aztor cme new

Evidence Efficacy and Experience

Statin Evolution

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This CME is brought to you by-

Sun Pharmaceutical (Bangladesh) Ltd.

Atorvastatin 10/20 mg Tablets

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Lipid-lowering Goals

Joint European Societies1 LDL-C Goal

Established CHD, other atherosclerotic <115 mg/dL (3.0 mmol/L)

disease, or high absolute risk

1 Wood D, et al. Atherosclerosis. 1998;140:1434-1503;

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2009 Canadian Guideline Updates

Primary target is LDL-C decrease to < 2.0 mmol/l or 50% relative reduction.

A 50% relative reduction in LDL-C confers close to optimal benefit.

2 Canadian Cardiovascular Society. Genest J et al. Can J Cardiol 2009; 25: 567-79

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US NCEP ATP III2

0-1 CHD risk factors <160 mg/dL (4.1

mmol/L)

>2 CHD risk factors <130 mg/dL (3.4

mmol/L)

CHD or CHD risk equivalent <100 mg/dL (2.6

mmol/L)

2 NCEP Expert Panel. JAMA. 2001;285:2486-2497.

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ATP III Lipid and Lipoprotein Classification

LDL Cholesterol (mg/dL)

<100 Optimal

100–129 Near optimal/above optimal

130–159 Borderline high

160–189 High

190 Very high

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HDL Cholesterol (mg/dL)

<40 Low

60 High

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Total Cholesterol (mg/dL)

<200 Desirable

200–239 Borderline high

240 High

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High Risk Patients

All persons with CHD or CHD risk equivalents can

be called high risk.

LDL goal: 100 mg/dl

- “Reasonable” optional goal: 70 mg/dl

Grundy SM, Cleeman JI, Merz CN, et al., J Am Coll Cardiol. 2004;44:720-732.

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CHD Risk Equivalents

Risk for major coronary events equal to that in established CHD

10-year risk for hard CHD >20%

Hard CHD = myocardial infarction + coronary death

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CHD Risk Equivalents

Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease)

Diabetes Multiple risk factors that confer a 10-year risk

for CHD >20%

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Major Risk Factors

Cigarette smoking Hypertension (BP 140/90 mmHg or on

antihypertensive medication) High LDL cholesterol (>100 mg/dl) Low HDL cholesterol (<40 mg/dl) Family history of premature CHD (CHD in male first

degree relative <55 years; CHD in female first degree relative <65 years)

Age (men 45 years; women 55 years)

2 NCEP Expert Panel. JAMA. 2001;285:2486-2497.

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ATP III: Major Risk Factors That Modify LDL Goals

LDL-C goal of <70 mg/dl for severe and poorly controlled risk factors Cigarette smokingDiabetesHypertensionLow HDL cholesterolMultiple risk factors of the metabolic syndrome

Grundy SM, Cleeman JI, Merz CN, et al., J Am Coll Cardiol. 2004;44:720-732.

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LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC)and Drug Therapy in Different Risk Categories

Risk CategoryLDL Goal(mg/dL)

LDL Level at Which to Initiate

Therapeutic Lifestyle Changes (TLC)

(mg/dL)

LDL Level at Which to Consider

Drug Therapy (mg/dL)

CHD or CHD Risk Equivalents(10-year risk

>20%)

<100 100130

(100–129: drug optional)

2+ Risk Factors (10-year risk

20%)<130 130

10-year risk 10–20%: 130

10-year risk <10%: 160

0–1 Risk Factor <160 160190

(160–189: LDL-lowering drug optional)

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LDL-Lowering Therapy in Patients With CHD and CHD Risk Equivalents

Baseline LDL Cholesterol: 130 mg/dL

Intensive lifestyle therapies Maximal control of other risk factors Consider starting LDL-lowering drugs

simultaneously with lifestyle therapies

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Baseline (or On-Treatment) LDL-C: 100–129 mg/dL

Therapeutic Options: LDL-lowering therapy

Initiate or intensify lifestyle therapies Initiate or intensify LDL-lowering drugs

Treatment of metabolic syndrome

Emphasize weight reduction and increased physical activity Drug therapy for other lipid risk factors

