Transcript Presentation Title

The REVERSAL Trial
Reversing Atherosclerosis
With Aggressive Lipid Lowering
Atherosclerosis: A Progressive Process
PHASE I: Initiation
PHASE II: Progression
PHASE III: Complication
Disease progression
Patients with CHD event (%)
Effects of Lipid-Lowering Therapy on CHD
Events in Statin Trials
Secondary
prevention
4S-P
25
Primary
prevention
20
4S-S
Simvastatin
LIPID-P
15
CARE-P
HPS-P
LIPID-S
10
CARE-S
5
Pravastatin
Lovastatin
WOSCOPS-P
Atorvastatin
WOSCOPS-S
HPS-S
ASCOT-P*
ASCOT-S*
S = statin-treated
P = placebo-treated
AFCAPS-P
AFCAPS-S
*Extrapolated to 5 y
0
90
110
130
150
170
LDL-C (mg/dL)
Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1): S17-S21.
190
210
What Is REVERSAL?
• Multicenter, randomized, double-blind, activecontrolled 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
Progression (MLD decrease), mm/y
Effects of Lipid Lowering With Statins on
Progression of CHD
0.06
Drug
Placebo
PLAC I
0.05
CCAIT
0.04
REGRESS
LCAS
PLAC I
0.03
MARS
CCAIT
0.02
MAAS
MARS
REGRESS
LCAS
0.01
MAAS
0
-40
-30
-20
-10
LDL-C reduction (%)
0
10
REVERSAL: Study Design
Double-blind period
Screening
visit*
Placebo
run-in
phase
*Includes baseline IVUS
Atorvastatin 80 mg/d
Randomization
654 patients
Pravastatin 40 mg/d
18-month follow-up with IVUS
Design: Prospective, multicenter, randomized, double-blind trial
Setting: 34 community and tertiary-care hospitals in the USA
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
REVERSAL: Why Was Pravastatin 40 mg
Used?
• REVERSAL is the first active-controlled, cholesterollowering, 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
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 < 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
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 < 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 implanted
cardiac defibrillator
– Known major hematologic, neoplastic, metabolic, gastrointestinal,
or endocrine dysfunction
What Is TAV?
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
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
REVERSAL: Baseline Characteristics
Characteristic
Atorvastatin 80 mg
(n = 253)
Pravastatin 40 mg
(n = 249)
Age* (y)
55.8 ± 9.8
56.6±9.2
Male (%)
71
73
White (%)
90
87
BMI* (kg/m2)
30.5 ± 6.5
30.5±5.6
Current smoker (%)
26
27
Diabetes (%)
20
18
Hypertension (%)
68
70
TC* (mmol/L [mg/dL])
6.0 ± 0.9][231.8 ± 34.2]
6.0 ± 0.9 [232.6 ± 34.1]
LDL-C* (mmol/L [mg/dL])
3.9 ± 0.7 [150.2 ± 27.9]
3.9 ± 0.7 [150.2 ± 25.9]
TG* (mmol/L [mg/dL])
2.2 ± 1.2 [197.2 ± 95.7]
2.2 ± 1.1 [197.7 ± 105.6]
HDL-C* (mmol/L [mg/dL])
1.1 ± 0.3 [42.3 ± 9.9]
1.1 ± 0.3 [42.9 ± 11.4]
*Mean ± SD.
Change From Baseline in Lipid Parameters
Change from baseline (%)
10
5.6
2.9
0
-6.8
-10
-20
-18.4
-20.0*
Pravastatin
-25.2
-30
Atorvastatin
-34.1*
-40
-46.3*
-50
TC
LDL-C
*P < 0.001 vs pravastatin.
Data are mean percent change from baseline to 18-month follow-up.
TGs
HDL-C
Primary End Point: Percent Change in TAV
P = 0.02
Change in TAV (%)
3
2.7*
2
1
0
-0.4†
-1
Pravastatin
Atorvastatin
Significant atherosclerotic
progression from baseline
No significant change from
baseline; atherosclerotic
progression was stopped
*Progression vs baseline (P = 0.001); †No change vs baseline (P = 0.98).
