Statin Evolution Evidence, Efficacy, and Experience

SENIOR GP CONSULTANT

S1

DYSLIPIDEMIA

THE SILENT KILLER DR. MOHAMMAD NASIM

SENIOR GP CONSULTANT

BADRUDDIN MEDICAL GROUP

 WHAT IS DYSLIPIDEMIA? DYSLIPIDEMIA IS A RANGE OF DISORDERS THAT INCLUDE ABNORMALLY HIGH AND LOW LEVELS OF LIPOPROTEINS AS WELL AS DISORDERS IN THE COMPOSITION OF THESE PARTICLES.


PRIMARY---

CAUSES

1.POLYGENIC HYPERCHOLESTROLEMIA 2.FAMILIAL HYPERCHOLESTEROLEMIA 3.FAMILIAL HYPERTRIGLYCERIDEMIA

4.CHYLOMICRONEMIA
5.FAMILIAL COMBINED DYSLIPIDEMIA

 SECONDARY 1. TYPE 2 DYSLIPIDEMIA 2.EXCESSIVE ALCOHOL CONSUMPTION

3.CHOLESTATIC LIVER DISEASES

4.NEPHROTIC SYNDROME 5.CHRONIC RENAL FAILURE 6.HYPOTHYROIDISM

7.CIGARETTE SMOKING
8.OBESITY 9.DRUGSRETINOIDS,ESTEROGENS/CONTRACEPTIVE PILLS,CORTICOSTEROIDS,CICLOSPORINS,DIURETICS,NON SELECTIVE BETA BLOCKER

 SIGNS AND SYMPTOMS-

DERMATOLOGIC SIGNS
The most common dermatologic manifestation of dyslipidemia is xanthomas and xanthelasma.Xanthomas are firm and nontender cutaneous deposits of cholesteryl ester-enriched foam cells are most commonly observed with high levels of LDL. Xanthomas deposit in ligaments and tendons, although they may also be detected in periosteum and fascia. They are classified as tendinous, tuberous, tuberoeruptive, and planar. The most common location for tendinous xanthomas is the Achilles tendon[9] followed by the hands, feet, elbows, and knees

 OPHTHALMOLOGIC SIGNS Corneal Arcus Corneal arcus is a grayish white opacification at the periphery of the cornea (Figure 1).[1] It is a particularly sensitive sign of familial hypercholesterolemia (FH), especially when detected in persons less than age 50 years, in which case it is also referred to as arcus juvenalis Corneal Opacification

Patients with very low high-density lipoprotein (HDL) cholesterol because of mutations in regulatory genes may also exhibit ocular findings like corneal opacification.

 Retinal Findings In addition to the eruptive xanthomas that may accompany marked chylomicronemia, another important clinical sign is lipemia retinalis or a "milky-white" appearance of the retina.

 MANAGEMENT-The management of lipid disorder greatly depends on the age, signs/symptoms of the affected persons. The following are remedies / treatment may apply to lower the level of LIPIDS in the body including: Eat well-balanced diet Almost fifteen (15) percent of cholesterol may decrease when strictly controlled. Eating foods that are naturally low in fat (whole grains, fruits, vegetables, etc.) a good sources of soluble fiber to prevent other health complications. Weight Management Exercise Regularly (walking, yoga, dancing, etc.) Exercise for at least thirty (30) minutes everyday. Maintain this habit and you will see the desired result. Quit smoking An important treatment to reduce the risk of heart disease and stroke.

MMNMM
MEDICAL MANAGEMENT 1.STATIN SIMVASTATIN,ATORVASTATIN,ROSUVASTATIN 2.FIBRATES 3.BILE ACID RESINS

4.NIACIN
5.NICOTINIC ACID 6.EZITIMIBE 7.FISH OIL

INCII

INCIDENCE IS MORE THAN HYPERTENSION AND DIABETES

RULE OF HALF APPLIES TO DYSLIPIODEMIA ALSO---HALF OF THE DYSLIPIDEMIA CASES ARE DIAGNOSED,HALF OF DIAGNOSED CASES BEING TREATED,HALF OF THE TREATED CASES ARE UNCONTROLLED

MANAGEMENT
The new guideline,ISSUED AT 12 NOV.,2013 BY ACC AND AHA, recommends moderate- or high-intensity statin therapy for these four groups: Patients who have cardiovascular disease; Patients with an LDL, or bad cholesterol level of 190 mg/dL or higher; Patients with Type 2 diabetes who are between 40 and 75 years of age; and Patients with an estimated 10-year risk of cardiovascular disease of 7.5 percent or higher who are between 40 and 75 years of age (the report provides formulas for calculating 10-year risk).

