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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
Ceriva
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PVD
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REVERSAL
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TREATMENT
-
Type II a/b
Type III/IV
TG
Homozygous FH
PVD
PROGRESSION
of Atherosclerosis
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PREVENTION
- Total Mortality
- CHD death/MI
a) Type 2 DM, HTN
b) Elderly
- Acute Mgment of UA
- Stroke in CHD
- Stroke in Non-CHD Stroke
- Aggressive lowering
 - Indications
TNT/IDEAL
ASPEN/ASCOT
SAGE
MIRACL
TNT/IDEAL
SPARCL
Many
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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
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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 Coronary
Event
???
4 mo.
MIRACL
Primary Prevention
Secondary Prevention
WOSCOPS
AFCAPSTexCAPS
6 mo.
t=0
3 mo.
4S
CARE
LIPID
MIRACL Study Design: Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering Study
Patient Population

Non-Q Wave Infarction or
Unstable Angina
 Randomized 24-96 hours
from admission
 Exclusions:
Usual Care + d/b PBO
3,000
Patients
atorvastatin 80 mg
4 months

Planned CABG/ PTCA
 Prior Q-wave <28 days,
 CABG <3 mo, PTCA <6 mo.,
 IIIb/IV CHF,

TC>270 mg/dL
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
-open-
Patient Population


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
2,443
Patients
Standard
care (HMO)
atorvastatin 10 mg
titrate every 4 wks.
to < 80 mg/dL LDL-C
4 years
Primary Endpoint
 Incidence rate of cardiovascular events
 Total mortality
 Cost of care between treatment groups
Key Question
Can aggressive lipid lowering show changes in atheroma and
demonstrate regression utilizing Intracoronary Ultrasound ?
REVERSAL Study Design
IVUS
IVUS
pravastatin 40mg
Patient Population
 Patients
with CAD
 Age :30-75 years
600
Patients
atorvastatin 80mg
Brachial Reactivity
18 Months
Primary Efficacy Parameter
 Change in Coronary Plaque Volume assessed by IVUS
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
Patient Population
Calcium Volume Score
Calcium Volume Score
pravastatin 40mg
Post-menopausal
women
 Dyslipidaemic
 Study conducted with
Gynecologists and
Obstetricians
 total coronary cal. Vol.
Score >30

600
Patients
atorvastatin 80mg
Primary Efficacy Parameter
 Change in plaque volume measured by EBCT
12 Months
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
Patient Population
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

2421
Patients
atorvastatin 10 mg
4 to 8 years
Primary Endpoint
 Time to CV event (CHD death, non-fatal
MI, recanalization, CABG, stroke)
CARDS Study Design: Collaborative AtoRvastatin Diabetes Study
Patient Population
d/b PBO

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
2750
Patients
atorvastatin 10 mg
4 years
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
Patient Population
Placebo
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

1,200
Patients
atorvastatin 20 mg
2.5 years follow-up
Primary Endpoint
Combined endpoint:Cardiovascular mortality rate
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
PROBE: 2x2 Factorial
Patient Population
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
TC (mmol)

Norvasc
Atenolol
>6.5
18,000
Patients
PBO
<6.5*
Ator
10 mg
1,150 events; ~5 years
* 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
Patient Population

Stroke/TIA 1-6 months
prior
 LDL 100-190 mg/dl

Exclusions:
d/b PBO
4,200
Patients
atorvastatin 80 mg

Age <18 years
 Hx of CAD
 Endarterectomy in
prior month

Subarachnoid
hemorrhage
 Many Neurologists as
investigators
5 years
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
4S-PBO
Secondary prevention
Primary prevention
25
LIPID-PBO
20
With CHD
event (%)
4S-Rx
15
CARE-Rx
10
CARE-PBO
LIPID-Rx
?
5
WOS-PBO
WOS-Rx
AFCAPS-Rx
AFCAPS-PBO
0
50
70
90
110
130
150
LDL-C (mg/dL)
170
190
210
TNT Study Design: Treating to New Targets
Double-Blind
Patient Population

35-75 y.o.

Major coronary event in
atorvastatin
10 mg
prior 5 years

LDL 130-250 mg/dl

TG <600 mg/dl

250 centers in 14
countries
atorvastatin
10 mg
Open Run-in
8,600
Patients
atorvastatin
80 mg
LDL< 130 mg
8 weeks
750 events or
5 years
IDEAL Study Design: Incremental Decrease in Endpoints through
Aggressive Lipid-lowering
PROBE/ Prescription Study
Patient Population
Men or women
 <78 y.o.
 Current or prior
definite AMI
 150 centers in
Scandinavia and
The Netherlands
simvastatin 20 mg;
titration to 40 mg for
TC<5 mmol

8600
Patients
atorvastatin 80 mg
1,880 events: ~5.5 years
Summary of the Atorvastatin Clinical Development Program
Key Questions
Study
Completion
Expected
Does aggressive lipid lowering...
Provide clinical benefit in stable CAD
referred for PTCA?
AVERT
1998 patients
Reduce acute events in unstable
coronary syndromes?
MIRACL
2000
Reduce plaque burden in
post-menopausal women?
BELLES
2001
Provide clinical benefits in PVD?
PVD
2002
Result in additional clinical/cost
benefits in MCO environment?
ALLIANCE
2002
Cause regression of diseased as
measured by IVUS?
REVERSAL
2002
Summary of the Atorvastatin Clinical Development Program
Key Questions
Study
Completion
Expected
Does aggressive lipid-lowering…
Produce clinical benefit in the elderly?
Reduce CHD risk combined with antioxidants?
SAGE
St Francis
2002
2003
Reduce ischemic events in hypertensives
with “normal” cholesterol?
ASCOT
2003
Reduce Ischemic events in NIDDM?
ASPEN/CARDS
Reduce occurrence of stroke in patients
without CHD?
SPARCL
2004
Produce additional CV benefit beyond
that shown with other therapies (IDEAL)
or beyond current recommended
guidelines (TNT)?
IDEAL/TNT
2004/5
2004
Summary: Atorvastatin Efficacy and Outcome Studies
Growing Evidence in
over 42000 patients
1998 1999 2000 2001 2002 2003 2004 2005