Secondary Efficacy Parameters
5
Nominal change in TAV
Change in PAV
P = 0.02
P < 0.001
1.8
4.4*
4
1.5
3
1.2
2
%
mm3
1.6*
1.6*
0.9
1
0.6
0
-1
-0.9†
-0.9†
-2
0.2†
0.2†
0.3
0
Pravastatin
Atorvastatin
*Progression vs baseline (P = 0.01).
†No change vs baseline (P = 0.72).
Pravastatin
Atorvastatin
*Progression vs baseline (P < 0.001).
†No change vs baseline (P = 0.18).
Change in CRP Levels From Baseline
CRP (mg/L)
Pravastatin
Atorvastatin
Baseline
3.0
2.8
18 months
2.9
1.8
Change (%)
0
-10
-5.2
-20
-30
-36.4*
-40
Pravastatin
*P < 0.001 vs pravastatin.
Atorvastatin
Nominal Change in TAV for 10-mm Vessel
Subsegment With Greatest Disease Severity
0
-1
-1.2*
mm3
-2
-3
-4
-4.2†
-5
P = 0.01
Pravastatin
*Regression vs baseline (P = 0.049).
†Regression vs baseline (P < 0.001).
Atorvastatin
Selected Prespecified Subgroup Analyses
5
4.8*
3.9*
4
3.2†
3.2*
3
2.5*
Change in TAV (%)
2.3†
2
1
0.7‡
0.7‡
0.5‡
2.1‡
0.2‡
0
-0.2‡
-1
-0.8‡
-1.5‡
-2
-1.2‡
-2.3‡
-3
-4
< Median  Median
Age
*P  0.01 for progression.
†P  0.05 for progression.
‡ P = NS for progression.
Male Female
Gender
Pravastatin
Yes
No
Diabetes
Atorvastatin
Yes
No
Metabolic syndrome
Percent Change in TAV Among Patients
Reaching NCEP ATP III Goal
Change in TAV (%)
3
2
Subgroup reaching NCEP ATP III goal (< 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])
1.9*
1
0
-0.9†
-1
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).
Change in atheroma volume (mm3)
Comparison of LDL-C Reduction and Change
in Atheroma Volume
Both treatment groups (n = 502)
20
15
10
5
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. 2004;291:1071-1080.
Change in atheroma volume (mm3)
Comparison of LDL-C Reduction and Change
in Atheroma Volume
Pravastatin group (n = 249)
Atorvastatin group (n = 253)
20
15
10
5
0
-5
-15
-20
-80 -70 -60 -50 -40 -30 -20 -10
0
10
20
-80 -70 -60 -50 -40 -30 -20 -10
0
10
% change in LDL-C
Patients receiving pravastatin who experienced
LDL-C reductions > 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. 2004;291:1071-1080.
20
Safety—AEs
Atorvastatin 80 mg
(n = 327)
Pravastatin 40 mg
(n = 327)
Death (any cause), n (%)
1 (0.3%)
1 (0.3%)
MI, n (%)
4 (1.2%)
7 (2.1%)
Stroke, n (%)
1 (0.3%)
1 (0.3%)
ALT > 3  ULN, n (%)
7/311 (2.3%)
5/316 (1.6%)
AST > 3  ULN, n (%)
2/311 (0.6%)
2/316 (0.6%)
0/311 (0%)
0/316 (0%)
Cardiovascular end point
Laboratory abnormality
CPK > 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
Safety—Drug Discontinuations
Atorvastatin 80 mg
(n = 327)
Pravastatin 40 mg
(n = 327)
21 (6.4)
22 (6.7)
Musculoskeletal complaint, n (%)
9 (2.8)
12 (3.4)
Abdominal complaint, n (%)
3 (0.9)
5 (1.5)
Cancer, n (%)
0
2 (0.6)
Chest pain, n (%)
0
2 (0.6)
ALT/AST < 3  ULN, n (%)
4 (1.2)
0
Other, n (%)
5 (1.5)
1 (0.6)
Drug discontinuation, n (%)
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
• 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.
LIPITOR is available in 10-mg, 20-mg, 40-mg, and 80-mg filmcoated tablets, administered once daily.
For further information please see prescribing information.
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