[PPT]PowerPoint Presentationclintrialresults.org/Slides/Gibson - pre pci statin therapy...

C. Michael Gibson, MS, MD Beth Israel Deaconess Medical CenterBoston, MA

The Benefit of Statin Therapy Before and After Coronary Revascularization

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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

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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

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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

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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

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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

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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


Cholesterol Data of Study Participants (Statin Arm/ Placebo Arm)

* Level at index procedure

LDL = low-density lipoprotein


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


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).


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).


Limitations

The follow-up periods ranged from 1 day to 45 months, making it difficult to assess the long-term benefits of statin therapy.


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.


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

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%

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

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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

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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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