Tratamiento con estatinas y antitrombotico Dr Briguori

Statin and antithrombotic therapy: Their role in risk reduction in

percutaneous coronary intervention

Carlo Briguori, MD, PhD Laboratoy of Interventional Cardiology

Clinica Mediterranea, Naples - Italy

• Periprocedural myocardial infarction is a frequent and prognostically important complication of PCI 1 .

• Serum CK-MB after an uncomplicated PCI is elevated in 1 to 38% patients 1-4

• A CK-MB elevation >3X ULN (which is considered to represent an infarction large enough to be associated with short-term complications) occurs in 7-18%

Background

1 Hermann J. Eur Heart J 2005; 25: 2493 2 Testa L. et al. . QJM 2009;102:2945 3 Stone GW et al. Circulation 2001;104:642 4 Califf RM et al. J Am Coll Cardiol 1998; 31: 241

How to Prevent Periprocedural MI?

Types of Peri-procedural Myocardial Ischemic Injury

Hermann J. Eur Heart J 2005; 25: 2493

• Antiplatelet therapy:

– Glycoprotein IIb IIIa inhibitors 1

– Thienopyridine 2-4

• Beta-blockers 5

• Statins 6-7

Pharmacological approaches to prevent periprocedural MI

1 Roffi M. et al. Eur Heart J 2002 Sep;23(18):1441-8 2 Steinhubl SR J Am Coll Cardiol. 1998;32:1366-1370. 3 Patti G et al. Circulation 2005 Apr 26;111(16):2099-106 4 Mahoney EM et al. Circulation. 2010 Jan 5;121(1):71-9 5 Erbel SG et al. Circulation. 2001;104:2685-2688 6 Pasceri V. et al. . Circulation 2004;110:674-8 7 Briguori C et al. Eur Heart J 2004;25:1822-8

• The available data suggest that statin prevent periprocedural MI 1-2

Statin & periprocedural MI

1 Pasceri V. et al. Circulation 2004;110:674-8 2 Briguori C et al. Eur Heart J 2004;25:1822-8

The first ARMYDA trial (N=153 pts) has demonstrated that a 7-day

pretreatment with atorvastatin (40 mg/day) is associated with 81% risk

reduction of peri-procedural myocardial infarction in patients with stable

angina undergoing elective PCI

0

10

20

30

Placebo Atorvastatin

P=0.025

Primary end point: Incidence of MI

18

5

Pasceri V, Patti G, Di Sciascio G, et al. Circulation 2004

Background

Briguori C et al. Eur Heart J 2004;25:1822-8

• Previous studies suggest that atorvastatin administration should be started at least 3 - 7 days before the procedure1-2

• In the ARMYDA trial:

– Atorvastatin 40 mg started 7 days before PCI

• This may imply the need to postpone the PCI in all statin naïve patients.

When to Start Atorvastatin to Prevent Periprocedural MI?

1 Pasceri V. et al. Circulation 2004;110:674-8 2 Briguori C et al. Eur Heart J 2004;25:1822-8

Clinical Pharmacokinetics of Atorvastatin

Lennernas H. Clin Pharmacokinet 2003;42:1141-60

• To assess whether a single, high (80 mg), loading (within 24 hours) dose of atorvastatin is effective in preventing elevation of biomarkers of MI following elective coronary stent implantation.

NAPLES II

Briguori C et al. J Am Coll Cardiol 2009;54:2157-63

NAPLES II

Prospective, randomized, double-arm, 2-center clinical study

Elective PCI in de novo lesions, in native coronary artery

No statin therapy Biomarker negative

Atorvastatin 80 mg No atorvastatin

ASA Clopidogrel

(loading dose 300 mg the day before procedure)