For high triglycerides/low HDL cholesterol Fibrates or nicotinic acid

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Baseline LDL-C: <100 mg/dL

Further LDL lowering not required Therapeutic Lifestyle Changes (TLC)

recommended Consider treatment of other lipid risk factors

Elevated triglycerides Low HDL cholesterol

Ongoing clinical trials are assessing benefit of further LDL lowering

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LDL-Lowering Therapy in Patients With Multiple (2+) Risk Factors and 10-Year Risk 20%

10-Year Risk 10–20% LDL-cholesterol goal <130 mg/dL Aim: reduce both short-term and long-term risk Immediate initiation of Therapeutic Lifestyle

Changes (TLC) if LDL-C is 130 mg/dL Consider drug therapy if LDL-C is 130 mg/dL

after 3 months of lifestyle therapies

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LDL-Lowering Therapy in Patients With Multiple (2+) Risk Factors and 10-Year Risk 20%

10-Year Risk <10%

LDL-cholesterol goal: <130 mg/dL Therapeutic aim: reduce long-term risk Initiate therapeutic lifestyle changes if LDL-C is

130 mg/dL Consider drug therapy if LDL-C is 160 mg/dL

after 3 months of lifestyle therapies

20

LDL-Lowering Therapy in Patients With 0–1 Risk Factor

Most persons have 10-year risk <10% Therapeutic goal: reduce long-term risk LDL-cholesterol goal: <160 mg/dL Initiate therapeutic lifestyle changes if LDL-C is

160 mg/dL If LDL-C is 190 mg/dL after 3 months of lifestyle

therapies, consider drug therapy If LDL-C is 160–189 mg/dL after 3 months of

lifestyle therapies, drug therapy is optional

21

Atherosclerosis Timeline

Phase I: InitiationLDL-C plays a major role in initiating the development of atherosclerotic plaque.

Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:995-1009; Libby P. J Intern Med. 2000;247:349-358.

Media

Intima

Phase II: ProgressionDisease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly.

LDL-C

Phase III: ComplicationExtensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture.

Lumen Unstable

Stable

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Potential plaque stabilizing effects of cholesterol lowering

Macrophage number ↓ Smooth muscle cell maturation↑ Interstitial collagen ↑ Matrix metalloproteinase expression ↓ (MMP-1, MMP-3, MM-9) Tissue factor expression ↓ Adhesion molecule expression ↓ CRP ↓ Endothelial function↑ Cytokines ↓

Libby P, Aikawa M. Mechanisms of plaque stabilization with statins. Am J Cardiol. 2003;91(suppl 4A):4B-8B.

STATINSLumen

LipidCore

LumenLipidCore

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Benefits of Statins

Arrests as well as prevents the process of atherosclerosis

Reduces total and cardiovascular mortality

Reduces CHD events such as nonfatal myocardial infarction, angina

Reduces incidence of heart failure

Reduces the risk of cerebrovascular events such as stroke

Reduces need for revascularization procedures such as angioplasty / bypass surgery

Reduces number of hospitalizations/duration of hospital stay

Ann Pharmacother 1998; 32: 1030–1043Atheroscler 1999; 143 (suppl 1): S17–S21

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Mode of Action

Staitin Lowers cholesterol by inhibiting the enzyme HMG CoA reductase in the liver.

Acetate HMG CoA

HMG CoAreductase

Mevalonic acid

Cholesterol

20 steps

Statin

25

Continue….

Inhibition of HMG CoA reductase in liver

--- Intracellular cholesterol synthesis--- Upregulation of LDL Receptors--- Binding of LDL-Receptors--- LDL catabolism in liver--- Clearance of LDL from circulation--- LDL in blood VLDL (TG) synthesis in liver

Total lipid in blood

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Indication & Usages

To reduce elevated total-Cholesterol, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia

As an adjunct to diet for the treatment of patients with elevated serum TG levels

For the treatment of patients with primary dysbetalipoproteinemia

To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia

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Adverse effects

Treating to New Targets Study (TNT ) In TNT was involved 10,001 patients with clinically evident

CHD during a median follow-up of 4.9 years. The adverse effects was following in low & high dose of atorvastatin.