Atherosclerosis Timeline

Phase I: Initiation
Media Intima LDL-C
Lumen

LDL-C plays a major role in initiating the development of atherosclerotic plaque.

Unstable

Phase II: Progression

Disease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly.

Stable

Phase III: Complication

Extensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture.

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.

S2

Lipid-lowering Goals

Joint European Societies1

Established CHD, other atherosclerotic disease, or high absolute risk

LDL-C Goal
<115 mg/dL (3.0 mmol/L)

US NCEP ATP III2

0-1 CHD risk factors >2 CHD risk factors <160 mg/dL (4.1 mmol/L) <130 mg/dL (3.4 mmol/L)

CHD or CHD risk equivalent

<100 mg/dL (2.6 mmol/L)

Wood D, et al. Atherosclerosis. 1998;140:1434-1503; 2 NCEP Expert Panel. JAMA. 2001;285:2486-2497.

S3

Statin Evolution

Evidence Efficacy Experience

S4

Statin Evidence: Landmark Statin Trials

4S-P

25

% with CHD event

20 15 10
CARE-S

4S-S LIPID-P CARE-P

Secondary prevention ( Primary prevention (

) )

Simvastatin
Pravastatin
WOSCOPS-P

LIPID-S
ASCOT-P* ASCOT-S* AFCAPS-S WOSCOPS-S AFCAPS-P

Lovastatin Atorvastatin
S = statin treated P = placebo treated

5 0

2.3 (90)

2.8 (110)

3.4 (130)

3.9 (150) 4.4 (170)

4.9 (190) 5.4 (210)

LDL-C, mmol/L (mg/dL)

*Extrapolated to 5 years

Adapted from Kastelein JP. Atherosclerosis. 1999;143(suppl 1):S17-S21.

S5

Statin Evidence: Expanding Benefits

Acute coronary event
No history of CAD Unstable CAD Stable CAD

4 mo
AFCAPS / TexCAPS/ WOSCOPS MIRACL

t=0 3 mo

CARE/LIPID

4S 6 mo

HPS ASCOT-LLA
Hypertension

Primary prevention

Secondary prevention
S6

Statin Evidence: Heart Protection Study

PATIENT POPULATION
CHD
n = 13,379 (65%)

20,536 patients

Hypertension
n = 8457 (41%)

with MI 8510 (41%)

no MI 4876 (24%)

with CHD 5595 (27%)

no CHD 2860 (14%)

CVD
n = 3280 (16%)

PVD
n = 6748 (33%)

Diabetes
n = 5963 (29%)

with CHD 1458 (7%)

no CHD 1822 (9%)

with CHD 4042 (20%)

no CHD 2701 (13%)

with CHD 1978 (10%)

no CHD 3982 (19%)

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.

S7

Statin Evidence: Heart Protection Study

Vascular event Major coronary event Nonfatal MI Coronary death Stroke Revascularization ANY MAJOR VASCULAR EVENT
0.4

Simvastatin better

Placebo better 27% risk reduction P <.0001

25% risk reduction P <.0001 24% risk reduction P <.0001 24% risk reduction P <.0001 0.6 0.8 1.0 1.2 1.4

Risk ratio and 95% CI

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.

S8

Statin Evidence: Heart Protection Study

Baseline level
LDL-C (mg/dL) <100 (2.6 mmol/L) >100 < 130 >130 (3.4 mmol/L)

Simvastatin better

Placebo better

24% risk reduction P < .0001

ALL PATIENTS

0.4

0.6

0.8

1.0

1.2

1.4

Risk Ratio and 95% CI

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.

S9

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

S10

Statin Evidence: ASCOT-LLA

18,000 patients R=Randomized

R
9000 beta-blocker diuretic 9000 CCB ACEI

5000 TC <250 mg/dL (<6.5 mmol/L)

4000 TC >250 mg/dL (>6.5 mmol/L)

4000 TC >250 mg/dL (>6.5 mmol/L)

5000 TC <250 mg/dL (<6.5 mmol/L)

500 open lipid lowering

4500

4500

500 open lipid lowering

R
2250 statin 2250 placebo 8000 open lipid lowering 2250 placebo

R
2250 statin

These are the target numbers of patients.

