The REVERSAL Trial

1
The REVERSAL Trial

• Reversing Atherosclerosis With Aggressive Lipid
  Lowering

2
Atherosclerosis A Progressive Process
PHASE I Initiation PHASE II
Progression PHASE III Complication
Disease progression
3
Effects of Lipid-Lowering Therapy on CHD Events
in Statin Trials
Secondary
4S
-
P
25
prevention
Primary
20
prevention
4S
-
S
Simvastatin
LIPID
-
P
15
CARE
-
P
Patients with CHD event ()
Pravastatin
HPS
-
P
Lovastatin
LIPID
-
S
10
WOSCOPS
-
P
Atorvastatin
CARE
-
S
WOSCOPS
-
S
HPS
-
S

ASCOT
-
P
S statin-treated
5

ASCOT
-
S
P placebo-treated
AFCAPS
-
P
AFCAPS
-
S
Extrapolated to 5 y
0
90
110
130
150
170
190
210
LDL-C (mg/dL)
Modified from Kastelein JJP. Atherosclerosis.
1999143(suppl 1) S17-S21.
4
What Is REVERSAL?

• Multicenter, randomized, double-blind, active-
  controlled trial
• Comparing the effects of atorvastatin 80 mg/d
  with pravastatin 40 mg/d administered for 18
  months
• Using IVUS to measure progression of
  atherosclerosis

5
Effects of Lipid Lowering With Statins on
Progression of CHD
0.06
Drug
Placebo
PLAC I
0.05
CCAIT
REGRESS
0.04
LCAS
PLAC I
0.03
Progression (MLD decrease), mm/y
MARS
MAAS
CCAIT
0.02
MARS
REGRESS
LCAS
0.01
MAAS
0
-40
-30
-20
-10
0
10
LDL-C reduction ()
6
REVERSAL Study Design
Double-blind period
Screeningvisit
Atorvastatin 80 mg/d
Placeborun-inphase
Randomization 654 patients
Pravastatin 40 mg/d
18-month follow-up with IVUS
Includes baseline IVUS
Design Prospective, multicenter, randomized,
double-blind trial Setting 34 community and
tertiary-care hospitals in the USA
7
REVERSAL Study Objective

• To compare the effects of aggressive
  lipid-lowering therapy (atorvastatin 80 mg/d) vs
  moderate lipid-lowering therapy (pravastatin 40
  mg/d) on percent change in TAV using IVUS
  imaging of the coronary arteries in patients with
  CHD

8
REVERSAL Why Was Pravastatin 40 mg Used?

• REVERSAL is the first active-controlled,
  cholesterol- lowering, coronary atherosclerosis
  progression trial
• Previous large-scale trials used placebo as a
  comparator
• Pravastatin has an indication to slow progression
  of atherosclerosis based on angiographic studies
• PLAC I 264 patients for 3 y vs placebo
• REGRESS 885 patients for 2 y vs placebo
• 40 mg was the highest approved dose of
  pravastatin at the initiation of REVERSAL

9
REVERSAL Patient Population

• Inclusion criteria
• Patients requiring diagnostic coronary
  angiography for a clinical indication
• Aged 30-75 y
• LDL-C ? 3.2 mmol/L (125 mg/dL) but ? 5.4 mmol/L
  (210 mg/dL)
• TGs lt 6.8 mmol/L (600 mg/dL)
• Angiographic inclusion criteria
• Angiographic evidence of CHD defined as ? 1
  lesion with ? 20 reduction in lumen diameter in
  any coronary artery
• ? 50 reduction in lumen diameter of the left
  main coronary artery
• The vessel undergoing IVUS evaluation (the
  target vessel) should have ? 50 stenosis
  throughout a segment of minimum length 30 mm

10
REVERSAL Patient Population

• Exclusion criteria
• Target vessel was considered suitable only if the
  artery had not undergone PTCA or CABG surgery
• Left ventricular ejection fraction of lt 0.4
• Moderate or more severe CHF
• Clinically significant valvular heart disease
• Uncontrolled hypertension
• Second- or third-degree heart block
• Sustained ventricular tachyarrhythmia or an
  implantedcardiac defibrillator
• Known major hematologic, neoplastic, metabolic,
  gastrointestinal, or endocrine dysfunction

11
What Is TAV?
12
REVERSAL Primary Efficacy Parameter

• The percent change from baseline in TAV for all
  slices of anatomically comparable segments of the
  target coronary artery as measured by IVUS

