C. Michael Gibson, MS, MD Beth Israel Deaconess Medical CenterBoston, MA
The Benefit of Statin Therapy Before and After Coronary Revascularization
*
ARMYDA Trial
Peak CK-MB
p = 0.007
Peak Troponin I
p = 0.0008
Circulation 2004;110:674-8
ng/mL
ng/mL
Atorvastatin
Atorvastatin
Placebo
Placebo
Chart1
2.97.5
Atorvastatin
Placebo
Sheet1
AtorvastatinPlacebo
2.97.5
Chart1
0.090.47
Atorvastatin
Placebo
Sheet1
AtorvastatinPlacebo
0.090.47
*
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
R
30 day follow-up
ACC 2007
Clopidogrel (600mg) loading dose at least 3h pre-PCI
*
Death, MI, or unplanned revascularization was lower in the atorvastatin (5%) group vs. placebo group (17%) (p=0.01).
This was driven by a reduction in peri-procedural MI for the atorvastatin group (5% vs. 15%, p=0.04).
MACE (%)
ARMYDA-ACS Trial: Primary Endpoint
n = 86
n = 85
p = 0.01
ACC 2007
Occurrence of MACE at 30 days
Chart1
0.05
0.17
Weight
Sheet1
Weight
Atorvastatin0.13000%
Placebo0.2
*
ARMYDA-ACS Trial: Secondary Endpoint
Patients (%) with elevated levels of CKMB and Troponin-I post-PCI
Post-PCI CKMB elevations occurred in fewer patients in the atorvastatin group than in the placebo group (7% vs. 27%, p=0.001).
Troponin-I elevation also occurred in fewer patients in the atorvastatin group than in the placebo group (41% vs. 58%, p=0.039).
n = 86
n = 85
n = 86
n = 85
Patients with Post-PCI elevation (%)
p = 0.039
p = 0.001
ACC 2007
Chart1
0.070.27
0.410.58
Atorvastatin
Placebo
Sheet1
AtorvastatinPlacebo
CKMB7%27%
Troponin-I41%58%
The percent increase in CRP from baseline was lower in the atorvastatin group (63%) than in the placebo group (147%) (p=0.01).
Increase in CRP from baseline (%)
ARMYDA-ACS Trial: Secondary Endpoint
n = 86
n = 85
p = 0.01
ACC 2007
Percent increase in CRP from pre to post-PCI
Chart1
0.63
1.47
Weight
Sheet1
Weight
Atorvastatin0.63000%
Placebo1.5
*
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 2007
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
6 studies were selected:PREDICT- Prevention of Restenosis by Elisor After Transluminal Coronary AngioplastyFLARE- Fluvastatin Angioplasty RestenosisGAIN- German Atorvastatin Intravascular UltrasoundLIPS- Lescol Intervention Prevention StudyARMYDA- Atorvastatin for Reduction of Myocardial Damage During AngioplastyBriguori et al- Randomized 3,941 patients (1,967 to statins and 1,974 to placebos)
Studies Included in Meta-Analysis
Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23
Cholesterol Data of Study Participants (Statin Arm/ Placebo Arm)
* Level at index procedure
LDL = low-density lipoprotein
Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23
VariablePREDICTFLAREGAINLIPSARMYDABriguori et alBaseline Total cholesterol (mg/dl)228/231222/223228/242200/199--197/196 LDL cholesterol (mg/dl)155/157153/153155/166131/132--121/122Follow-up Total cholesterol (mg/dl)195/239--156/215----168/193* LDL cholesterol (mg/dl)119/159102/14986/14095/147--93/121*
Odds Ratio 95% CI
OR=0.57
(0.42-0.78)
PREDICT
FLARE
GAIN
LIPS
Briguori
ARMYDA
Overall
Mood et al. Am J Cardiol. 2007 Sep 15;100(6):919-23
Odds of MI after PCI
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
p = 0.001
MV O.R. 0.63, p=0.001*
Non-TVR
p = 0.012
MV O.R. 0.87, p=0.364*
%
%
* MV model adjusted for on treatment LDL
11.6%
16.0%
8.5%
11.3%
Atorva 80 mg
Atorva 80 mg
Prava 40 mg
Prava 40 mg
(167/1440)
(227/1420)
(122/1440)
(227/1420)
Gibson CM, ACC 2005
Chart1
11.616
Atorvastatin (80 mg)
Pravastatin (40 mg)
Sheet1
Atorvastatin (80 mg)Pravastatin (40 mg)
11.616
Chart1
8.511.3
Atorvastatin (80 mg)
Pravastatin (40 mg)
Sheet1
Atorvastatin (80 mg)Pravastatin (40 mg)
8.511.3
*
%
p=0.004
p=0.003
N=367
N=44
N= 429
N= 49
* Statin use within 2 weeks
Association of Statin Use with Myocardial Perfusion After Fibrinolysis
Gibson CM 2004
Chart1
37.953.3
32.447.8
Sheet1
90 Min TMPG 2/3 flow90 Min TMPG 3 flow
37.932.4
53.347.8
*
Simvastatin Prior to CABG is Associated with Improved Post Operative Flow on PET Scanning
Improvement in PET Blood Flow
1.3
9.6
3.8
48.6
Placebo
Dotani, Gibson Am J Cardio 2003; 91: 1107-9
Simvastatin
Bypassed Segment
Bypassed Segment
Non- Bypassed Segment
Non- Bypassed Segment
p
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
% Occurrence AE
The risk of Death/MI was reduced from 8% to 0% (p=0.01)
18%
57%
p
ARMYDA-3 Trial: Primary Endpoint
Post-operative occurrence of atrial fibrillation (%) p=0.003
% Occurrence AF
Presented at ACC 2006
200 patients undergoing elective cardiac surgery were randomized to 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
Chart1
35
57
Percent
35%
57%
Sheet1
Percent
Atorvastatin35.0
Placebo57.0
*
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 -chain of the 2-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
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