CCB=calcium channel blocker, ACEI=angiotensin converting enzyme inhibitor

S11

Statin Evidence: ASCOT-LLA

Eligibility criteria for ASCOT-LLA SBP >160 mm Hg and/or DBP >100 mm Hg (untreated) or
SBP >140 mm Hg and/or DBP >90 mm Hg (treated)

TC <250 mg/dL (<6.5 mmol/L) and triglycerides <400 mg/dL

(<4.5 mmol/L)

40-79 years of age

3+ CVD risk factors No history of CHD
Sever PS, et al. Lancet. 2003;361:1149-1158.

S12

Statin Evidence: ASCOT-LLA

Objective of ASCOT-LLA
To evaluate the cardiovascular benefits of cholesterol lowering with atorvastatin 10 mg in hypertensive patients with total cholesterol levels of <250 mg/dL (<6.5 mmol/L).

Study end points

Primary: Combined nonfatal MI (including silent MI) and fatal CHD Fatal and nonfatal stroke Total cardiovascular events and procedures Total coronary events

Secondary:

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

S13

Statin Evidence: ASCOT-LLA

September 2002

The DSMB reported that in ASCOT-LLA there was a highly

significant reduction in the primary end point as well as a significant reduction in stroke

The DSMB recommended that the double-blind, cholesterollowering study treatment arm be terminated since the results were outside of the stopping rules of the trial

The Steering Committee endorsed the recommendation of the

DSMB, and the lipid arm was closed after a median follow-up period of 3.3 years; the blood pressure-lowering arm of the study is expected to complete in 2005
Sever PS, et al. Lancet. 2003;361:1149-1158.

S14

Statin Evidence: ASCOT-LLA

Patient Inclusion and Follow-Up Status
19,342 patients randomized to antihypertensive treatment
10,305 randomized in lipid-lowering arm

5168 atorvastatin

5137 placebo

4928 alive with complete information

185 dead with complete information

4861 alive with complete information

212 dead with complete information

Incomplete information: 39 alive after Oct 1, 2002 4 alive before Oct 1, 2002 5 withdrew consent 7 lost to follow-up

Incomplete information: 42 alive after Oct 1, 2002 3 alive before Oct 1, 2002 9 withdrew consent 10 lost to follow-up

Complete information obtained on 98.8% of patients

S15

Statin Evidence: ASCOT-LLA

Blood Pressure Changes
170
SBP (mm Hg)

Atorvastatin 10 mg Placebo
Baseline 164/95 mm Hg Treated 138/80 mm Hg

160 150 140 130 0

100 95 90 85 80 75
0 1
Years

LLA Close-out

DBP (mm Hg)

LLA Close-out S16

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

Statin Evidence: ASCOT-LLA

6

Total cholesterol (mmol/L)

4 Atorvastatin 10 mg Placebo 2 0 1 2 3

150 100

150 125 46.5 mg/dL (1.2 mmol/L) 38.7 mg/dL (1.0 mmol/L)

LDL cholesterol (mmol/L)

3
2

100
75

1
0 1 2 3
LLA Close-out S17

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

(mg/dL)

(mg/dL)

50 mg/dL (1.3 mmol/L)

38.7 mg/dL (1.0 mmol/L)

200

Statin Evidence: ASCOT-LLA

Primary Endpoint:
Nonfatal MI and Fatal CHD
4

Secondary Endpoint:
Fatal and Nonfatal Stroke
3 Cumulative Incidence (%)

Cumulative Incidence (%)

36% reduction

27% reduction
2

1
HR = 0.73 (0.56-0.96) P = .0236

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

0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Years

Atorvastatin 10 mg Placebo

Number of events Number of events

100 154

Atorvastatin 10 mg Placebo

Number of events Number of events

89 121

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

S18

Statin Evidence: ASCOT-LLA

Secondary Endpoint:
All CV Events and Procedures
12 Cumulative Incidence (%) Cumulative Incidence (%) 10 8 6 4 2 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Atorvastatin 10 mg Placebo Number of events Number of events 389 486 Atorvastatin 10 mg Placebo
HR = 0.79 (0.69-0.90) P = .0005

Secondary Endpoint: All Coronary Events

6 5 4 3

21% reduction

29% reduction

2
1 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Number of events Number of events 178 247
HR = 0.71 (0.59-0.86) P = .0005

