Atorvastatin Versus Revascularization Treatments (AVERT) Trial Presented at The American Heart Association Scientific Sessions 1998 Presented by Dr. Bertram Pitt AVERT Trial

AVERT Trial: Background The goal of the AVERT trial was to assess the effect of aggressive lipid-lowering therapy on ischemic events in low-risk patients with single- or double- vessel CAD.The goal of the AVERT trial was to assess the effect of aggressive lipid-lowering therapy on ischemic events in low-risk patients with single- or double- vessel CAD. Presented atAHA 1998 Presented at AHA 1998

AVERT Trial: Study Design  Primary Endpoint: Occurrence of ischemic events (death, nonfatal MI, cerebral vascular accident, CABG, angioplasty, hospitalization due to worsening angina).  Secondary Endpoint: Time to first ischemic event.  Primary Endpoint: Occurrence of ischemic events (death, nonfatal MI, cerebral vascular accident, CABG, angioplasty, hospitalization due to worsening angina).  Secondary Endpoint: Time to first ischemic event. High-dose atorvastatin and usual medical therapy n=164 n=164 Angioplasty + usual care, including standard lipid lowering n=177 n= patients with documented single- or double-vessel CAD, > 50% stenosis in target lesion, high LDL (>115 mg/dL or > 3.0 mmol/L), LVEF >40%, able to exercise >4 minutes on a Bruce protocol or bicycle exercise protocol without developing ischemia 341 patients with documented single- or double-vessel CAD, > 50% stenosis in target lesion, high LDL (> 115 mg/dL or > 3.0 mmol/L), LVEF > 40%, able to exercise > 4 minutes on a Bruce protocol or bicycle exercise protocol without developing ischemia 16% female, mean age 58 years, mean follow-up 18 months, mean EF 61% 341 patients with documented single- or double-vessel CAD, > 50% stenosis in target lesion, high LDL (>115 mg/dL or > 3.0 mmol/L), LVEF >40%, able to exercise >4 minutes on a Bruce protocol or bicycle exercise protocol without developing ischemia 341 patients with documented single- or double-vessel CAD, > 50% stenosis in target lesion, high LDL (> 115 mg/dL or > 3.0 mmol/L), LVEF > 40%, able to exercise > 4 minutes on a Bruce protocol or bicycle exercise protocol without developing ischemia 16% female, mean age 58 years, mean follow-up 18 months, mean EF 61% Pitt B et al. N Engl J Med. 1999;341: Months

Pitt B et al. N Engl J Med. 1999;341: McCormick LS et al. Am J Cardiol. 1997;80: AVERT: Major Exclusion Criteria Left main disease or 3-vessel diseaseLeft main disease or 3-vessel disease Unstable anginaUnstable angina MI within previous 14 daysMI within previous 14 days Known ejection fraction <40% or NYHA Class III or IV heart failureKnown ejection fraction <40% or NYHA Class III or IV heart failure Previous CABG, unless grafts were patent and patient did not have 3-vessel diseasePrevious CABG, unless grafts were patent and patient did not have 3-vessel disease CABG recommended based on current angiogramCABG recommended based on current angiogram Percutaneous revascularization in previous 6 monthsPercutaneous revascularization in previous 6 months Known hypersensitivity to HMG-CoA reductase inhibitorsKnown hypersensitivity to HMG-CoA reductase inhibitors AST/ALT >2 x ULNAST/ALT >2 x ULN CPK >3 x ULN or unexplained elevationsCPK >3 x ULN or unexplained elevations

Pitt B et al. N Engl J Med. 1999;341: McCormick LS et al. Am J Cardiol. 1997;80: AVERT: Overview of Study Procedures Treatment phase Patients randomized to atorvastatinPatients randomized to atorvastatin –discontinued other lipid-lowering medication and immediately began atorvastatin 80 mg/d Patients randomized to angioplasty/usual care (UC)Patients randomized to angioplasty/usual care (UC) –underwent angioplasty followed by “usual care” usual care may or may not have included lipid-lowering therapy (eg, diet, behavior modification, or medication)usual care may or may not have included lipid-lowering therapy (eg, diet, behavior modification, or medication) angioplasty may or may not have included stentingangioplasty may or may not have included stenting usual care was determined by investigator or patient’s primary physicianusual care was determined by investigator or patient’s primary physician

