C. Michael Gibson, MS, MD Beth Israel Deaconess Medical Center Boston, MA The Benefit of Statin Therapy Before and After Coronary Revascularization

ARMYDA Trial Peak CK-MB p = Peak Troponin I p = Circulation 2004;110:674-8 ng/mL Atorvastatin Placebo

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 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). 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  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.  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. Atorvastatin (80mg 12h pre-PCI; 40mg immediately pre-PCI) n=86Atorvastatin n=86 Matching Placebo (80mg 12h pre-PCI; 40mg immediately pre-PCI) n=85 Matching Placebo (80mg 12h pre-PCI; 40mg immediately pre-PCI) n= 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 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 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).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).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 = ACC 2007 Occurrence of MACE at 30 days

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). 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).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 = p = ACC 2007

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

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. 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. 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. 4ACC 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 Sep 15;100(6):919-23

6 studies were selected: l l PREDICT- Prevention of Restenosis by Elisor After Transluminal Coronary Angioplasty l l FLARE- Fluvastatin Angioplasty Restenosis l l GAIN- German Atorvastatin Intravascular Ultrasound l l LIPS- Lescol Intervention Prevention Study l l ARMYDA- Atorvastatin for Reduction of Myocardial Damage During Angioplasty l l Briguori 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 Sep 15;100(6):919-23

Cholesterol Data of Study Participants (Statin Arm/ Placebo Arm) VariablePREDICTFLAREGAINLIPSARMYDABriguori et al Baseline Total cholesterol (mg/dl) 228/231222/223228/242200/ /196 LDL cholesterol (mg/dl) 155/157153/153155/166131/ /122 Follow-up Total cholesterol (mg/dl) 195/ / /193* LDL cholesterol (mg/dl) 119/159102/14986/14095/ /121* * Level at index procedure LDL = low-density lipoprotein * Level at index procedure LDL = low-density lipoprotein Mood et al. Am J Cardiol Sep 15;100(6):919-23

Odds Ratio 95% CI OR=0.57 ( ) PREDICT FLARE GAIN LIPS Briguori ARMYDA Overall Mood et al. Am J Cardiol Sep 15;100(6): 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 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 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 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 Sep 15;100(6):919-23

Intensive Lipid Lowering and TVR (Clinical Restenosis) and Non-TVR (Lesion Progression) TVR p = MV O.R. 0.63, p=0.001* Non-TVR p = 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 Prava 40 mg (167/1440)(227/1420) (122/1440) (227/1420) Gibson CM, ACC 2005

% 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

Simvastatin Prior to CABG is Associated with Improved Post Operative Flow on PET Scanning Improvement in PET Blood Flow Placebo Dotani, … Gibson Am J Cardio 2003; 91: Simvastatin Bypassed Segment Non- Bypassed Segment p<0.001

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< Dotani, … Gibson et al Am J Cardio 2003 No statin Statin

ARMYDA-3 Trial: Primary Endpoint Post-operative occurrence of atrial fibrillation (%) p=0.003 % Occurrence AF Presented at ACC patientsundergoing elective cardiac surgery were randomized to either atorvastatin or placebobeginning 7 days before the operation 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

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 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 Inhibit neutrophil and monocyte chemotaxis Upregulation of endothelial NO synthesis or inhibit hypoxia- mediated inhibition of NOS 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