cholesterol is a

major risk factor for CHD

2) Primary preventative measures can

greatly reduce CHD risk

3) A 1% reduction of blood cholesterol

reduces CHD risk by 2%
 Atherosclerosis CAN be Reversed
Regression only Progression only Lipid effects
 athero
LDL HDL TG

39 Niacin + Colestipol 25 P = 0.005 -32% 43% -29%

32 Lovastatin + Colestipol 21 -46% 15% -9%

11 Conventional 46 -7% 5% 15%

-40 -20 0 20 40
Global change score
Definite lesion changes in the FATS trial according to the three treatment
groups. The numbers in the horizontal bars on the graph represent
percentage of patients. The numbers in the squares on the right represent
the lipid and lipoprotein changes in each of the corresponding treatment
groups.
 Examples of regression - FATS
LAD OMB RCA OMB LCx

Baseline

Mean % Stemosis 100% 39% 48% 69% 44%

After
2.5 years

Mean % Stemosis 28% 18% 30% 37% 30%

 OBJECTIVES
Randomised trial of cholesterol lowering in 4444
patients with coronary heart disease: The
Scandinavian Simvastatin Study (4S)

Lancet 344, 1994

To investigate whether long-term simvastatin

therapy reduces total mortality and coronary
events in post-MI and angina patients with serum
total cholesterol levels of 5.5 to 8.0 mmol/L (212-
309 mg/dl)
Simvastatin and Platelet Dysfunction
8 TAC ADP pM PLATELET TXB2 ng/108 pits

mean + SD 70
* * P < 0.01 **
6
* * 60 *
50 *
4 40

30

2 20

10

0 0
B 1 4 8 12 B 1 4 8 12 B 1 4 8 12 B 1 4 8 12
 Decrease in Ischemia
With Decrease in LDL
24 Placebo 24 Treatment
(n = 20) (n = 20)
Episodes of ischemia / 48 hours

17 17

15 15

10 10

5 5

0 0
Baseline 6 months Baseline 6 months
Proportion (%) of patients without events MAJOR CORONARY EVENTS
Coronary death and nonfatal MI
100

90 Simvastatin

80 Placebo

P < 0.00001
70 34%
Risk reduction

0
1 2 3 4 5 6
Years since randomization
 Women and older patients
BACKGROUND

• CHD is the chief cause of death in women

• More than 75 percent of deaths from CHD occur in

individuals older than age 65

• Few clinical trials have focused on therapeutic

intervention in women and the elderly

Subgroups of both women and the elderly (> 60

years) were included in the Scandinavian
Simvastatin Survival Study
 Women
MAJOR CORONARY EVENTS
Coronary death and nonfatal MI

100 35%
Number of patients

Risk reduction
75

50
91
25 59 P = 0.01
0
Placebo Simvastatin
 CAD: Therapeutic
Strategies for the 2000’s
• Antiatherogenic
• Antithrombogenic
• Angiogenic
•Obesity and Diet