The Benefit of Statin Therapy

Before and After Coronary

Revascularization

C. Michael Gibson, MS, MD

Beth Israel Deaconess Medical Center
Boston, MA
 ARMYDA Trial
Peak CK-MB Peak Troponin I
p = 0.007 p = 0.0008
ng/mL

ng/mL

Atorvastatin Placebo Atorvastatin Placebo

Circulation 2004;110:674-8
 ARMYDA-ACS Trial: Background

• The original ARMYDA study showed a reduction in

peri-procedural MI with atorvastatin pre-treatment
in a low-risk, stable angina, elective PCI
population.

• The goal of the trial was to evaluate the effect of

atorvastatin compared with placebo among
patients with acute coronary syndromes (ACS)
undergoing percutaneous coronary intervention
(PCI).

ACC 2007
 ARMYDA-ACS Trial: Study Design
171 patients with non-ST-segment elevation ACS sent to early coronary angiography
within 48 hours.
Placebo-controlled. Double-blind. Randomized. Mean follow-up 30 days.
Atorvastatin (40mg) indefinitely; Clopidogrel (75mg/day) 6 mos. post-PCI; Aspirin (100mg/day) indefinitely
Mean age 66 years. 21% female
Clopidogrel (600mg) loading
R dose at least 3h pre-PCI

Atorvastatin Matching Placebo

(80mg 12h pre-PCI; 40mg (80mg 12h pre-PCI; 40mg
immediately pre-PCI) immediately pre-PCI)
n=86 n=85

30 day follow-up

 Primary Endpoint: 30 day major adverse cardiac events (MACE), defined

as death, myocardial infarction (MI), or unplanned revascularization
 Secondary Endpoint: Post-procedural increase of markers of myocardial
injury above the upper limit of normal (CK-MB, troponin-I, myoglobin);
post-procedural variations from baseline CRP levels.
ACC 2007
 ARMYDA-ACS Trial: Primary Endpoint

Occurrence of MACE at 30 days

• Death, MI, or
unplanned
revascularization
MACE (%)

was lower in the

p = 0.01 atorvastatin (5%)
group vs. placebo
group (17%) (p=0.01).

• This was driven by a

reduction in peri-
n = 86 n = 85 procedural MI for the
atorvastatin group
(5% vs. 15%, p=0.04).

ACC
 ARMYDA-ACS Trial: Secondary Endpoint
Patients (%) with elevated levels
of CKMB and Troponin-I post-PCI • Post-PCI CKMB
p = 0.039 elevations occurred
in fewer patients in
the atorvastatin
group than in the
Patients with Post-PCI

placebo group (7%

elevation (%)

p = 0.001
vs. 27%, p=0.001).

•Troponin-I elevation
also occurred in
fewer patients in the
atorvastatin group
n = 86 n = 85 n = 86 n = 85
than in the placebo
group (41% vs. 58%,
p=0.039).

ACC
 ARMYDA-ACS Trial: Secondary Endpoint
Percent increase in CRP from pre to post-PCI

• The percent
Increase in CRP from baseline (%)

increase in CRP
p = 0.01 from baseline
was lower in the
atorvastatin
group (63%) than
in the placebo
group (147%)
n = 86 n = 85
(p=0.01).

ACC 2007
 ARMYDA-ACS Trial: Limitations

• The optimal timing of a pre-treatment atorvastatin

load is unknown, as is the impact of delaying PCI
to pre-treat with atorvastatin in an ACS
population.

• Pre-treatment in the present study was for 12

hours, with a mean time to PCI of 23 hours.
However, in an unstable population, time to
revascularization is often shorter.

ACC
 Meta-Analysis of the Role of Statin
Therapy in Reducing Myocardial
Infarction Following Elective
Percutaneous Coronary
Intervention

Girish R. Mood, MD; Anthony A. Bavry, MD, MPH; Henri Roukoz,

MD; and Deepak L. Bhatt, MD
 Methods

• Mood et al. selected studies that randomized

patients who underwent elective PCI to statin
therapy versus placebo / usual care.
• To be included, statin therapy was required to be
initiated around the time of coronary intervention,
and individual outcome data were required to be
collected.
• The primary end point was MI.
• The secondary end points were all-cause
mortality, cardiovascular mortality, surgical or
percutaneous revascularization, and stroke.