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

S19

Statin Evidence: ASCOT-LLA

Safety
No significant difference between atorvastatin and placebo in:
Incidence of fatal cancers Incidence of serious adverse events Incidence of liver enzyme abnormalities

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

S20

Statin Evidence: ASCOT-LLA

The benefits of atorvastatin therapy in well-managed hypertensive patients at modest risk of cardiovascular events and with normal to mildly elevated cholesterol levels were: Large given the short follow-up time (median 3.3 years)
and emerged earlier than in many other statin trials

Not significantly different among prespecified subgroups Unrelated to baseline cholesterol levels Occurred in the absence of any significant increase in
adverse events.
S21

Statin Evidence: MIRACL Study

Double-blind period

Atorvastatin 80 mg/day
Randomization (1-4 days) 3086 patients

Initial
hospitalization

Placebo plus usual care

16-week treatment phase

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

S22

Statin Evidence: MIRACL Study

Primary Efficacy Measure

Placebo
15

17.4% 14.8%

Cumulative Incidence (%)

Atorvastatin
10 Time to first occurrence of: Death (any cause) Nonfatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalization 0 4 8

Relative risk = 0.84 P = .048 95% CI 0.701-0.999

12 16

Time Since Randomization (weeks)

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

S23

Statin Evidence: MIRACL Study

Fatal and Nonfatal Stroke
2

Cumulative Incidence (%)

1.5

Placebo

Atorvastatin
Relative risk = 0.49 P = .04 95% CI 0.24-0.98
0 4 8 12 16

0.5

Time Since Randomization (weeks)

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

S24

Statin Evidence: GREACE Study

Structured care (n = 800) Atorvastatin 10 to 80 mg/d Goal: LDL-C < 100 mg/dL 1600 hypercholesterolemic patients with CHD

(LDL-C > 100 mg/dL [ > 2.59 mmol/L] after 6-week trial of lipid-lowering diet)

Mean follow-up, 3 years

Usual care (n = 800)

Begin recruitment January 1998

End recruitment November 1999

End of study December 2001

S25

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

Statin Evidence: GREACE Study

10 0
2 7
Usual Care Structured Care

-10
-20

-4

-5

-3

-3

-6

-30
-40 -50
-36 -31

*
-46

-32

*
-44

*
Total-C LDL-C TG HDL-C VLDL-C

*
Non-HDL-C

-60
*P < .0001; P = .0028. Mean atorvastatin dose, 24 mg/day.

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

S26

Statin Evidence: GREACE Study

Usual Care

8
P = .0001

Structured Care
P = .0011

6.4

P = .0021

P = .0017

5.6

4.8

4
2.9 2.5
P = .0032

P = .021

2.6

2.6

2.7

2.7

P = .034

2.1 1.2 1.3 1.1

0
Total Mortality Coronary Mortality Nonfatal MI Unstable Angina PTCA/CABG CHF Stroke

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

S27

Statin Evidence: GREACE Study

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.

S28

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.

S29

Statin Evolution

Evidence Efficacy Experience

S30

Statin Efficacy: Lipid Lowering

Drug Class Statins* Bile Acid Sequestrants Nicotinic Acid Fibric Acids
v v v v

LDL-C 18% to 60%*** 15% to 30%

v v v v

HDL-C 5% to 15% 3% to 5%

Triglycerides
v

7% to 37%***

No change or increase

5% to 25% 5% to 20%**

15% to 35% 10% to 20%

v v

20% to 50% 20% to 50%

*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.

S31

Statin Efficacy: LDL-C Reduction

10 mg (n = 73) 20 mg (n = 51) 40 mg (n = 61) 80 mg (n = 10) 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) 80 mg (n = 11)

-38%** -46%** -51%** -54% -28% -35% -41% -19% -24% -34% -29% -31% -48% -17% -23%

Atorvastatin Simvastatin* Pravastatin Lovastatin Fluvastatin

20 mg (n = 12) 40 mg (n = 12)

-10

-20

-30

-40

-50

-60

*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).

