Atorvastatin Clinical Study Program

Atorvastatin Clinical Program

• Atorvastatin Studies fall into 3 main areas:– Lipid Efficacy and Safety Studies : ACCESS,ASSET,CHALLENGE

– Intermediate/Surrogate Endpoint Studies : ASAP, BELLES,PVD, REVERSAL,

SAGE

– Clinical Endpoint Studies : ALLIANCE, ASCOT,ASPEN,AVERT, CARDS,

4D,IDEAL, MIRACL,Saint Francis Heart Study, SPARCL, TNT

• Close to 400 atorvastatin clinical trial protocols

Current Statin Indications and Atorvastatin Clinical Testing -1999

Atorva Simva Prava Lova Fluva CerivaTREATMENT- Type II a/b - Type III/IV - TG - Homozygous FH - PVD PVD

PROGRESSION of Atherosclerosis REVERSAL

PREVENTION- Total Mortality - CHD death/MI TNT/IDEAL a) Type 2 DM, HTN ASPEN/ASCOT b) Elderly SAGE - Acute Mgment of UA MIRACL- Stroke in CHD TNT/IDEAL - Stroke in Non-CHD Stroke SPARCL- Aggressive lowering Many

- Indications

Major Objective of the Atorvastatin Clinical Study Program

• To provide scientific answers to many of the remaining questions in the area of lipidology and the clinical consequences of atherosclerosis.

Key Question

Is aggressive lipid lowering associated with acute event reduction in patients with unstable coronary syndromes?

MIRACL Rationale

• Background– No early separation in CHD event rates seen in major statin trials

– However, studies have systematically excluded acute patients

• 4S- entry >6 months post event

• CARE- entry 3 to 20 months post event

• LIPID- entry 3 months to 3 years post event

– Hypothesis: improved endothelial function and plaque stabilization with aggressive lipid lowering will reduce acute CHD risk

MIRACL Timeframe

Acute CoronaryEvent

MIRACL

t=0

6 mo.4SWOSCOPS

AFCAPS-TexCAPS

Primary Prevention Secondary Prevention

3 mo.

CARE

LIPID

4 mo.? ? ?

MIRACL Study Design: Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study

4 months

atorvastatin 80 mg

3,000Patients

Usual Care + d/b PBO Non-Q Wave Infarction or

Unstable Angina Randomized 24-96 hours

from admission Exclusions:

Planned CABG/ PTCA Prior Q-wave <28 days, CABG <3 mo, PTCA <6 mo., IIIb/IV CHF, TC>270 mg/dL

Patient Population

Primary Endpoint Time to ischemic events (CHD death, non-fatal MI,cardiac arrest, documented angina requiring hospitalization)

Key Question

Does aggressive lipid lowering provide additional clinical benefits and cost-effective CHD event reductions in a managed care setting?

ALLIANCE Study Design: Aggressive Lipid Lowering Initiation Abates New Cardiac Endpoints

4 years

Primary EndpointIncidence rate of cardiovascular eventsTotal mortalityCost of care between treatment groups

History of CHD Hypercholesterolemia

LDL-C >130 and <250

mg/dL off lipid-lowering

therapy or LDL-C >110 and <200

mg/dL on lipid-lowering

therapy 18 Managed Care Centers

in USA

Patient PopulationStandardcare (HMO)

atorvastatin 10 mgtitrate every 4 wks.to < 80 mg/dL LDL-C

-open-

2,443 Patients

04/18/23 19:11P0168.PFIZER.Lipitor.Slide_Kit.A.dh07

Key Question

Can aggressive lipid lowering show changes in atheroma and demonstrate regression utilizing Intracoronary Ultrasound ?

REVERSAL Study Design

IVUS

18 Months

600Patients

atorvastatin 80mg

IVUS

Brachial Reactivity

Patient Population

Patients with CAD Age :30-75 years

Primary Efficacy Parameter Change in Coronary Plaque Volume assessed by IVUS

pravastatin 40mg

Key Question

Does aggressive lipid lowering reduce coronary plaque burden more than moderate lipid lowering in post-menopausal dyslipidemic women ?