Dose Aderse events Discontinuation

Atorvastatin 10 mg

(n=5006)

1.4% 8.1%

Atorvastatin 80 mg

(n=4995)

1.8% 9.9%

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Statin Evolution

Evidence

Efficacy

Experience

29

Statin Evidence: ASCOT-LLA

ASCOT is a multicenter, international trial that involves 2 treatment comparisons in a factorial design:

• A Prospective, Randomized, Open, Blinded End point (PROBE) design comparing 2 antihypertensive regimens

• A double-blind, placebo-controlled trial of atorvastatin 10 mg in a large prospective cohort of those hypertensive patients studied (lipid-lowering arm [ASCOT-LLA])

ASCOT is composed of almost 20,000 hypertensive patients with multiple risk factors for CHD

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Atorvastatin 10 mgPlacebo

Baseline 164/95 mm HgTreated 138/80 mm Hg

130

140

150

160

170

0 1 2 3

SB

P (

mm

Hg

)

LLA Close-out

DB

P (

mm

Hg

)

75

80

85

90

95

100

0 1 2 3Years

LLA Close-out

Sever PS, et al. Lancet. 2003;361:1149-1158.

Blood Pressure Changes


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Statin Evidence: ASCOT-LLAT

ota

l ch

ole

ster

ol

(mm

ol/L

)L

DL

ch

ole

ster

ol

(mm

ol/L

)6

0 1 2 3

200

150

100

(mg

/dL

)50 mg/dL (1.3 mmol/L)

38.7 mg/dL (1.0 mmol/L)

2

4

Atorvastatin 10 mg

Placebo

150

75

125

100 (mg

/dL

)

YearsLLA Close-out

1

2

3

4

0 1 2 3


38.7 mg/dL (1.0 mmol/L)

46.5 mg/dL (1.2 mmol/L)

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Atorvastatin 10 mg Number of events 89

Placebo Number of events 121

0

1

2

3

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cu

mu

lati

ve I

nci

den

ce (

%)

HR = 0.73 (0.56-0.96)P = .0236

27% reduction


Primary Endpoint:

Nonfatal MI and Fatal CHD

Secondary Endpoint:

Fatal and Nonfatal Stroke

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

Inc

ide

nc

e (

%)



36% reduction

HR = 0.64 (0.50-0.83)P = .0005


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Secondary Endpoint:

All CV Events and Procedures

Secondary Endpoint:

All Coronary Events

0

2

4

6

8

10

12

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cu

mu

lati

ve

In

cid

en

ce

(%

) 21% reduction

HR = 0.79 (0.69-0.90)P = .0005





0

1

2

3

4

5

6

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cu

mu

lati

ve

In

cid

en

ce

(%

) 29% reduction

HR = 0.71 (0.59-0.86)P = .0005


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Safety

• No significant difference between atorvastatin and placebo in:

• Incidence of fatal cancers• Incidence of serious adverse events• Incidence of liver enzyme abnormalities



35

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

Statin Evidence: MIRACL Study

Placebo plus usual care

Initial

hospitalization

Randomization(1-4 days)

3086 patients

Double-blind period

Atorvastatin 80 mg/day

16-week treatment phase

36


Relative risk = 0.84P = .04895% CI 0.701-0.999

Atorvastatin

Placebo

0

5

10

15

0 4 8 12 16

Time Since Randomization (weeks)

Cu

mu

lati

ve In

cid

ence

(%

)

Time to first occurrence of:• Death (any cause)• Nonfatal MI• Resuscitated cardiac arrest• Worsening angina with new

objective evidence and urgent rehospitalization

17.4%

14.8%

Primary Efficacy Measure

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

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0

0.5

1

1.5

2

0 4 8 12 16

Time Since Randomization (weeks)

Cu

mu

lati

ve In

cid

ence

(%

)

Relative risk = 0.49P = .0495% CI 0.24-0.98

Atorvastatin

Placebo

Fatal and Nonfatal Stroke

Waters DD, et al. Circulation. 2002;106:1690-1695.

38

-4

-36

-5

-46

-3

-31

27

-3

-32

-6

-44

-60

-50

-40

-30

-20

-10

0

10

Total-C LDL-C TG HDL-C VLDL-C Non-HDL-C

Statin Evidence: GREACE Study

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

**

**

** **

**

††

Mea

n %

Ch

ang

e F

rom

Bas

elin

e

Usual Care

Structured Care

*P < .0001; †P = .0028. Mean atorvastatin dose, 24 mg/day.