13
REVERSAL Selected Secondary Efficacy Parameters

• Nominal change from baseline in TAV
• Change from baseline in PAV
• Change from baseline in lipid parameters
• Change from baseline in CRP

14
REVERSAL Baseline Characteristics
Characteristic
Atorvastatin 80 mg (n 253)
Pravastatin 40 mg (n 249)
55.8 9.8 71 90 30.5 6.5 26 20 68 6.0
0.9231.8 34.2 3.9 0.7 150.2 27.9 2.2
1.2 197.2 95.7 1.1 0.3 42.3 9.9
Age (y) Male () White () BMI (kg/m2) Current
smoker () Diabetes () Hypertension () TC
(mmol/L mg/dL) LDL-C (mmol/L mg/dL) TG
(mmol/L mg/dL) HDL-C (mmol/L mg/dL)
56.69.2 73 87 30.55.6 27 18 70 6.0 0.9
232.6 34.1 3.9 0.7 150.2 25.9 2.2
1.1 197.7 105.6 1.1 0.3 42.9 11.4
Mean SD.
15
Change From Baseline in Lipid Parameters
10
2.9
5.6
0
-6.8
-10
-20
-18.4
Change from baseline ()
-20.0
Pravastatin
-25.2
-30
Atorvastatin
-34.1
-40
-46.3
-50
TC
LDL-C
TGs
HDL-C
P lt 0.001 vs pravastatin.
Data are mean percent change from baseline to
18-month follow-up.
16
Primary End Point Percent Change in TAV
3
2.7
2
Change in TAV ()
1
0
-0.4
-1
Pravastatin
Atorvastatin
No significant change frombaseline
atheroscleroticprogression was stopped
Significant atheroscleroticprogression from
baseline
Progression vs baseline (P 0.001) No change
vs baseline (P 0.98).
17
Secondary Efficacy Parameters
Nominal change in TAV
Change in PAV
P 0.02
5
1.8
1.6
4.4
1.6
4
1.5
3
1.2
2

mm3
0.9
1
0.6
0
0.2
0.2
0.3
-1
-0.9
-0.9
0
-2
Pravastatin
Atorvastatin
Pravastatin
Atorvastatin
Progression vs baseline (P 0.01).No change
vs baseline (P 0.72).
Progression vs baseline (P lt 0.001).No change
vs baseline (P 0.18).
18
Change in CRP Levels From Baseline
CRP (mg/L)
Atorvastatin
Pravastatin
2.8
3.0
Baseline
1.8
2.9
18 months
0
-5.2
-10
Change ()
-20
-30
-36.4
-40
Atorvastatin
Pravastatin
P lt 0.001 vs pravastatin.
19
Nominal Change in TAV for 10-mm Vessel Subsegment
With Greatest Disease Severity
0
-1
-1.2
-2
mm3
-3
-4
-4.2
-5
P 0.01
Atorvastatin
Pravastatin
Regression vs baseline (P 0.049).
Regression vs baseline (P lt 0.001).
20
Selected Prespecified Subgroup Analyses
5
4.8
4
3.9
3.2
3.2
3
2.5
2.3
2.1
2
1
0.7
0.7
0.5
0.2
Change in TAV ()
0
-0.2
-1
-0.8
-1.2
-1.5
-2
-2.3
-3
-4
? Median
Yes
No
Yes
No
lt Median
Male
Female
Diabetes
Metabolic syndrome
Age
Gender
P ? 0.01 for progression. P ? 0.05 for
progression. P NS for progression.
Atorvastatin
Pravastatin
21
Percent Change in TAV Among Patients Reaching
NCEP ATP III Goal
Subgroup reaching NCEP ATP III goal (lt 2.59
mmol/L 100 mg/dL) 161/249 (65) pravastatin
patients (mean LDL-C 2.27 mmol/L 87.5
mg/dL) 246/253 (97) atorvastatin patients (mean
LDL-C 1.75 mmol/L 67.7 mg/dL)
3
1.9
2
Change in TAV ()
1
0
-1
-0.9
Pravastatin
Atorvastatin
Significant atherosclerotic progression from
baseline occurred even among pravastatin patients
reaching NCEP ATP III goal
Progression vs baseline (P 0.01) No change
vs baseline (P 0.93).
22
Comparison of LDL-C Reduction and Change in
Atheroma Volume
Both treatment groups (n 502)
20
15
10
5
Change in atheroma volume (mm3)
0
-5
-10
-15
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
change in LDL-C
Regardless of the agent used, an LDL-C reduction
of at least 50 was required to halt progression
The dashed lines indicate upper and lower 95 CIs
for the mean values.Nissen SE, et al. JAMA.
20042911071-1080.
23
Comparison of LDL-C Reduction and Change in
Atheroma Volume
Pravastatin group (n 249)
Atorvastatin group (n 253)
20
15
10
5
Change in atheroma volume (mm3)
0
-5
-15
-20
change in LDL-C
Patients receiving pravastatin who experienced
LDL-C reductions gt 50 continued to show disease
progression
The progression rate at any level of LDL-C
reduction was lower with atorvastatin than with
pravastatin
The dashed lines indicate upper and lower 95 CIs
for the mean values.Nissen SE, et al. JAMA.
20042911071-1080.
24
SafetyAEs
Pravastatin 40 mg (n 327)
Atorvastatin 80 mg
(n 327)
Cardiovascular end point
1 (0.3)
1 (0.3)
Death (any cause), n ()
7 (2.1)
4 (1.2)
MI, n ()
1 (0.3)
1 (0.3)
Stroke, n ()
Laboratory abnormality
5/316 (1.6)
7/311 (2.3)
ALT gt 3 ? ULN, n ()
2/316 (0.6)
2/311 (0.6)
AST gt 3 ? ULN, n ()
0/316 (0)
0/311 (0)
CPK gt 10 ? ULN, n ()

