The REVERSAL TrialThe REVERSAL TrialReversing Atherosclerosis With Aggressive Lipid LoweringReversing Atherosclerosis With Aggressive Lipid Lowering

Atherosclerosis: A Progressive ProcessAtherosclerosis: A Progressive Process

Disease progression

PHASE I: Initiation PHASE II: Progression PHASE III: Complication

Effects of Lipid-Lowering Therapy on CHD Events in Statin TrialsEffects of Lipid-Lowering Therapy on CHD Events in Statin Trials

25

20

15

10

5

0

Pat

ien

ts w

ith

CH

D e

ven

t (%

)

90 110 130 150 170 190 210

S = statin-treated P = placebo-treated

*Extrapolated to 5 y

4S-P

CARE-P

LIPID-P4S-S

WOSCOPS-SWOSCOPS-P

AFCAPS-PAFCAPS-S

LIPID-S

CARE-S

Primary prevention

Simvastatin

Pravastatin

Lovastatin

Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1): S17-S21.

HPS-S

HPS-P

Atorvastatin

ASCOT-S*ASCOT-P*

Secondary prevention

LDL-C (mg/dL)

What Is REVERSAL?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

Effects of Lipid Lowering With Statins on Progression of CHDEffects of Lipid Lowering With Statins on Progression of CHD

0

0.01

0.02

0.03

0.04

0.05

0.06

-40 -30 -20 -10 0 10

MARS

MAAS

CCAIT

PLAC I

REGRESS

LCAS

MARS MAAS

LCAS

CCAIT

PLAC I

LDL-C reduction (%)

Pro

gre

ssio

n (

ML

D d

ecre

ase)

, m

m/y

REGRESS

Drug Placebo

ScreeningScreeningvisit*visit*

Atorvastatin 80 mg/d

Pravastatin 40 mg/d

REVERSAL: Study DesignREVERSAL: Study Design

Design: Prospective, multicenter, randomized, double-blind trial

Setting: 34 community and tertiary-care hospitals in the USA

Double-blind period

18-month follow-up with IVUS*Includes baseline IVUS

PlaceboPlaceborun-inrun-inphasephase

Randomization

654 patients

REVERSAL: Study ObjectiveREVERSAL: 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: 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

REVERSAL: Patient PopulationREVERSAL: 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 PopulationREVERSAL: 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 implantedcardiac defibrillator

– Known major hematologic, neoplastic, metabolic, gastrointestinal, or endocrine dysfunction

What Is TAV?What Is TAV?

REVERSAL: Primary Efficacy ParameterREVERSAL: 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 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

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])

55.8 ± 9.8

71

90

30.5 ± 6.5

26

20

68

6.0 ± 0.9][231.8 ± 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]

Characteristic Atorvastatin 80 mg(n = 253)

REVERSAL: Baseline CharacteristicsREVERSAL: Baseline Characteristics

56.6±9.2

73

87

30.5±5.6

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]

Pravastatin 40 mg(n = 249)

*Mean ± SD.

*P < 0.001 vs pravastatin.

Data are mean percent change from baseline to 18-month follow-up.

-40

-30

-20

-10

0

10

Atorvastatin

Change From Baseline in Lipid Parameters Change From Baseline in Lipid Parameters

-50

Ch

ang

e fr

om

bas

elin

e (%

)

TC LDL-C

-25.2

-18.4

5.6

-6.8

-46.3*

-34.1*

2.9

-20.0*

TGs HDL-C

Pravastatin

2.7*

Pravastatin

Significant atheroscleroticprogression from baseline

-0.4†

Atorvastatin

No significant change frombaseline; atheroscleroticprogression was stopped

Primary End Point: Percent Change in TAVPrimary End Point: Percent Change in TAVC

han

ge

in T

AV

(%

)

-1

0

1

2

3

*Progression vs baseline (P = 0.001); †No change vs baseline (P = 0.98).

P = 0.02

0.2†

Atorvastatin

1.6*

PravastatinAtorvastatin

4.4*

Pravastatin

Nominal change in TAV

*Progression vs baseline (P = 0.01).†No change vs baseline (P = 0.72).

0

0.3

0.6

0.9

1.2

1.5

1.8

*Progression vs baseline (P < 0.001).†No change vs baseline (P = 0.18).

