The REVERSAL Trial Reversing Atherosclerosis With Aggressive Lipid Lowering

Atherosclerosis: A Progressive Process Disease progression PHASE I: Initiation PHASE II: ProgressionPHASE III: Complication

Effects of Lipid-Lowering Therapy on CHD Events in Statin Trials Patients with CHD event (%) S = statin-treated P = placebo-treated *Extrapolated to 5 y 4S-P CARE-P LIPID-P 4S-S WOSCOPS-S -P AFCAPS-P -S LIPID-S CARE-S Primary prevention Simvastatin Pravastatin Lovastatin Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1): S17-S21. HPS-S -P Atorvastatin ASCOT-S * -P * Secondary prevention LDL-C (mg/dL)

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 CHD MARS MAAS CCAIT PLAC I REGRESS LCAS MARS MAAS LCAS CCAIT PLAC I LDL-C reduction (%) Progression (MLD decrease), mm/y REGRESS DrugPlacebo

Screening visit* Atorvastatin 80 mg/d Pravastatin 40 mg/d REVERSAL: 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 Placebo run-in phase Randomization 654 patients

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, 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 Population Inclusion criteria: –Patients requiring diagnostic coronary angiography for a clinical indication –Aged 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

Age* (y) Male (%) White (%) BMI* (kg/m 2 ) 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 ± ± ± 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 Characteristics 56.6± ± ± 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 < vs pravastatin. Data are mean percent change from baseline to 18-month follow-up Atorvastatin Change From Baseline in Lipid Parameters -50 Change from baseline (%) TCLDL-C * -34.1* * TGsHDL-C Pravastatin

2.7* Pravastatin Significant atherosclerotic progression from baseline -0.4 † Atorvastatin No significant change from baseline; atherosclerotic progression was stopped Primary End Point: Percent Change in TAV Change in TAV (%) *Progression vs baseline (P = 0.001); † No change vs baseline (P = 0.98). P = 0.02

0.2† Atorvastatin 1.6* Pravastatin Atorvastatin 4.4* Pravastatin Nominal change in TAV *Progression vs baseline (P = 0.01). † No change vs baseline (P = 0.72) *Progression vs baseline (P < 0.001). † No change vs baseline (P = 0.18). Change in PAV † P = 0.02 P < % mm 3 Secondary Efficacy Parameters -0.9 † 1.6* 0.2 †

-36.4* Atorvastatin -5.2 Pravastatin Change in CRP Levels From Baseline Change (%) *P < vs pravastatin months Baseline AtorvastatinPravastatin CRP (mg/L)

*Regression vs baseline (P = 0.049). † Regression vs baseline (P < 0.001). P = † * Atorvastatin Pravastatin mm 3 Nominal Change in TAV for 10-mm Vessel Subsegment With Greatest Disease Severity

0.5 ‡ -1.5 ‡ 0.7 ‡ -2.3 ‡ AtorvastatinPravastatin < Median  Median MaleFemale AgeGender -0.2 ‡ 4.8* 2.3 † 3.9 * Change in TAV (%) *P  0.01 for progression. † P  0.05 for progression. ‡ P = NS for progression. YesNoYesNo DiabetesMetabolic syndrome 0.7 ‡ -0.8 ‡ -1.2 ‡ 0.2 ‡ 3.2 † 2.5* 2.1 ‡ 3.2* Selected Prespecified Subgroup Analyses

Percent 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 Change in TAV (%) Pravastatin * † Atorvastatin 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 Volume % change in LDL-C Change in atheroma volume (mm 3 ) 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:

Comparison of LDL-C Reduction and Change in Atheroma Volume 20 Change in atheroma volume (mm 3 ) % change in LDL-C Pravastatin group (n = 249)Atorvastatin group (n = 253) 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:

Safety—AEs Pravastatin 40 mg (n = 327) Atorvastatin 80 mg (n = 327) 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 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 (%) 0 4 (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 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 ניאופרם בע"מ בית ניאופרם, רח' השילוח 8, ת.ד פתח תקוה 49170, טל , פקס , E- 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