Elective PCI

CKMB >3X ULN Briguori C et al. J Am Coll Cardiol 2009;54:2157-63

• Hypothesis: • Reduction in the primary endpoint from 15% in the Control group

to 8% in the Atorvastatin group1-2

• Sample size: – A total of 650 patients (325 each group) will be necessary to gave the

study 80% power and a significance level <0.05

Sample size

1 Pasceri V. et al. . Circulation 2004;110:674-8 2 Briguori C et al. Eur Heart J 2004;25:1822-8

Inclusion criteria

Age 18 y

De novo lesion in a native coronary artery

Elective PCI

Normal cardiac biomarkers

No statin therapy


Exclusion criteria

• Primary or rescue PCI

ACS with elevated cardiac markers

Pregnancy

Restenotic lesion

SVG or LIMA treatment

Active statin therapy


–Periprocedural Myocardial Infarction = CKMB 3X ULN

Definitions

Thygesen K et al. Eur Heart J 2007;28:2525-38.8

338 patients included

Patients assessed for eligibility (n=1385)

Excluded (n=31)

9 withdrew consent 28 did not meet the inclusion criteria

1348 patients randomized

676 allocated to Atorvastatin group 676 received the allocated treatment

672 allocated to Control group 672 received the allocated treatment

330 patients included

338 excluded because: 155 had coronary angiography alone and not PCI 98 had PCI for ISR and/or on a bypass vessel 80 were referred for elective CABG 5 were lost at follow-up

342 excluded because: 174 had coronary angiography alone and not PCI 91 had PCI for ISR and/or on a bypass vessel 71 were referred for eventual CABG 6 were lost at follow-up

338 patients included 330 patients included 338 patients included


Clinical Characteristics Atorvastatin

Group

(N=338)

Control Group

(N=330)

Age, yrs (mean SD) 64 9 65 10

Male, % 266 (78.7%) 263 (79.7%)

BMI (kg/m2) 27.8 3.8 27.4 3.5

Symptoms Asymptomatic Stable angina Unstable angina

45 (13.3%) 285 (84.3%

8 (2.4%)

34 (10.3%)

288 (87.3%) 8 (2.4%)

Family history for CAD 101 (30%) 112 (34%) Diabetes mellitus 130 (38.6%) 121 (36.8%) Hypertension, % 131 (78%) 125 (74.9%) Current smoker, % 79 (24%) 66 (20%) Prior MI, % 113 (33.4%) 97 (29.4%) Prior PCI*, % 41 (12.1%) 31 (9.4%) Prior CABG, % 24 (7.1%) 27 (8.1%) LVEF, % (mean SD) 55.7 9.5 55.5 9.9 -blockers 130 (38.5%) 129 (39.1%)

* Percutaneous intervention performed in a different vessel and/or lesion.

Briguori C et al. J Am

Coll Cardiol

2009;54:2157-63

Biochemical Characteristics

Atorvastatin

Group

(N=338)

Control Group

(N=330)

Serum creatinine, median (IQR)

GFR (ml/min/1.73 m2)

GFR < 60

1.16 (1.00-1.32)

65 17 124 (36.6%)

1.18 (1.00-1.35)

64 19 140 (42.4%)

Fibrinogen, mg/dL 379 123 363 100 Lipid, mg/dL Total Cholesterol LDL-C HDL-C Tryglicerides

211 46 126 35 48 11

159 88

210 42 129 37 48 12

151 88


Rate of high CRP

0

10

20

30

40

50

Atorvastatin group (n= 338)

Control group (n = 330)

p = 0.31

25.4

29.4

%


Angiographic & Procedural Characteristics

Atorvastatin

Group

(N=338)

Control Group

(N=330)

Distribution of CAD

1-vessel

2-vessel

3-vessel

128 (37.9%)

121 (35.8%)

89 (26.3%)

125 (37.9%)

117 (35.5%)

88 (26.6%) Target vessel

LAD

Cx

RCA

LM

371

186 (50.1%)

72 (19.5%)

107 (28.8%)

6 (1.6%)

366

185 (50.5%)

71 (19.4%)

105 (28.5%)

6 (1.6%) Lesion site

Ostial

Proximal

Mid

Distal

436

46 (10.7%)

193 (44.2%)

161 (36.9%)

35 (8.2%)

426

47 (11%)

189 (44.4%)

172 (40.4%)

18 (4.2%)

Briguori C et al.