Pitt B et al. N Engl J Med. 1999;341: –angioplasty (other than the original procedure in angioplasty/usual care group) –worsening angina verified by objective evidence resulting in hospitalization CVA=cerebrovascular accident. AVERT: Primary Efficacy Assessment Incidence of an ischemic event in each treatment groupIncidence of an ischemic event in each treatment group Ischemic event was defined as occurrence of one of the following:Ischemic event was defined as occurrence of one of the following: –cardiac death –resuscitation after cardiac arrest –nonfatal MI –CVA –CABG

Pitt B et al. N Engl J Med. 1999;341: McCormick LS et al. Am J Cardiol. 1997;80: AVERT: Secondary Efficacy Assessments Time from randomization to ischemic event Time from randomization to ischemic event Percent change from baseline in TC, LDL-C, HDL-C, TG, apo A1, apo B, and Lp(a) Percent change from baseline in TC, LDL-C, HDL-C, TG, apo A1, apo B, and Lp(a) All-cause mortality All-cause mortality Change from baseline in angina class Change from baseline in angina class Worsening angina with objective evidence Worsening angina with objective evidence Change in quality of life Change in quality of life Economic assessment Economic assessment

Atorvastatin (n=164)Angioplasty/UC (n=177) Age (yr), mean5958 Gender Male130 (79%) 157 (89%) Female34 (21%)20 (11%) Mean ejection fraction61%61% Nature of CHD Single vessel94 (57%)99 (56%) Double vessel70 (43%)78 (44%) Mean % stenosis80%81% Mean no. of risk factors Prior MI73 (45%)70 (40%) Patients with target lesion LAD70 (43%)53 (30%) LCX59 (36%)63 (36%) RCA59 (36%)64 (36%) CCS Angina Class Asymptomatic29 (18%)27 (15%) Class I74 (45%)70 (40%) Class II60 (37%)77 (44%) Class III1 (1%)2 (1%) Class IV0 (0%)1 (1%) Pitt B et al. N Engl J Med. 1999;341: AVERT: Baseline Patient Characteristics

Number (%) of patients experiencing an ischemic event AtorvastatinAngioplasty/UC n=164n=177%  Any Ischemic event22 (13) 37 (21) -36* Death1 (0.6)1 (0.6) Resuscitated cardiac arrest0 (0.0)0 (0.0) Nonfatal MI4 (2.4)5 (2.8) CVA0 (0.0)0 (0.0) CABG2 (1.2)9 (5.1) Revascularization18 (11.0)21 (11.9) Worsening angina with objective evidence & hospitalization11 (6.7)25 (14.1) *P=0.048 vs an adjusted significance level of Pitt B et al. N Engl J Med. 1999;341: AVERT: Ischemic Events

*P=0.048 vs an adjusted significance level of atorvastatin vs angioplasty/UC. Data from Pitt B et al. N Engl J Med. 1999;341: AtorvastatinAngioplasty/UC % of patients with an ischemic event 13% 21% -36% difference * (P=0.048) n=22 of 164 n=37 of 177 AVERT: Ischemic Events

P=0.03 Cumulative incidence (%) Time since randomization (months) Pitt B et al. N Engl J Med. 1999;341: Atorvastatin (n=164) Angioplasty/UC (n=177) AVERT: Time to First Ischemic Event

