Pfizer Talk Final

Pfizer Talk

Family Medicine

13/1/2010Dr Ihab Suliman

43 years old male with Chest Pain

Acute Inferior STEMI in NSR.

Atherosclerosis

The Impact of Elevated LDL-C and

Associated Atherosclerosis

Atherosclerosis is caused by a build-up of plaque in

arterial walls, obstructing blood flow

Atherosclerosis accounts for more than 70%

of all deaths from cardiovascular disease in the US

Elevated LDL (low-density lipoprotein) cholesterol

increases risk of atherosclerosis and coronary heart

disease

The risk of coronary heart disease increases by about

2% for each 1% elevation in total cholesterol

National Center for Health Statistics. Health, United States, 2005.http://www.cdc.gov/nchs/hus.htm. Accessed May 17, 2006

Kwiterovich PO Jr. Am J Cardiol. 1998,82:3U-17U

Cholesterol is important in so many metabolic

activities , there fore it is more important in

adults or infants????

What is the normal Cholesterol level in

Infancy???.

Cholesterol Levels By Species

Mean Total Cholesterol Level

50 70 90 110 130 150 170 190 210

Wild Primates:

Hunter-Gatherer

Humans: Hazda

InuitIKungPygmy

San

BaboonHowler Monkey

Night Monkey

Wild Mammals:HorseBoar

PeccaryBlack RhinocerosAfrican Elephant

Modern Human:

Infant

Adult American

JACC 2004;43:2142-6

Discovery of statins Some drugs available but not effective

In 1971,Endo and Kuroda (Sankyo Pharmaceuticals in Japan) began search for better drugs

Cholesterol pathway known and they wanted to find a HMG-CoA reductase inhibitor – looked for a microorganism – screened over 6000 Two (3rd later) cmpds identified - one was from Penicillium

citrinum - named mevastatin

In 1976 isolated and crystallized

Clinical trials started in 1978 and quickly stopped because of animal tumors

Modifiable Risk Factors

Medical conditions

Hypertension

Diabetes mellitus

Hypercholesterolemia

Obesity

Insulin resistance?

Cardiac diseases

Atrial fibrillation

Coronary artery disease

CHF

Behaviours

Cigarette smoking

Heavy alcohol use

Physical inactivity

Causes of death, 2001:

1. Infectious and parasitic diseases: 14.9 million

2. Heart diseases: 11.1 million

3. Cancers: 7.3 million

4. Stroke: 5.5 million

5. Respiratory diseases: 3.6 million

6. Accidents, fires, drowning, etc.: 3.5 million

7. Maternal and perinatal: 3.0 million

8. Violence (war, homicide, suicide): 1.6 million

World Health Organization

World Health Report 2002

Population: 6,122,210,000

Deaths: 56,554,000

USA

6.

1.

2.

3.

4.

5.

Therapeutic lifestyle change is the cornerstone of the

management of hyperlipidemia and dyslipidemia?

LDL-C with AHA diet: ~ 5%

Response variability: familial/genetic

Hypocaloric diets in overweight & obese

A high fat, low carb diet does not worsen serum

lipids/lipoproteins and improves glycemic control in

patients with diabetes

LDL-C is unchanged

HDL-C is unchanged or slightly higher

Triglyceride is lower by~25%

Variability in response?

HbA1c better than with LFHC diet

Dietary Nuances

Fish: twice/wk; omega-3 fatty acids, 1000 mg/d

Eliminate/reduce trans FA

Plant stanols/sterols reduce LDL-C by ~10%

Antioxidant vitamins are not cardioprotective and interfere with effects of niacin on HDL-C

Homocysteine: folic acid, vitamins B6 and B12

not proven to be cardioprotective.

The 2004 NCEP LDL-C goal:

lower may be better

Acute Coronary Syndromes

• MIRACL: LDL-C, 125 72 mg/dl

• PROVE-IT: LDL-C, 106 62 mg/dl

Stable CHD

• HPS: benefit if basal LDL-C < 100 mg/dl

• ALLIANCE: 111 95 mg/dl

• REVERSAL: 150 79 mg/dl

How low a LDL-C is safe?

Newborn LDL-C is 35-50 mg/dl.

