Upstream statin in ACS : Do we need to reload our patient?By

Ashraf Reda, MD, FESCProf and head of cardiology dep.-Menofiya university

President of EGYBACChairman of WGLVR

Effects of Statin Therapy on hs-CRP

when did the story begin?

-20

-15

-10

-5

0

5Placebo Statin

Per

cen

t C

han

ge

in M

edia

n C

RP

CAREPravastatin

5 yearsN = 472

AFCAPSLovastatin

1 yearN = 5719

BayerCerivastatin

8 weeksN = 785

4 SSimvastatin

4 monthsN = 249

PRINCEPravastatin12/24 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 Placebo NNT

Low TC:HDL-C / low CRP 0.025 0.026 983

Low TC:HDL-C / high CRP 0.026 0.050 43

High TC:HDL-C / low CRP 0.022 0.051 35

High TC:HDL-C / high CRP 0.042 0.058 62

Median TC:HDL-C = 5.9 mg/dLMedian 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 CADMen >55, Women > 65

LDL-C <130 mg/dL CRP >2 mg/L

Rosuvastatin 20 mg (n = 7500) MIStroke

Unstable Angina

CVD DeathCABG/PTCA

LDLCRPFHS

Lipidshs-CRP LFTs

Lipidshs-CRPHbA1C

JUPITER*: hitting the sweet spotRandomized 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

Lipidshs-CRP LFTsHbA1C

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;107:499-511

ACS from MIRACLE to PROVE-IT

ACS:PROVE-IT TIMI 224162 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 <70 mg/dL and CRP >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 naïf

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

8.69.1

P=0.045

ARMYDA-RECAPTURE: RESULTS

%

CompositePrimary End Point

3.4

0

3

6

9

12

Cardiac

death

MI TVR MACE

Atorvastatin

Placebo

0.5 0.5

3.4

0

3

6

9

12

15

Stable angina

%

0

3

6

9

12

15

ACS

%

4.3

5.3

2.4

13.8

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