J Am Coll

Cardiol 2009;

54:2157-63

Angiographic & Procedural Characteristics

Atorvastatin

Group

(N=338)

Control Group

(N=330)

Multivessel stenting 37 (11%) 33 (10%) Direct stenting 28.5% 30.3% Atherectomy 1.5% 2.1% No. treated vessel/patient 1.1 0.5 1.1 0.3 No. treated lesion/patient 1.3 0.6 1.3 0.6 CTO 64 (18.9%) 59 (17.9%) Thrombus 6 (1.7%) 9 (2.7%) Complex (B2/C) lesions 173 (51.3%) 177 (53.7%) Bifurcation lesions 56 (16.7%) 55 (16.6%) Calcified lesions 80 (23.7%) 88 (26.8%)


Atorvastatin

Group

(N=338)

Control Group

(N=330) Preprocedural QCA

RVD, mm

MLD, mm

DS, %

Lesion length, mm

3.16 0.62

0.51 0.44

85 12

18 10

3.23 0.59

0.51 0.40

84 13

19 8 Postprocedural QCA

RVD, mm

MLD, mm

DS, %

3.36 0.61

3.34 0.61

2 6

3.41 0.58

3.37 0.60

2 3 Stent length, mm 30 16 30 16 Max inflation pressure, atm 15 4 15 4 TIMI flow grade pre

0/1

2/3

54 (16%)

284 (84%)

54 (16.5%)

276 (83.5%) TIMI flow grade post

0/1

2/3

1 (0.3%)

337 (99.7%)

0

330 (100%) BA ratio 1.05 0.12 1.03 0.09


Angiographic Complications

Atorvastatin

Group

(N=338)

Control Group

(N=330) P

Major dissection 1 (0.59%) 3 (0.90%) 0.68 Abrupt closure 1 (0.29%) 0 0.48 Slow/No reflow 2 (0.59%) 8 (2.40%) 0.06 Thrombus formation 2 (0.59%) 0 0.50 Side branch closure/compromise 5 (1.48%) 7 (2.12%) 0.57 Distal embolization 2 (0.59%) 2 (0.60%) 1.00 Perforation 2 (0.59%) 2 (0.60%) 1.00 Any of the above 16 (4.7%) 22 (6.6%) 0.31


CKMB >3X ULN

0

2

4

6

8

10

12

14

16



p = 0.014

(OR = 0.56; 95% CI = 0.35-0.89)

%

9.5

15.8


cTnI >3X ULN

0

5

10

15

20

25

30

35

40

26.6

39.1



p <0.001

(OR = 0.56; 95% CI = 0.40-0.78)

%


28/252

35/233

11.1

15

4/86

16/97

4.6

16.5

0

2

4

6

8

10

12

14

16

18



p = 0.18 p = 0.016

CKMB 3X ULN & CRP

Normal CRP High CRP

%


31

39.5

15.1

38.1

0

5

10

15

20

25

30

35

40

Normal CRP High CRP



p = 0.056 p = 0.002

TnI 3X ULN & CRP

%

78/252

92/233

13/86

37/97


No interaction between Atorvastatin & Gp IIb/IIIa inhibitors


ARMYDA-RECAPTURE trial: Study design

793 Patients

with

stable angina

or NSTE-ACS

undergoing

coronary

angiography

Ran

dom

izati

on

(N

=420)

Atorvastatin reload:

80 mg

12 hrs before

angio;

further 40 mg

2 hrs before

N=210

Coronary

angiography

Placebo

12 hrs before

angio; further

dose 2 hrs

before

N=210

Primary end

point:

30-day

occurrence of

cardiac death,

MI, TVR

1st blood sample

(before PCI)

CK-MB, Troponin-I, HS-CRP

2nd and 3rd

blood samples

(8 and 24 hours

after PCI)

30 days

373 patients excluded for:

- 243 no chronic statin therapy (31%)

- 38 emergency angiography

- 82 ejection fraction <30%

- 10 severe renal failure

PCI

atorvastatin

N=177

PCI

placebo

N=175

68 patients excluded for indication to:

- medical therapy (N=30)

- bypass surgery (N=38)