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

 Studies Included in Meta-Analysis

• 6 studies were selected:

 PREDICT- Prevention of Restenosis by Elisor After
Transluminal Coronary Angioplasty
 FLARE- Fluvastatin Angioplasty Restenosis
 GAIN- German Atorvastatin Intravascular
Ultrasound
 LIPS- Lescol Intervention Prevention Study
 ARMYDA- Atorvastatin for Reduction of
Myocardial Damage During Angioplasty
 Briguori et al- Randomized 3,941 patients (1,967 to
statins and 1,974 to placebos)

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

 Cholesterol Data of Study Participants
(Statin Arm/ Placebo Arm)
Variable PREDICT FLARE GAIN LIPS ARMYDA Briguori
et al
Baseline
Total cholesterol 228/231 222/223 228/242 200/199 -- 197/196
(mg/dl)
LDL cholesterol 155/157 153/153 155/166 131/132 -- 121/122
(mg/dl)
Follow-up
Total cholesterol 195/239 -- 156/215 -- -- 168/193*
(mg/dl)
LDL cholesterol 119/159 102/149 86/140 95/147 -- 93/121*
(mg/dl)

* Level at index procedure

LDL = low-density lipoprotein

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

 Odds of MI after PCI

Odds Ratio
95% CI

PREDICT
FLARE
GAIN
LIPS

ARMYDA
Briguori

Overall OR=0.57
(0.42-0.78)

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

 Cumulative Cardiovascular Mortality Results

• The cumulative incidence of cardiovascular

mortality in patients among the statin group vs
placebo group was 0.71% vs 1.2%, respectively
(OR 0.58, 95% CI 0.30 to 1.11, p=0.10).
• The weighted mean duration of follow-up was
20.6 months, and the absolute difference between
the groups was 0.8% ( p = 0.10).

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

 Cumulative Repeat Surgical or Percutaneous
Revascularization

• Among the patients randomized to statin therapy

versus placebo, the cumulative incidence of
repeat surgical or percutaneous revascularization
was 19.6% vs 21.9%, respectively (OR 0.89, 95%
CI 0.78 to 1.02, p = 0.098).
• The weighted mean duration of follow-up was
22.7 months, and the absolute difference between
the groups was 2.3% ( p = 0.098).

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

 Limitations

• The follow-up periods ranged from 1 day to 45

months, making it difficult to assess the long-term
benefits of statin therapy.

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

 Conclusion

• Statin therapy initiated at the time of elective PCI

significantly reduces myocardial infarction.

• The reduction in MI appeared to occur early and

was sustained late after PCI. It is possible that the
initiation of statin therapy before PCI may be
preferential to initiation after the procedure.

Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23

Intensive Lipid Lowering and TVR (Clinical Restenosis)
and Non-TVR (Lesion Progression)
TVR Non-TVR
p = 0.001 p = 0.012
MV O.R. 0.63, p=0.001* MV O.R. 0.87, p=0.364*

16.0%
11.3%

11.6% 8.5%
%

(167/1440) (227/1420) (122/1440) (227/1420)

Atorva 80 mg Prava 40 mg Atorva 80 mg Prava 40 mg

* MV model adjusted for on treatment LDL Gibson CM, ACC 2005

 Association of Statin Use with Myocardial
Perfusion After Fibrinolysis
p=0.004 p=0.003

N= 429 N= 49 N=367 N=44

* Statin use within 2 weeks

Gibson CM 2004
 Simvastatin Prior to CABG is Associated with Improved
Post Operative Flow on PET Scanning

48.6
Improvement in PET Blood Flow

p<0.001

9.6
3.8
1.3
Non- Bypassed Bypassed Non- Bypassed Bypassed
Segment Segment Segment Segment
Placebo Simvastatin
Dotani, … Gibson Am J Cardio 2003; 91: 1107-9
 1 Year MACE After CABG: Comparison of Statin vs Other Lipid-
Lowering Agent Before CABG

Post-operative incidence of Death, MI,

Unstable angina, Arrhythmia, CHF, Stroke

57%
% Occurrence AE

The risk of
p<0.0001 Death/MI was
reduced from 8%
to 0% (p=0.01)
18%

No statin Statin

Dotani, … Gibson et al Am J Cardio 2003

 ARMYDA-3 Trial: Primary Endpoint

Post-operative occurrence of atrial

fibrillation (%) p=0.003
200 patients undergoing
elective cardiac surgery
were randomized to
% Occurrence AF

either atorvastatin or
placebo beginning 7
days before the
operation
Placebo-controlled.
Randomized. Blinded
Patients had no previous
history of statin
treatment or atrial
fibrillation

Presented at ACC 2006

 Mechanisms by Which Statins Reduce Reperfusion Injury

• Reduce monocyte CD11b expression and monocyte adhesion to

the endothelium in patients independent of cholesterol-lowering
effect CD11b is the α-chain of the β2-integrins, which promote
firm adhesion of leukocytes to the endothelium

• Inhibit neutrophil and monocyte chemotaxis

• Upregulation of endothelial NO synthesis or inhibit hypoxia-

mediated inhibition of NOS
NO has been shown to act as a physiological inhibitor of
leukocyte– endothelial cell interaction by suppressing
upregulation of several endothelial cell adhesion molecules,
including P-selectin,VCAM-1, and ICAM-1