* Significantly different from angioplasty/UC (P<0.05). † Baseline values represented patients at randomization without a washout period from existing lipid-lowering therapy. Note: 73% of angioplasty/UC-treated patients were on lipid-lowering medication. Pitt B et al. N Engl J Med. 1999;341: mg/dL(mmol/L) Atorvastatin end of study Angioplasty/UC baseline † Angioplasty/UC end of study Atorvastatin baseline † 10%  LDL-CTCTGHDL-C 18%  31%  * 46%  * 10%  11%  * 8%  11%  (6.5) (2.6) (3.9) (5.2) (1.3) AVERT: Summary of Lipid Parameters

months >6-18 months Atorvastatin Angioplasty/UC 24% difference 46% difference % of patients with an ischemic event 7% 6% 10% 11% Pitt B et al. N Engl J Med. 1999;341: AVERT: Incidence of First Ischemic Event by Time

Pitt B et al. N Engl J Med. 1999;341: AVERT: Safety Evaluation Elevations in AST or ALT (consecutive elevations >3 x ULN)Elevations in AST or ALT (consecutive elevations >3 x ULN) –4 (2.4%) atorvastatin-treated patients –none in angioplasty/UC-treated patients Elevations in CPK (>10 x ULN)Elevations in CPK (>10 x ULN) –none in either treatment group There were no clinically significant differences in adverse event rates between the two treatment groupsThere were no clinically significant differences in adverse event rates between the two treatment groups –in this study, eight patients discontinued atorvastatin treatment due to an adverse event, seven of which remained in the study

AVERT Trial: Limitations The patients enrolled in the AVERT trial were extremely low-risk, with stable CAD, 1 or 2 vessel CAD, and normal ventricular function.The patients enrolled in the AVERT trial were extremely low-risk, with stable CAD, 1 or 2 vessel CAD, and normal ventricular function. The low-risk patient population randomized to angioplasty in this study may not reflect the population of patients that receive percutaneous interventions in clinical practice.The low-risk patient population randomized to angioplasty in this study may not reflect the population of patients that receive percutaneous interventions in clinical practice. The patients enrolled in the AVERT trial were extremely low-risk, with stable CAD, 1 or 2 vessel CAD, and normal ventricular function.The patients enrolled in the AVERT trial were extremely low-risk, with stable CAD, 1 or 2 vessel CAD, and normal ventricular function. The low-risk patient population randomized to angioplasty in this study may not reflect the population of patients that receive percutaneous interventions in clinical practice.The low-risk patient population randomized to angioplasty in this study may not reflect the population of patients that receive percutaneous interventions in clinical practice. Presented at AHA 1998

AVERT Trial: Limitations (cont.) Although the primary endpoint was clinically interesting, it was not statistically significant after alpha adjustment for interim analyses.Although the primary endpoint was clinically interesting, it was not statistically significant after alpha adjustment for interim analyses. Looking at the KM curves, it appears that the benefit of atorvastatin for ischemic events is not apparent until six months from the onset of therapy Looking at the KM curves, it appears that the benefit of atorvastatin for ischemic events is not apparent until six months from the onset of therapy It could be speculated that this is due to the time required for plaque stabilization and a reduction in new lesion development.It could be speculated that this is due to the time required for plaque stabilization and a reduction in new lesion development. Although the primary endpoint was clinically interesting, it was not statistically significant after alpha adjustment for interim analyses.Although the primary endpoint was clinically interesting, it was not statistically significant after alpha adjustment for interim analyses. Looking at the KM curves, it appears that the benefit of atorvastatin for ischemic events is not apparent until six months from the onset of therapy Looking at the KM curves, it appears that the benefit of atorvastatin for ischemic events is not apparent until six months from the onset of therapy It could be speculated that this is due to the time required for plaque stabilization and a reduction in new lesion development.It could be speculated that this is due to the time required for plaque stabilization and a reduction in new lesion development. Presented at AHA 1998

Reduces ischemic events by 36% Reduces ischemic events by 36% Delays the time to first event Delays the time to first event Is safe Is safe Can delay or prevent the need for percutaneous revascularization Can delay or prevent the need for percutaneous revascularization Pitt B et al. N Engl J Med. 1999;341: Aggressive lipid lowering with atorvastatin in stable CAD patients: AVERT: Conclusions