N=352

Di Sciascio G, Patti G et al – J Am Coll Cardiol 2009; 54:558

Individual and Combined Outcome Measures

of the Primary Endpoint at 30 days

8.6 9.1

P=0.045

ARMYDA-RECAPTURE: RESULTS

%

Composite

Primary End Point

48% RRR at MV analysis

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


Potential Mechanisms

Types of Peri-procedural Myocardial Ischemic Injury

Hermann J. Eur Heart J 2005; 25: 2493

Anti-inflammatory Effects

Anti-inflammatory Effects

Morales-Villegas E. et al. International J Hypertension 2011

Statins Loading & CRP

Ostadal P. et al. Mol Cell Biochem 2003;246:45-50

Antiplatelet Effects

0,0%

5,0%

10,0%

15,0%

20,0%

0 1 2 3 4

Marcucci et al

Price et al

Patti et al

N=683

N=380

N=160

Increasing Risk With Greater Residual Reactivity

Event Rates In Prospective PCI Studies Stratified By PRU Quartile

PRU Quartile Price MJ et al. Circulation 2009; 119:2625-32

Even

t ra

te

The VerifyNow System •The first easy, rapid and proven system for measuring individual response to every major antiplatelet medication

– Aspirin – P2Y12 inhibitors (e.g. clopidogrel, prasugrel and ticlopidine) – GP IIb/IIIa inhibitors (e.g. ReoPro® and Integrilin®)

•System Consists of: – Light-Detection Instrument – Single use Test Devices – Electronic Quality Controls – Wet Quality Controls

Mechanism Of Action •Platelet response is measured as a function of an increase in light transmission through whole blood as platelets are activated by various agonists

If there is low residual platelet reactivity, there is decreased light that is transmitted and detected.

If there is high residual platelet reactivity, there is increased light that is transmitted and detected.

•

VerifyNow P2Y12 Assay & Outcome after PCI

Price MJ et al. Circulation 2009; 119:2625-32

Endothelial Effects

Statins & Endothelial cells

Morales-Villegas E. et al. International J Hypertension 2011

Endothelial Progenitor Cells

60 45 30 15 0 -15

CF

U-E

C (

4x10

6 P

BM

Cs)

105

70

35

0

stenosis (%)

r = -0.30

p = 0.004

Briguori C et al. FASEB J 2010 (in press)

Time (months)

24 18 12 6 0

Even

t F

ree S

urv

ival

1.0

0.8

0.6

0.4

0.2

0

Log rank p = 0.003

Endothelial Progenitor Cells

Briguori C et al. FASEB J 2010 (in press)

Low EPCs group

High EPCs group

Endothelial Progenitor Cells & Statins

Duckers HJ et al. Eurointerv 2007; 3: 67-75

High-dose atorvastatin reload pre-PCI increases circulating levels of EPCs

Atorvastatin Placebo

r t0 t8 t24 r t0 t8 t24 0

1

2

3

4

5

6

7

CD

45

dim

/C

D13

3+/

C

D34

+/

KD

R+ (

%)

Patti G et al. European Society of Cardiology Congress 2009

Safety concerns?

Major safety outcomes from PROVE IT-TIMI 22

Wiviott SD et al. J Am Coll Cardiol 2006; 46: 1411

Major safety outcomes

Wenger NK et al. Ann Intern Med 2007; 147: 19

Conclusions

Atorvastatin prevents per-procedural myorcadial damage

A single, high (80 mg) loading (within 24 hours) dose of atorvastatin reduces the incidence of periprocedural MI in elective PCI.

Preliminary data suggests the effect of the loading 80 mg atorvastatin dose on

Inflammatory pattern Platelet reactivity Circulating endothelial progenitor cells

The high loading dose of atorvastatin seems to be safe and effective

Optimal Peri-PCI Therapy

-UFH or Bivalirudin -GP IIbIIIa inhibitor (when

indicated)

ASA (100 mg/day) Clopidogrel (600 mg loading dose) Atorvastatin (80 mg loading dose)

The day before procedure

-DAT (1-12 months) -Atorvastatin

Intra-procedural

Post-procedure

Tratamiento con estatinas y antitrombotico Dr Briguori

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