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Should we Monitor Anti-Platelet Treatment?. Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular Research Hotel Dieu de France Hospital Associate Professor of Medicine Saint Joseph University School of Medicine. Should we Monitor Anti-Platelet Treatment?.

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should we monitor anti platelet treatment

Should we Monitor Anti-Platelet Treatment?

Rabih R. Azar, MD, MSc, FACC

Director of Cardiovascular Research

Hotel Dieu de France Hospital

Associate Professor of Medicine

Saint Joseph University School of Medicine

should we monitor anti platelet treatment2
Should we Monitor Anti-Platelet Treatment?
  • Is there a reliable test to measure platelet function?
  • Is there a variability in the response to anti-platelet therapy?
  • Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
  • Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
how to measure platelets aggregation
How to Measure Platelets Aggregation?
  • Platelets function is measured in vitro by light transmission aggregometry
  • This method is considered the gold standard
  • Disadvantages:
    • Limited reproducibility
    • Complex sample preparation
    • Cannot be routinely performed
slide8

Excellent Correlation Between Light Transmission Aggregometry and Plateletworks Test (Cathet Cardiovasc Intervent 2001;53:346-351)

slide9

VERIFYNOW Point of Care Test

It measures the rate and extent of changes in light transmittance caused by platelet aggregation in a pre-set tube in which whole blood in placed

It thus mimics light transmission aggregometry

Samples containing inhibited platelets will produce low level of light transmittance while samples containing normally functioning platelets will aggregate more rapidly, resulting in higher level of light transmittance

slide10

The VASP test: A Specific Test to Measure P2Y12 Inhibition

  • VASP is not phosphorylated at basal state
  • PGE1 activates VASP phosphorylation
  • ADP inhhibits VASP phosphorylation via the P2Y12 receptor
  • Thus high VASP = active form of P2Y12 receptor
  • Low VASP (high VASP-P) = inhibition of P2Y12 receptor
should we monitor anti platelet treatment11
Should we Monitor Anti-Platelet Treatment?
  • Is there a reliable test to measure platelet function?
  • Is there a variability in the response to anti-platelet therapy?
  • Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
  • Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
slide13

Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or 48% inhibition at 30 days)

Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in aggregation compared to baseline)

acc aha guidelines 2005 percutaneous coronary interventions oral antiplatelet therapy
ACC/AHA Guidelines (2005)Percutaneous Coronary Interventions: Oral Antiplatelet Therapy

Prevalence of inadequate response to clopidogrel 4% to 30%

Nguyen et al. J Am Coll Cardiol 2005;45:1157-64

should we monitor anti platelet treatment16
Should we Monitor Anti-Platelet Treatment?
  • Is there a reliable test to measure platelet function?
  • Is there a variability in the response to anti-platelet therapy?
  • Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
  • Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
platelet reactivity and early drug eluting stent thrombosis
Platelet Reactivity And Early Drug-Eluting Stent Thrombosis

Sibbing et al. JACC 2009;53:849-56

1608 consecutive patients with CAD and planned drug eluting stent implantation

All received a loading of 600 mg of clopidogrel prior to stenting

Blood was obtained directly prior to PCI

ADP induced platelet aggregation was assessed with a point of care assay: Multiple Electrode Platelet Aggregometry (MEA) (principle of impedance aggregometry)

Poor response to clopidogrel was prospectively defined by a cutoff point at the upper quintile of MEA measurments

clinical characteristics associated with low response to cloopidogrel
Clinical Characteristics Associated With Low Response to Cloopidogrel

Sibbing et al. JACC 2009;53:849-56

normal response Low response p

n = 1285 n = 323

BMI 27.3 + 4.2 28.3 + 4.9 < 0.001

Ejection Fraction 54.9 + 10.9 53.2 + 12.6 0.03

Diabetes mellitus 27.4% 34.1% 0.02

Active smokers 12.1% 18.6% 0.002

ACS 31.4% 39.9% 0.001

Platelet count 213 + 62 236 + 64 < 0.001

Time from loading (h) 4 (2-15.5) 3 (2-7) < 0.001

clinical outcome according to clopidogrel response
Clinical Outcome According to Clopidogrel Response

Sibbing et al. JACC 2009;53:849-56

P = < 0.001 0.07 0.02 0.005 0.03

should we monitor anti platelet treatment22
Should we Monitor Anti-Platelet Treatment?
  • Is there a reliable test to measure platelet function?
  • Is there a variability in the response to anti-platelet therapy?
  • Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
  • Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
slide23

TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET REACTIVITY MONITORING DECREASE EARLY STENT THROMBOSIS

L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg,

P Barragan, F Dignat-George, F Paganelli.