Aim : To determine whether aggressive lipid-lowering therapy with atorvastatin 80 mg/day compared with moderate treatment with pravastatin 40 mg/day can produce greater reductions in coronary artery calcification in postmenopausal women with hypercholesterolemia

BELLES Study Design: Beyond Endorsed Lipid Lowering with EBCT Study

Calcium Volume Score

12 Months12 Months

pravastatin 40mg

600Patients

atorvastatin 80mg

Calcium Volume ScorePatient Population

Post-menopausal

women Dyslipidaemic Study conducted with

Gynecologists and

Obstetricians total coronary cal. Vol.

Score >30

Primary Efficacy Parameter Change in plaque volume measured by EBCT

BELLES Study

• EBCT : Electron Beam Computed Tomography is a noninvasive technique that is becoming the method of choice for evaluating atherosclerosis progression as a surrogate marker for atherosclerotic disease

Key Question

Does robust lipid lowering reduce ischemic events in type 2 diabetics?

Aim : To assess the efficacy of atorvastatin 10 mg vs placebo in the prevention of CHD in patients with type 2 diabetes with or without previous MI

ASPEN Study Design: AtorvaStatin as Prevention of CHD Endpoints in NIDDM

4 to 8 years4 to 8 years4 to 8 years4 to 8 years

atorvastatin 10 mg

2421Patients

d/b PBO Type 2 diabetics No prior MI:

LDL-C <160 mg/dL TG <600 mg/dL

Prior MI: LDL-C <140 mg/dL TG <600 mg/dL

Age 40-75 years

Patient Population

Primary Endpoint Time to CV event (CHD death, non-fatal MI, recanalization, CABG, stroke)

CARDS Study Design: Collaborative AtoRvastatin Diabetes Study

4 years4 years4 years4 years

atorvastatin 10 mg

2750

Patients

d/b PBO

Patient Population

Type 2 diabetics No prior MI or CAD Other risk factors + Lipid profile:

LDL-C <159 mg/dL (4.14 mmol/L) TG <600 mg/dL (6.78 mmol/L)

Collaboration in the UK

with BDA and NHS

Primary Endpoint Time to major CV event(CHD death,

non-fatal MI, recanalization, CABG)

Key Question

Does aggressive lipid lowering produce reductions in event rates for NIDDM patients with end stage renal failure ?

Aim : To determine whether atorvastatin 20 mg will provide greater reductions in cardiovascular mortality rates and nonfatal MI than placebo in patients with type 2 diabetes who have undergone hemodialysis for no more than 2 years

4D Study Design: Determination of cardiovascular endpoints in NIDDM Dialysis patients

atorvastatin 20 mg

Placebo

1,200Patients

Primary EndpointCombined endpoint:Cardiovascular mortality rate

Patient Population

Type 2 diabetics Receiving Renal Dialysis for less than 2 yrs LDL-C 80-190 mg/dL TGs <1000 mg/dL Age 18-80 years

2.5 years follow-up

Key Question

Does robust lipid lowering reduce ischemic events in hypertensives with “normal” cholesterol levels?

Aim : To compare the effects of atorvastatin 10 mg with placebo on the incidence of nonfatal MI and fatal CHD in hypertensive patients with TC level <= 250 mg/dL

ASCOT Study Design: Anglo-Scandinavian Cardiac Outcomes Trial

1,150 events; ~5 years

18,000Patients

Hypertensive: >160 SBP or >100 DBP 40-79 years old 3+ CVD risk factors

LVH ,ECG abn., NIDDM, PVD, TIA, male, >55 y.o., microalb., smoker, TC/HDL>6, Fx of early CAD

Scandinavian and UK centers

Patient PopulationPROBE: 2x2 Factorial

Norvasc AtenololTC (mmol)TC (mmol)

>6.5

<6.5*PBO

Ator10 mg

* 9,000 expected to be randomized in lipid arm

ASCOT Study

• 1th endpoints : nonfatal MI, fatal CHD

• 2nd endpoints: all-cause mortality

» fatal and nonfatal stroke» » fatal and nonfatal heart failure

Key Question

Does robust lipid lowering reduce the occurrence of stroke in patients without CHD?