Change in PAV

-2

-1

0

1

2

3

4

5

-0.9†

P = 0.02 P < 0.001

%

mm

3

Secondary Efficacy ParametersSecondary Efficacy Parameters

-0.9†

1.6*

0.2†

-36.4*

Atorvastatin

-5.2

Pravastatin

Change in CRP Levels From Baseline Change in CRP Levels From Baseline C

han

ge

(%)

*P < 0.001 vs pravastatin.

-40

-30

-20

-10

0

1.82.918 months

2.83.0Baseline

AtorvastatinPravastatin

CRP (mg/L)

*Regression vs baseline (P = 0.049). †Regression vs baseline (P < 0.001).

P = 0.01

-4.2†

-5

-4

-3

-2

-1

0

-1.2*

AtorvastatinPravastatin

mm

3Nominal Change in TAV for 10-mm Vessel Subsegment With Greatest Disease SeverityNominal Change in TAV for 10-mm Vessel Subsegment With Greatest Disease Severity

0.5‡

-1.5‡

0.7‡

-2.3‡

AtorvastatinPravastatin

< Median Median Male FemaleAge Gender

-0.2‡

4.8*

2.3†

3.9*

Ch

ang

e in

TA

V (

%)

*P 0.01 for progression.†P 0.05 for progression.‡ P = NS for progression.

Yes No Yes NoDiabetes Metabolic syndrome

0.7‡

-0.8‡

-1.2‡

0.2‡

3.2†

2.5*2.1‡

3.2*

0

1

2

3

4

5

-1

-2

-3

-4

Selected Prespecified Subgroup AnalysesSelected Prespecified Subgroup Analyses

Percent Change in TAV Among Patients Reaching NCEP ATP III GoalPercent Change in TAV Among Patients Reaching NCEP ATP III Goal

*Progression vs baseline (P = 0.01); †No change vs baseline (P = 0.93).

Significant atherosclerotic progression from baseline occurred even among pravastatin patients reaching NCEP ATP III goal

Ch

ang

e in

TA

V (

%)

Pravastatin

0

1

21.9*

3

-0.9†

Atorvastatin

-1

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])

Comparison of LDL-C Reduction and Change in Atheroma VolumeComparison of LDL-C Reduction and Change in Atheroma Volume

% change in LDL-C

20

15

10

5

0

-5

-10

-15Ch

ang

e in

ath

ero

ma

volu

me

(mm

3 )

-80 -70 -60 -50 -40 -30 -20 -10 0 10 20

Both treatment groups (n = 502)

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.

Comparison of LDL-C Reduction and Change in Atheroma VolumeComparison of LDL-C Reduction and Change in Atheroma Volume

20

Ch

ang

e i

n a

ther

om

a vo

lum

e (m

m3)

% change in LDL-C

15

10

5

0

-5

-15

-20

Pravastatin group (n = 249) Atorvastatin group (n = 253)

-80 -70 -60 -50 -40 -30 -20 -10 0 10 20 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20

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.

Safety—AEsSafety—AEs

Pravastatin 40 mg (n = 327)

Atorvastatin 80 mg (n =

327)

1 (0.3%)1 (0.3%)Stroke, n (%)

2/316 (0.6%)2/311 (0.6%)AST > 3 ULN, n (%)

5/316 (1.6%)7/311 (2.3%)ALT > 3 ULN, n (%)

0/316 (0%)

7 (2.1%)

1 (0.3%)

0/311 (0%)CPK > 10 ULN, n (%)

Laboratory abnormality

4 (1.2%)MI, n (%)

1 (0.3%)Death (any cause), n (%)

Cardiovascular end point

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

Safety—Drug DiscontinuationsSafety—Drug Discontinuations

22 (6.7)21 (6.4)Drug discontinuation, n (%)

Pravastatin 40 mg (n = 327)

Atorvastatin 80 mg (n =

327)

2 (0.6)0 Cancer, n (%)

04 (1.2) ALT/AST < 3 ULN, n (%)

2 (0.6)0 Chest pain, n (%)

1 (0.6)

5 (1.5)

12 (3.4)

5 (1.5) Other, n (%)

3 (0.9) Abdominal complaint, n (%)

9 (2.8) Musculoskeletal complaint, n (%)

Summary and Conclusions Summary and Conclusions

• 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

Treatment with atorvastatin stopped further progression of atherosclerosis

• 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.

0 

 

פתח תקוה 7063, ת.ד. 8 בית ניאופרם, רח' השילוח ניאופרם בע"מ49170,

-E, 03 9373716, פקס.03 9373737 טל-mail:Neopharm@Neopharmisrael.com

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