• Rates of CV end points were similar between
  groups
• Rates of liver- and muscle-enzyme
  abnormalities were low and similar between groups

25
SafetyDrug Discontinuations
Pravastatin 40 mg (n 327)
Atorvastatin 80 mg
(n 327)
22 (6.7)
21 (6.4)
Drug discontinuation, n ()
Musculoskeletal complaint, n ()
12 (3.4)
9 (2.8)
3 (0.9)
Abdominal complaint, n ()
5 (1.5)
0
Cancer, n ()
2 (0.6)
0
Chest pain, n ()
2 (0.6)
4 (1.2)
ALT/AST lt 3 ? ULN, n ()
0
5 (1.5)
Other, n ()
1 (0.6)
26
Summary and Conclusions
Treatment with atorvastatin stopped further
progression of atherosclerosis

• First large-scale trial to compare the impact of
  2 statins on atherosclerotic disease progression
  by using IVUS, a more sensitive approach than
  QCA, to measure plaque burden
• There was no change in TAV in the atorvastatin
  80-mg group, indicating that atorvastatin stopped
  the progression of atherosclerosis
• Atorvastatin significantly impacted LDL-C, TGs,
  and the biomarker CRP to a greater extent than
  did pravastatin
• The safety profile of atorvastatin 80 mg was
  comparable to that of pravastatin 40 mg

27

• LIPITOR (atorvastatin calcium) is indicated as an
  adjunct to diet to reduce elevated total
  cholesterol, LDL-cholesterol, apo B, and TG
  levels and to increase HDL-cholesterol in
  patients with primary hypercholesterolemia
  (heterozygous familial) or combined
  hyperlipidemia.
• In clinical trials, the most common adverse
  events were constipation, flatulence, dyspepsia
  and abdominal pain, headache, nausea, myalgia,
  asthenia, diarrhea, insomnia.
• LIPITOR is contraindicated in patients with
  hypersensitivity to any component of this
  medication in patients with active liver disease
  or unexplained persistent elevation of serum
  transaminases myopathy in women during
  pregnancy, in nursing mothers, and in women of
  child-bearing potential not using appropriate
  contraceptive measures.
• Liver function tests should be performed before
  the initiation of treatment, at 6 and 12 weeks
  after initiation of therapy or elevation in dose,
  and periodically thereafter. LIPITOR should be
  used with caution in patients who consume
  substantial quantities of alcohol and/or have a
  history of liver disease. LIPITOR therapy should
  be discontinued if markedly elevated CPK levels
  occur or myopathy is diagnosed or suspected.

28
 
0  

• LIPITOR is available in 10-mg, 20-mg, 40-mg, and
  80-mg film-coated tablets, administered once
  daily.
• For further information please see prescribing
  information.
• Lip01FE05

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