% LDL-C reduction

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

S32

Statin Efficacy: ACCESS

Atorvastatin 10 to 80 mg Men and women With or without CHD and/or PAD Type IIa/IIb TG < 400 mg/dL (4.5 mmol/L) ~ 70% with CHD and/or PAD Lovastatin 10 to 80 mg Pravastatin 10 to 40 mg Simvastatin 10 to 40 mg

Primary efficacy parameter:

Fluvastatin 20 to 80 mg

Reduction in plasma LDL-C from baseline

54 week open-label treatment

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

S33

Statin Efficacy: ACCESS

Atorvastatin Effectively Lowered LDL-C
10
5% 6% 5% 6% 6%

0 -10 -20 -30 -40

-42% -29% -28% -19% -7% -9% -12% -13%

-36%

-36%

Atorvastatin 10 to 80 (avg 24) mg (n = 1902) Fluvastatin 20 to 80 (avg 62) mg (n = 477) Lovastatin 20 to 80 (avg 52) mg (n = 476) Pravastatin 10 to 40 (avg 31) mg (n = 462) Simvastatin 10 to 80 (avg 23) mg (n = 468)

% Change

-50

*
LDL-C TG HDL-C

*P < .01 vs all other treatments

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

S34

Statin Efficacy: ACCESS

100

Percent of patients achieving goal

NCEP Goal Attainment

75

* * *

50

25

0 Atorvastatin
10 to 80 mg

Simvastatin
10 to 80 mg

Pravastatin
10 to 40 mg

Lovastatin
20 to 80 mg

Fluvastatin
20 to 80 mg

*Significant difference vs atorvastatin (P < 0.05)

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

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)

S35

Statin Efficacy: NASDAC Study

NASDAC study88% of dyslipidemic patients receiving a starting dose of 10 to 40 mg atorvastatin once daily reached their NCEP ATP III LDL-C goal.
Patients without CHD and no CHD equivalents

88%

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

10 mg

20 mg

40 mg

79%
(n = 76)
Pfizer Inc. Data on file: NASDAC study.

88%
(n = 68)

98%
(n = 64)
S36

Statin Efficacy: Atorvastatin

Excellent efficacy across the dose range for all lipid parameters: LDL-C HDL-C -39% to -60% +5% to +9%

Triglycerides -19% to -37%

In clinical trials, the vast majority of patients on atorvastatin reached LDL-C goal.

Pfizer Inc. Data on file.

S37

Statin Evolution

Evidence Efficacy Experience

S38

Atorvastatin Experience: Clinical Safety Data

Safety of atorvastatin derived from analysis of 44 completed clinical trials in 9416 patients:
n Atorvastatin (all doses) Other statins 9416 5290

Placebo

1789

Involved many different patient types:

eg, mixed dyslipidemia, diabetes, postmenopausal women, FH

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

S39

Atorvastatin Experience: Clinical Safety Data

Treatment-Associated AEs > 1% of Patients
Body system Placebo n = 1789 (%) 4 5 1 2 1 1 <1 1 2 Atorvastatin (all doses) n = 9416 (%) 8 5 3 3 2 1 1 1 1 All other statins combined n = 5290 (%) 9 6 4 3 2 1 <1 1 1

Digestive Body as a whole Musculoskeletal Nervous Skin and appendages Metabolic/Nutritional Special senses Urogenital Cardiovascular

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

S40

Atorvastatin Experience: Clinical Safety Data

Patient Withdrawal due to Treatment-Associated AEs
5 4 3 2 1 0 Placebo n = 16/1789 Atorvastatin (all doses) n = 241/9416 All other statins combined n = 188/5290 0.9% 2.6%

Patients withdrawing due to treatment-associated adverse events (%)

3.6%

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

S41

Atorvastatin Experience: Clinical Safety Data

ALT/AST elevations > 3x ULN:

0.5% of patients treated with atorvastatin 10 to 80 mg
experienced ALT/AST elevations > 3x ULN.

Myalgia
Incidence of myalgia across all the atorvastatin doses
was low (1.9%) and directly comparable to the incidence of myalgia observed in patients receiving other statins combined.

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

S42

Atorvastatin Experience: Summary

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.
S43

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

Atorvastatin Evolution: Future

Atorvastatin Clinical Trial Program (> 44,000 Patients)
REVERSAL BELLES LEADe

CARDS

SAGE

ALLIANCE ASPEN BONES

4D

SPARCL

AVALON

ASCOT

SPARKS

TNT

IDEAL

2002

2003

2004

2005

S44

Atorvastatin Evolution
When choosing a statin consider:

Evidence Efficacy Experience

S45