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Atorvastatin Versus Revascularization Treatments (AVERT) Trial

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

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Atorvastatin Versus Revascularization Treatments (AVERT) Trial

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

  2. 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. Presented atAHA 1998

  3. AVERT Trial: Study Design 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% Angioplasty + usual care, including standard lipid lowering n=177 High-dose atorvastatin and usual medical therapy n=164 18 Months • 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. Pitt B et al. N Engl J Med. 1999;341:70-76.

  4. Left main disease or 3-vessel disease Unstable angina MI within previous 14 days Known ejection fraction <40% or NYHA Class III or IV heart failure Previous CABG, unless grafts were patent and patient did not have 3-vessel disease CABG recommended based on current angiogram Percutaneous revascularization in previous 6 months Known hypersensitivity to HMG-CoA reductaseinhibitors AST/ALT >2 x ULN CPK >3 x ULN or unexplained elevations AVERT: Major Exclusion Criteria Pitt B et al. N Engl J Med. 1999;341:70-76. McCormick LS et al. Am J Cardiol. 1997;80:1130-1133.

  5. AVERT: Overview of Study Procedures Treatment phase • Patients randomized to atorvastatin • discontinued other lipid-lowering medication and immediately began atorvastatin 80 mg/d • 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) • angioplasty may or may not have included stenting • usual care was determined by investigator or patient’s primary physician Pitt B et al. N Engl J Med. 1999;341:70-76. McCormick LS et al. Am J Cardiol. 1997;80:1130-1133.

  6. AVERT: Primary Efficacy Assessment • Incidence of an ischemic event in each treatment group • Ischemic event was defined as occurrence of one of the following: • cardiac death • resuscitation aftercardiac arrest • nonfatal MI • CVA • CABG • angioplasty (other than the original procedure in angioplasty/usual care group) • worsening angina verified by objective evidence resulting in hospitalization CVA=cerebrovascular accident. Pitt B et al. N Engl J Med. 1999;341:70-76.

  7. AVERT: Secondary Efficacy Assessments • Time from randomization to ischemic event • Percent change from baseline in TC, LDL-C, HDL-C, TG, apo A1, apo B, and Lp(a) • All-cause mortality • Change from baseline in angina class • Worsening angina with objective evidence • Change in quality of life • Economic assessment Pitt B et al. N Engl J Med. 1999;341:70-76. McCormick LS et al. Am J Cardiol. 1997;80:1130-1133.

  8. AVERT: Baseline Patient Characteristics • Atorvastatin (n=164) Angioplasty/UC (n=177) • Age (yr), mean 59 58 • Gender • Male 130 (79%) 157 (89%) • Female 34 (21%) 20 (11%) • Mean ejection fraction 61% 61% • Nature of CHD • Single vessel 94 (57%) 99 (56%) • Double vessel 70 (43%) 78 (44%) • Mean % stenosis 80% 81% • Mean no. of risk factors 2.5 2.5 • Prior MI 73 (45%) 70 (40%) • Patients with target lesion • LAD 70 (43%) 53 (30%) • LCX 59 (36%) 63 (36%) • RCA 59 (36%) 64 (36%) • CCS Angina Class • Asymptomatic 29 (18%) 27 (15%) • Class I 74 (45%) 70 (40%) • Class II 60 (37%) 77 (44%) • Class III 1 (1%) 2 (1%) • Class IV 0 (0%) 1 (1%) Pitt B et al. N Engl J Med. 1999;341:70-76.

  9. AVERT: Ischemic Events Number (%) of patients experiencing an ischemic event Atorvastatin Angioplasty/UC n=164 n=177 % Any Ischemic event 22 (13) 37 (21) -36* Death 1 (0.6) 1 (0.6) Resuscitated cardiac arrest 0 (0.0) 0 (0.0) Nonfatal MI 4 (2.4) 5 (2.8) CVA 0 (0.0) 0 (0.0) CABG 2 (1.2) 9 (5.1) Revascularization 18 (11.0) 21 (11.9) Worsening angina with objectiveevidence & hospitalization 11 (6.7) 25 (14.1) *P=0.048 vs an adjusted significance level of 0.045. Pitt B et al. N Engl J Med. 1999;341:70-76.

  10. -36% difference* (P=0.048) 25 21% 20 % of patients with an ischemic event 13% 15 10 5 0 Atorvastatin Angioplasty/UC n=22 of 164 n=37 of 177 AVERT: Ischemic Events * P=0.048 vs an adjusted significance level of 0.045 atorvastatin vs angioplasty/UC. Data from Pitt B et al. N Engl J Med. 1999;341:70-76.

  11. AVERT: Time to First Ischemic Event Angioplasty/UC (n=177) Atorvastatin (n=164) P=0.03 Cumulative incidence (%) Time since randomization (months) Pitt B et al. N Engl J Med. 1999;341:70-76.

  12. AVERT: Summary of Lipid Parameters Atorvastatin baseline† 250 31% * (6.5) 10%  Atorvastatin end of study Angioplasty/UC baseline† Angioplasty/UC end of study 200 11% * (5.2) 46% * 10%  18%  mg/dL (mmol/L) 150 (3.9) 100 (2.6) 8%  11%  50 (1.3) 0 LDL-C TC TG HDL-C *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;341:70-76.

  13. AVERT: Incidence of First Ischemic Event by Time Atorvastatin 20 Angioplasty/UC 46% difference 24% difference 15 11% % of patients with an ischemic event 10% 10 7% 6% 5 0 0-6 months >6-18 months Pitt B et al. N Engl J Med. 1999;341:70-76.

  14. AVERT: Safety Evaluation • 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) • none in either treatment group • There 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 Pitt B et al. N Engl J Med. 1999;341:70-76.

  15. 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 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

  16. AVERT Trial: Limitations (cont.) • 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 • 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

  17. AVERT: Conclusions Aggressive lipid lowering with atorvastatin in stable CAD patients: • Reduces ischemic events by 36% • Delays the time to first event • Is safe • Can delay or prevent the need for percutaneous revascularization Pitt B et al. N Engl J Med. 1999;341:70-76.

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