39

5

2.9

4.8

2.5

6.4

2.6 2.6

1.2

5.6

2.7 2.7

1.3

2.1

1.1

0

2

4

6

8

TotalMortality

CoronaryMortality

Nonfatal MI UnstableAngina

PTCA/CABG CHF Stroke


P = .0021 P = .0017

P = .0011

P = .034

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

% o

f P

atie

nts

P = .0001

P = .0032P = .021

Usual Care

Structured Care

40


Structured Care Group

• 95% of patients reached the NCEP LDL-C goal

• Mean dose of atorvastatin 24 mg/day

• 96% of patients reached the European LDL-C goal

• Mean dose of atorvastatin was 22 mg/day

Usual Care Group

• 3% of patients reached the NCEP LDL-C goal

• 5.5% of patients reached the European LDL-C goal

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228; Athyros VG, et al. Data on file.

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Statin Evidence: Benefits

• The statin trials have demonstrated significant decreases in

CVD morbidity and mortality.

• Reduction in CVD events has been demonstrated in patients

with stable CHD as well as acute coronary syndrome patients.

• Additionally, lowering LDL-C to target levels has beneficial

effects in patients with normal or moderately elevated LDL-C.

42

Statin Evidence: SPARCL

Stroke Prevention by Aggressive Reduction

in Cholesterol Levels trial

43

Time since randomization (years)

SPARCL: High-dose statin treatment reduces fatal/nonfatal stroke

*Adjusted SPARCL Investigators. N Engl J Med. 2006;355:549-59.

Fatal/ nonfatal stroke

(%)

00 1 2 3 4 5 6

16

12

8

4

16% RRR*HR 0.84 (0.71–0.99)P = 0.03

Placebo

Atorvastatin

NNT = 46 patientsfor 5 years

Primary outcome

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SPARCL: Treatment effect on stroke and TIA

Hazard ratio

SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Adjusted

HR* (95% CI)

0.84 (0.71–0.99)

0.57 (0.35–0.95)

0.87 (0.73–1.03)

0.77 (0.67–0.88)

0.74 (0.60–0.91)

Primary outcome

Stroke (total)

Fatal

Nonfatal

Secondary outcomes

Stroke or TIA

TIA

P

0.03

0.03

0.11

<0.001

0.004

0.3 1.0 1.7

N = 4731Aggressive statin therapy

Better Worse

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SPARCL: High-dose statin reduces majorcoronary events and stroke

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

*Cardiac death, MI, resuscitatedcardiac arrest, and stroke

00

30

20

10

1 2 3 4 5 6


Major CV events*

(%)

20% RRRHR 0.80 (0.69–0.92)P = 0.002

Placebo

Atorvastatin

NNT = 29 patientsfor 5 years

46

SPARCL: Reductions in major coronary events

SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest

00

10

6

2

1 2 3 4 5 6


Major coronary events*

(%)

35% RRRHR 0.65 (0.49–0.87)P = 0.003

Placebo

Atorvastatin

8

4

47

SPARCL: Summary

Atorvastatin 80 mg yielded:

Primary end point

16% fatal/nonfatal stroke (P = 0.03) Significant benefit despite small hemorrhagic stroke

with atorvastatin (2.3%) vs placebo (1.4%)

Secondary end points

35% major coronary events (P = 0.003)

20% major CV events (P = 0.002)

42% any coronary events (P < 0.001)

26% any CV events (P < 0.001)

45% revascularizations (P < 0.001)


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SPARCL: Implications

Aggressive statin therapy should be strongly considered soon after stroke or TIA

Magnitude of benefit may vary depending on baseline stroke subtype

SPARCL results support the concept of stroke or TIA as a CHD risk equivalent


49

Statin Evolution

Evidence

Efficacy

Experience

50

Drug Class LDL-C HDL-C Triglycerides

Statins* 18% to 60%*** 5% to 15% 7% to 37%***

Bile Acid 15% to 30% 3% to 5% No change or

Sequestrants increase

Nicotinic Acid 5% to 25% 15% to 35% 20% to 50%

Fibric Acids 5% to 20%** 10% to 20% 20% to 50%

Statin Efficacy: Lipid Lowering

*Lovastatin (20 to 80 mg), pravastatin (20 to 40 mg), simvastatin (20 to 80 mg), fluvastatin (20 to 80 mg), atorvastatin (10 to 80 mg), and rosuvastatin (10 to 40 mg).