Patients with hypobetalipoproteinemia are healthy

and have enhanced survival

ATP III Treatment Priorities

Reduce LDL-C to goal (new goals)

Correct residual lipid/lipoprotein abnormalities(

non-HDL-cholesterol)

Address the metabolic syndrome

Utility of the non-HDL-cholesterol

Total minus HDL-C

Includes all atherogenic lipoproteins

• LDL-C, Lp(a), IDL, VLDL

Surrogate for apoprotein B

Optimum; add 30 mg/dl to LDL-C goals

All patients should receive TLC advise.

Simultaneous drug therapy should be started

in:

Patients with symptomatic CHD

All high risk patients

Intermediate risk

• men@40-45 yrs

• women@50-55 yrs

Options for reducing LDL-

cholesterol

• Statins

• Cholesterol absorption inhibitors

• Bile acid binding resins

• Niacin

Muscle Adverse Effects

Myalgia

Weakness

Fatigue

Myopathy without CK

Predisposing factors:• Combined hyperlipidemia

• Subclinical hypothyroidism

• Suboptimum thyroxine replacement

MODIFY RISK FACTORS

Hyperlipidemia in Pregnancy TC & TG levels increase throughout pregnancy

average cholesterol increase: 30 to 40 mg/dL around weeks

36 to 39

TGs may increase as much as 150 mg/dL

Drug therapy typically not initiated/continued during

pregnancy

TLC is the mainstay but BARs & absorption inhibitors

may be considered in high risk patients

ezetimibe: category C

Statins: category X

24

Statin Therapy Can Reduce the

Risk of Coronary Heart Disease (CHD)

Friday KE. Exp Biol Med. 2003,228:769-778

Wilt TJ et al. Arch Intern Med. 2004;164:1427-1436

Key Clinical Trial Data Efficacy Endpoint

Primary prevention

WOSCOPS

(pravastatin 40 mg)31% relative-risk (r-risk) reduction inCHD death or myocardial infarction

AFCAPS/TexCAPS

(lovastatin 20-40 mg)37% r-risk reduction in 1st acute coronary event

Secondary Prevention

4S

(simvastatin 10-40 mg)30% r-risk reduction in all-cause mortality

CARE

(pravastatin 40 mg)24% r-risk reduction in CHD death or MI

LIPID

(pravastatin 40 mg)24% r-risk reduction in CHD mortality

TJ Wilt meta-analysis 23% decreased CHD mortality

Diabetic Dyslipidemia Characterized by hypertriglyceridemia, low HDL, &

minimally elevated LDL

DM ATP III CHD risk equivalent

Small, dense LDL (pattern B) in DM patients is more

atherogenic than larger, more buoyant LDL (pattern A)

1˚target: LDL

Goal of treatment: LDL-C < 100 mg/dL

LDL > 130 mg/dL: TLC + drug therapy often required

Statins often considered initial drugs of choice

26

Expert Panel on Detection E, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol

Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood

Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.

Diabetic Dyslipidemia

Collaborative Atorvastatin Diabetes Study (CARDS)

LDL lowering for 1˚ CHD prevention in type 2 DM

Randomized, double-blinded placebo controlled

Atorvastatin 10 mg/day versus placebo (n=2,838)

diabetes to reduce first CHD events

Baseline LDL: 118 mg/dL; LDL ↓ 46 mg/dL with

atorvastatin

27

Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2

diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial.

Lancet 2004;364:685–696.

Collaborative Atorvastatin Diabetes Study (CARDS)

Type 2 diabetes mellitus

Men and women 40–75 years

of age

Primary CHD and stroke

prevention

LDL-C 160 mg/dL ( 4.14

mmol/L)

TG 600 mg/dL

( 6.78 mmol/L)

1 additional RF

HTN (or on HTN

treatment)

Retinopathy

Albuminuria

Current smoking

Colhoun HM et al. Lancet 2004;364:685-696.

Patient Population

Primary endpoint: time to first major CV

event (CHD death, nonfatal MI, unstable

angina, resuscitated cardiac arrest, coronary

revascularization, stroke

Secondary endpoints: total mortality, any CV

endpoint, lipids, and lipoproteins

2838 patients

4-year follow-up

Atorvastatin 10 mg (n=1428)

Double-blind placebo (n=1410)

CARDS: Patient Baseline

CharacteristicsPlacebo

(n = 1410)

Atorvastatin

(n = 1428)

Age

Mean (SD) years 61.8 (8.0) 61.5 (8.3)

<60 529 (38%) 558 (39%)

60–70 708 (50%) 703 (49%)

>70 173 (12%) 167 (12%)

Women 453 (32%) 456 (32%)

White ethnicity 1326 (94%) 1350 (95%)

BMI

Mean (SD), kg/m2 28.8 (3.5) 28.7 (3.6)

Obese (BMI >30 kg/m2) 538 (38%) 515 (36%)

Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.