Aim : To determine whether aggressive cholesterol-lowering therpy with atorvastatin 80 mg can reduce the incidence of cerebrovascular endpoints compared with placebo in patients with out a history of CHD who have experienced a prior stroke or TIA

SPARCL Study Design: Stroke Prevention by Aggressive Reduction of Cholesterol Levels

5 years

atorvastatin 80 mg

4,200Patients

d/b PBO Stroke/TIA 1-6 months

prior LDL 100-190 mg/dl Exclusions:

Age <18 years Hx of CAD Endarterectomy in

prior month Subarachnoid

hemorrhage Many Neurologists as

investigators

Patient Population

Primary Endpoint•Time to first fatal or non-fatal stroke

Key Question

Does aggressive lipid lowering produce additional coronary benefit beyond that shown with other therapy or currently recommended guidelines ?

Aim : To assess whether reducing LDL-C aggressively to 75 mg/dL will provide a greater reduction in CHD events than lowering LDL-C more moderately to 100 mg/dL

Study Hypothesis: Lower Is Better

With CHDevent (%)

50 70 90 110 130 150 170 190 210

0

5

10

15

20

25

LIPID-Rx

CARE-PBOCARE-Rx

4S-RxLIPID-PBO

4S-PBO

AFCAPS-Rx

WOS-RxWOS-PBO

AFCAPS-PBO

LDL-C (mg/dL)

Secondary preventionPrimary prevention

?

TNT Study Design: Treating to New Targets

750 events or5 years

atorvastatin 80 mg

atorvastatin 10 mg 35-75 y.o.

Major coronary event in

prior 5 years

LDL 130-250 mg/dl

TG <600 mg/dl

250 centers in 14

countries

Patient Population

atorvastatin 10 mg

LDL< 130 mg

Open Run-in

Double-Blind

8,600Patients

8 weeks

IDEAL Study Design: Incremental Decrease in Endpoints through Aggressive Lipid-lowering

1,880 events: ~5.5 years

atorvastatin 80 mg

8600Patients

simvastatin 20 mg; titration to 40 mg for TC<5 mmol

Men or women <78 y.o. Current or prior

definite AMI 150 centers in

Scandinavia and

The Netherlands

Patient PopulationPROBE/ Prescription Study

Summary of the Atorvastatin Clinical Development Program

Completion Expected

Completion ExpectedStudyStudyKey QuestionsKey Questions

Does aggressive lipid lowering...

Provide clinical benefit in stable CAD AVERT 1998 patients referred for PTCA?

Reduce acute events in unstable MIRACL 2000coronary syndromes?

Reduce plaque burden in BELLES 2001post-menopausal women?

Provide clinical benefits in PVD? PVD 2002

Result in additional clinical/cost ALLIANCE 2002benefits in MCO environment?

Cause regression of diseased as REVERSAL 2002measured by IVUS?

Summary of the Atorvastatin Clinical Development Program

Completion Expected

Completion ExpectedStudyStudyKey QuestionsKey Questions

Does aggressive lipid-lowering…

Produce clinical benefit in the elderly? SAGE 2002

Reduce CHD risk combined with antioxidants? St Francis 2003

Reduce ischemic events in hypertensives ASCOT 2003with “normal” cholesterol?

Reduce Ischemic events in NIDDM? ASPEN/CARDS 2004

Reduce occurrence of stroke in patients SPARCL 2004without CHD?

Produce additional CV benefit beyond IDEAL/TNT 2004/5that shown with other therapies (IDEAL) or beyond current recommended guidelines (TNT)?

Summary: Atorvastatin Efficacy and Outcome Studies

1998 1999 2000 2001 2002 2003 2004 2005

Growing Evidence in over 42000 patients