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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

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
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

avert trial study design
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.

avert major exclusion criteria
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.

avert overview of study procedures
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.

avert primary efficacy assessment
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.

avert secondary efficacy assessments
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.

avert baseline patient characteristics
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.

avert ischemic events
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.

avert ischemic events10

-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.

avert time to first ischemic event
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.

avert summary of lipid parameters
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.

avert incidence of first ischemic event by time
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.

avert safety evaluation
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.

avert trial limitations
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

avert trial limitations cont
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

avert conclusions
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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