CARDS: Patient Baseline LipidsPlacebo

(n = 1410)

Mean (SD)

Atorvastatin

(n = 1428)

Mean (SD)

Total cholesterol (mg/dL)

(mmol/L)

207 (32)

5.35 (0.82)

207 (32)

5.36 (0.83)

LDL cholesterol (mg/dL)

(mmol/L)

117 (27)

3.02 (0.70)

118 (28)

3.04 (0.72)

HDL cholesterol (mg/dL)

(mmol/L)

55 (13)

1.42 (0.34)

54 (12)

1.39 (0.32)

Triglycerides* (mg/dL)

(mmol/L)

148 (104–212)

1.67 (1.17–2.40)

150 (106–212)

1.70 (1.20–2.40)

*Median (interquartile range)


0

80

160

240

CARDS: Lipid Levels by Treatment

Total Cholesterol (mg/dL)

Average difference 26%,

54 mg/dL; P<0.0001

Media

n T

C (

mg/d

L)*

Years of Study

0 1 2 3 4 4.50

40

80

120

160

Media

n L

DL-

C (

mg/d

L)*

Years of Study

0 1 2 3 4 4.5

LDL Cholesterol (mg/dL)

Average difference 40%,

46 mg/dL; P<0.0001

Atorvastatin

Atorvastatin

PlaceboPlacebo


0

5

10

15

CARDS: Effect of Atorvastatin on the Primary

Endpoint: Major CV Events Including StrokeCum

ula

tive H

azard

, (%

)

Years0 1 2 3 4

Relative Risk Reduction 37% (95% CI, 17–52)P = 0.001

1410

1428

1351

1392

Placebo

Atorvastatin

4.75

1306

1361

1022

1074

651

694

305

328

Placebo127 events

Atorvastatin83 events


CARDS: Adverse and Serious Adverse

Events

Type of Event

Patients (%) with Event

Placebo

(n = 1410)

Atorvastatin 10 mg

(n = 1428)

Serious adverse event

possibly associated with

study drug

20 (1.1%) 19 (1.1%)

Discontinued for AE 145 (10%) 122 (9%)

Rhabdomyolysis 0 0

Myopathy AE report 1 (0.1%) 1 (0.1%)

CPK 10 ULN 10 (0.7%) 2 (0.1%)

ALT 3 ULN 14 (1%) 17 (1%)

AST 3 ULN 4 (0.3%) 6 (0.4%)

Colhoun HM et al. Lancet 2004;364:685-696.

Diabetic Dyslipidemia

CARDS trial: 37% reduction in composite 1˚end

point

1˚ endpoint: acute CHD death, nonfatal MI,

hospitalized unstable angina, resuscitated cardiac

arrest, coronary revascularization, or stroke

Suggests diabetics should have target LDL much

lower than 100 mg/dL

34

Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2

diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial.

Lancet 2004;364:685–696.

ASCOT: Primary Endpoint:

Nonfatal MI/Fatal CHD

0

1

2

3

4

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cu

mu

lati

ve I

ncid

en

ce (

%)

36%

reduction

HR = 0.64 (0.50-0.83)

Atorvastatin 10 mg Number of events 100

Placebo Number of events 154

P = 0.0005

Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

Comparing 2 statin drugs

Atarvastatin – 80 mg.

Pravastatin – 40 mg.

Equivalent doses

Trial was designed to demonstrate non-inferiority of pravastatin. Instead, it showed ataravastatin to be superior.

Not only did ataravastatin lower cholesterol more (and faster), but it lowered death rate by 16%

Study was stopped “early.”

FDA 2007

The FDA approved atorvastatin for reducing

the risk for nonfatal MI, reducing the risk for

fatal and nonfatal strokes, for use in certain

types of heart surgery, for reductions in the risk

of hospitalization for heart failure, and to reduce

chest pain in patients with heart disease.

Atorvastatin is the first cholesterol-lowering

drug to be approved for reducing the risk of

hospitalization for heart failure.

Thank You

Very Much

Business

Pfizer Talk Final