Service de cardiologie, Hôpital Universitaire Nord, Marseille; FRANCE

Laboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCE

Service de cardiologie, Hôpital d’aubagne, Aubagne; FRANCE

Service de cardiologie, Clinique clairval, Marseille; FRANCE

Service de cardiologie, Clinique Bouchard, Marseille; FRANCE

Service de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCE

Laboratoire de statistique, Faculté de la Timone, Marseille; FRANCE

Service de cardiologie, Polyclinique les Fleurs, Ollioules, FRANCE

Am J Cardiol 2009;103:5-10

design

Non-emergent PCI : ACS and Stable angina (n= 1122)

Loading dose (LD) -ASA 250mg -Clopidogrel 600mg

DESIGN

VASP ≥ 50%

Randomization

(n=429)

CONTROL (n =215)

VASP-guided LD (n =214)

Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCI

Maintenance dose -ASA 160 mg

-Clopidogrel 75 mg

1° endpoint: Definite stent thrombosis (ARC definition)

2° endpoints: MACE including CV death, MI and U-TVR

TIMI major and minor bleeding at 30 days

platelet reactivity monitoring

VASP after first LD

66 ± 11

67 ± 10

VASP after sensitization

37 ± 12†

† p <0.01

Platelet reactivity monitoring

17 patients (8%)

timing of early stent thrombosis

Timing of early stent thrombosis

All early stent thrombosis occured during the first 7 days

Am J Cardiol 2009;103:5-10

secondary end point mace

Secondary end-point: MACE

 Endpoint n, (%)

Control

(n= 214)

VASP-guided

(n= 215)

p

Cardiovascular death

4 (1.8)

0

0.06

Myocardial infarction

10 (4.8)

1 (0.5)

0.01

Urgent revascularization

5 (2.3)

0

0.06

All MACE

19 (8.9)

1 (0.5)

< 0.001

slide28

Tailoring Treatment with Tirofiban

in patients showing Resistance to

aspirin and/or Resistance to clopidogrel

M. Valgimigli, MD, PhD

On behalf of 3T/2R

Investigators

tailored gp iib iiia receptor blockade according to clopidogrel resistance
Tailored GP IIb/IIIa Receptor Blockade According to Clopidogrel Resistance
  • 149 Clopidorel resistant patients
  • Resistance defined by inhibition < 30% using light transmission aggregometry
  • Elective PCI
  • Randomized to :
    • Conventional therapy: 600 mg Clopidogrel
    • Active therapy: 600 mg Clopidogrel + GP IIb/IIIa blockade
  • Combined end-point of: death, periprocedural MI, stent thrombosis and recurrent ACS at 1 month

Cuisset et al. JACC Interventions. 2008;1:649-53

events according to gpiib iiia blockade in clopidogrel resistant patients
Events According to GPIIb/IIIa Blockade in Clopidogrel Resistant Patients

P=0.006

Cuisset et al. JACC Interventions. 2008;1:649-53

how can we solve the problem caused by clopidogrel resistance

How Can We Solve the Problem Caused by Clopidogrel Resistance?

Is the answer by increasing the dose?

should we monitor anti platelet treatment42
Should we Monitor Anti-Platelet Treatment?

FACTS:

1- More potent anti-platelet therapy is associated with better outcome

2- But it is also associated with more bleeding !!!

WHAT TO DO IN PRACTICE:

1- Give all patients potent drugs: double dose clopidogrel, or better: prasugrel. Proven to be better, but risk of bleeding

2- Monitor platelet response and adjust therapy accordingly. Waiting confirmation in large clinical trials (GRAVITAS)