Upstream statin in ACS : Do we need to reload our patient? By Ashraf Reda, MD, FESC Prof and head of cardiology dep.-Menofiya university President of EGYBAC Chairman of WGLVR

Effects of Statin Therapy on hs-CRP when did the story begin? Placebo Statin Percent Change in Median CRP CARE Pravastatin 5 years N = 472 AFCAPS Lovastatin 1 year N = 5719 Bayer Cerivastatin 8 weeks N = S Simvastatin 4 months N = 249 PRINCE Pravastatin 12/24 weeks N = 2400 Ridker PM. Eur Heart J. 2001;22:2135–2137.

CRP as Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Study Group Statin PlaceboNNT Low TC:HDL-C / low CRP Low TC:HDL-C / high CRP High TC:HDL-C / low CRP High TC:HDL-C / high CRP Median TC:HDL-C = 5.9 mg/dL Median CRP = 0.16 mg/dL Bermudez EA, Ridker PM. Prev Cardiol. 2002;5:42-46.

Atherosclerosis is an inflammatory disorder “Inflammation is the reaction of the tissues to local injuries calling for protective and reparative measures; an imperfect pathologic adaptation often leading to consequences that per se are dangerous and defeat its purpose” —LF Baker (1897)

No History of CAD Men >55, Women > 65 LDL-C <130 mg/dL CRP >2 mg/L Rosuvastatin 20 mg (n = 7500) MI Stroke Unstable Angina CVD Death CABG/PTCA LDL CRP FHS Lipids hs-CRP LFTs Lipids hs-CRP HbA 1C JUPITER * : hitting the sweet spot Randomized Trial of Rosuvastatin 20 mg po qd in the Primary Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL-C and Elevated Levels of CRP 4 week Run-in Screening Visit Randomization Visit Safety Visit Bi-Annual Follow-Up Visits End of Study Visit Lipids hs-CRP LFTs HbA 1C Placebo (n = 7500) * Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin

AHA/CDC Scientific Statement Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice Impressive scientific and epidemiologic evidence that atherosclerosis is an inflammatory response CRP risk cutpoints Low risk:  1.0 mg/L Average risk: 1.0 – 3.0 mg/L High risk:  3.0 mg/L AHA/CDC Scientific Statement. Circulation. 2003;107:

ACS from MIRACLE to PROVE-IT

ACS:PROVE-IT TIMI Pts With ACS 40mg Pravastatin 80mg Atorvastatin Mean follow up:24 months 95 mg/dl (2.46 mmol/l)62 mg/dl (1.6 mmol/l) LDL 26.3%22.4% 1ry end points 16%RRR (p0.005)

Treating to dual targets Investigators also further stratified patients based on levels of CRP and LDL cholesterol:  LDL cholesterol >70 mg/dL and CRP >2.0 mg/L.  LDL cholesterol >70 mg/dL and CRP <2.0 mg/L. II  LDL cholesterol 2.0 mg/L.  LDL cholesterol <70 mg/dL and CRP <2.0 mg/L. "Even with the most aggressive statin that we have used to date, 56% of patients still did not make it to the dual target," 56% 64%

The CRP continuum The early Pravastatin trials AF-CAPS, TEX-CAPS PROVE-IT JUPITER

Statin loading ARMYDA: PCI in statin na ï f ARMYD-RECUPTURE: PCI in pts. on chronic statin

ARMYDA-RECAPTURE (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) trial Prospective, multicenter, randomized, double blind trial investigating efficacy of atorvastatin reload in patients on chronic statin therapy undergoing PCI Principal Investigators: Giuseppe Patti, Vincenzo Pasceri, Achille Gaspardone, Giuseppe Colonna Investigators: Andrea D’Ambrosio, Marco Miglionico, Annunziata Nusca, Rosetta Melfi, Laura Gatto, Elisabetta Ricottini, Gianluca Pendenza, Antonio Montinaro Chairman: Germano Di Sciascio

Statin loading before PCI Pts with chronic statin (NSTE- ACS or stable AP) 80 mg atorva 12 Hrs before and 40 mg 2 hrs after 30 day MACE Benefit more clear in ACS

Individual and Combined Outcome Measures of the Primary Endpoint at 30 days P=0.045 ARMYDA-RECAPTURE: RESULTS % Composite Primary End Point Cardiac death MI TVR MACE Atorvastatin Placebo

% % P=0.97 P=0.016 ARMYDA-RECAPTURE Secondary endpoints MACE according to clinical presentation (stable angina or ACS) Test for Interaction: z=2.0; P=0.022 Atorvastatin Placebo

Loading and biomarkers Significant CPK reduction Significant troponin reduction Non significant CRP production LDL reduction????

Statin: the mechanism of benefit ? LDL lowering Pleotopic and anti-inflammatory Molecule effect

ARMYDA-RECAPTURE  Reloading with high dose atorvastatin is associated with improved clinical outcome in patients on chronic statin therapy undergoing PCI  Acute atorvastatin bolus pre-PCI gives a 48% Relative Risk Reduction of 30-day MACE at MV analysis (NNT = 17)  The benefit is largely localized to patients who presented with ACS (87% Risk Reduction, NNT = 9)  Rapid LDL-independent cardioprotective effects may be responsible of this phenomenon