**May be increased in patients with high triglycerides.

***Up to 60% reduction in LDL-C, and 37% reduction in triglycerides, as indicated in the atorvastatin PI.

Adapted from NCEP Expert Panel. JAMA. 2001;285:2486-2497.

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Statin Efficacy: CURVES Trial

*Simvastatin 80 mg not available at time of study. **Significantly greater than mg-equivalent doses of comparative agents (P <.01). †Significantly less than atorvastatin 10 mg (P <.02). ‡Significantly less than atorvastatin 20 mg (P <.01).

Jones P, et al, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.

Atorvastatin

Simvastatin*

Pravastatin

Lovastatin

Fluvastatin

0 -60-50-40-30-20-10

10 mg (n = 73)

20 mg (n = 51)

40 mg (n = 61)

10 mg (n = 70)

20 mg (n = 49)

40 mg (n = 61)

10 mg (n = 14)

20 mg (n = 41)40 mg (n = 25)

20 mg (n = 16)40 mg (n = 16)

40 mg (n = 12)

20 mg (n = 12)

-38%**-46%**

-51%**

-28%†

-35%‡

-41%‡

-19%†

-24%†

-34%‡

-29%†

-31%†‡

-17%†

-23%†‡

80 mg (n = 10) -54%

80 mg (n = 11) -48%

% LDL-C reduction

Atorvastatin Significantly Lowered LDL-C

52

Andrews TC, et al. Am J Med. 2001;111:185-191.

*P < .01 vs all other treatments

Atorvastatin Effectively Lowered LDL-C

% C

han

ge

LDL-C TG HDL-C

**

**

-42%

-29%

-36%

-28%

-36%

-19%

-7%

-12%

-9%

-13%

5%6%

10

0

-10

-20

-30

-40

-50

5%6% 6%

Atorvastatin 10 to 80 (avg 24) mg (n = 1902)Fluvastatin 20 to 80 (avg 62) mg (n = 477)

Simvastatin 10 to 80 (avg 23) mg (n = 468)

Lovastatin 20 to 80 (avg 52) mg(n = 476) Pravastatin 10 to 40 (avg 31) mg (n = 462)

Statin Efficacy: ACCESS study

53

Statin Efficacy: ACCESS study

*Significant difference vs atorvastatin (P < 0.05)

*

**

*

0

25

50

100

Atorvastatin10 to 80 mg

Per

cen

t o

f p

atie

nts

ach

ievi

ng

go

al

75

Simvastatin10 to 80 mg

Pravastatin10 to 40 mg

Lovastatin20 to 80 mg

Fluvastatin20 to 80 mg

NCEP ATP II LDL-C Goals< 2 CHD risk factors is < 160 mg/dL (4.1 mmol/L)

> 2 CHD risk factors is < 130 mg/dL (3.4 mmol/L)Andrews TC, et al. Am J Med. 2001;111:185-191.

NCEP Goal Attainment

54

Statin Efficacy: NASDAC Study

NASDAC study—88% of dyslipidemic patients receiving a starting dose of 10 to 40 mg atorvastatin once daily reached their NCEP ATP III LDL-C goal.

88% Percentage of patients reaching LDL-C goal at 10, 20, or 40 mg

10 mg 20 mg 40 mg

79% 88% 98%(n = 76) (n = 68) (n = 64)

Patients without CHD and no CHD equivalents

Pfizer Inc. Data on file: NASDAC study.

55

Statin Efficacy: Atorvastatin

• Excellent efficacy across the dose range for all lipid parameters:

LDL-C -39% to -60%

Triglycerides -19% to -37%

HDL-C +5% to +9%

• In clinical trials, the vast majority of patients onatorvastatin reached LDL-C goal.

Lipitor-Pfizer Inc. Data on file.

56

Statin Evolution

Evidence

Efficacy

Experience

57

Atorvastatin Experience: Summary

Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.

• A recent analysis of 44 completed clinical trials demonstrated

that atorvastatin is well tolerated and has excellent safety

across the 10 mg to 80 mg atorvastatin dose range.

• The overall incidence of AEs with atorvastatin in clinical trials

does not increase across the dose range, and is similar to

that observed with placebo, and in patients treated with other

statins.

• Specific analysis of musculoskeletal and hepatic AEs showed

that these occurred infrequently and rarely resulted in

treatment discontinuation.

58

Atorvastatin Evolution

When choosing a Statin consider:

Evidence

Efficacy

Experience

aztor cme new

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