Should%20we%20Monitor%20Anti-Platelet%20Treatment?

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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

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Should we Monitor Anti-Platelet Treatment?

1. Is there a reliable test to measure platelet
   function?
2. Is there a variability in the response to
   anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of
   adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy
   according to tests results, improve the outcome
   of PCI?

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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

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WHAT ARE THE ALTERNATIVES TO LIGHT TRANSMISSION
AGGREGOMETRY?
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Rapid Platelet Function AssayPlateletworksAn
alternative to light transmission aggregometry
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Plateletworks
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Excellent Correlation Between Light Transmission
Aggregometry and Plateletworks Test (Cathet
Cardiovasc Intervent 200153346-351)
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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
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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

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Should we Monitor Anti-Platelet Treatment?

1. Is there a reliable test to measure platelet
   function?
2. Is there a variability in the response to
   anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of
   adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy
   according to tests results, improve the outcome
   of PCI?

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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 lt
10 reduction in aggregation compared to baseline)
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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 2005451157-64

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Clopidogrel Metabolism

• Clopidogrel is a prodrug
• It requires oxidation by the hepatic cytochrome
  P450 to generate the active metabolite
• Only a small proportion of clopidogrel undergoes
  metabolism by CYP450
• Clopidogrel is mostly hydrolyzed by esterases to
  an inactive carboxylic acid derivative that
  accounts for 85 of clopidogrel-related
  circulating compounds
• Any drugs that affects CYP450 may affect the
  efficacy of clopidogrel

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Should we Monitor Anti-Platelet Treatment?

1. Is there a reliable test to measure platelet
   function?
2. Is there a variability in the response to
   anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of
   adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy
   according to tests results, improve the outcome
   of PCI?

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Platelet Reactivity And Early Drug-Eluting Stent
Thrombosis

• 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

Sibbing et al. JACC 200953849-56
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Clinical Characteristics Associated With Low
Response to Cloopidogrel

• normal response Low response p
• n 1285 n 323
• BMI 27.3 4.2 28.3 4.9 lt 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 lt 0.001
• Time from loading (h) 4 (2-15.5) 3 (2-7) lt
  0.001

Sibbing et al. JACC 200953849-56
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Clinical Outcome According to Clopidogrel Response
Sibbing et al. JACC 200953849-56
P lt 0.001 0.07 0.02
0.005 0.03
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Dual Resistance to Aspirin and Clopidogrel in
Patients Undergoing PCI

• 150 patients referred for elective PCI
• All were on aspirin 81 to 325 mg/day for gt 1 week
• Clopidogrel was given immediately following PCI
• The response to clopidogrel was tested at 24
  hours post loading dose
• 12.7 resistant to aspirin
• 24 resistant to clopidogrel
• 47 of aspirin resistant patients were also
  resistant to clopidogrel

J Am Coll Cardiol 20064727-33
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Incidence of CK-MB Elevation Following PCI
According to Aspirin and Clopidogrel
Responsiveness J Am Coll Cardiol 20064727-33
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Link between low-response and thrombotic events
Endpoint
Author
Platelet assay
n
Stent thrombosis
Barragan
VASP index
36
 
Gurbel
VASP index, ADP aggregometry
120
 
Buonamici
ADP- aggregometry
804
Blindt
VASP index, ADP aggregometry
99
Ischemic events
CV death, MI, unstable angina, stroke
Gurbel
ADP aggregometry
192
Death, MI, stent thrombosis, stroke, ischemia
Bliden
ADP aggregometry
100
CV death, acute or subacute ST, ACS, ischemic
stroke
Cuisset
ADP aggregometry, VASP index
195
Death, MI, TLR
Trenk
ADP aggregometry
802
CV death, MI, urgent TVR
Bonello
VASP index
144
CV death, acute and subacute stent thrombosis, MI
Price
VerifyNow P2Y12
380
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Should we Monitor Anti-Platelet Treatment?

1. Is there a reliable test to measure platelet
   function?
2. Is there a variability in the response to
   anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of
   adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy
   according to tests results, improve the outcome
   of PCI?

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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 dhématologie,
INSERM UMRS 608, Hôpital conception Marseille
FRANCE Service de cardiologie, Hôpital daubagne,
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 20091035-10
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DESIGN
Non-emergent PCI ACS and Stable angina (n 1122)
Loading dose (LD) -ASA 250mg -Clopidogrel 600mg
VASP 50
Randomization (n429)
CONTROL (n 215)
VASP-guided LD (n 214)
Up-to 3 additional LD of 600 mg every 24 hours
until VASP lt 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
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Platelet reactivity monitoring
VASP after first LD
66 11
67 10
VASP after sensitization
?
37 12
p lt0.01
17 patients (8)
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Timing of early stent thrombosis
All early stent thrombosis occured during the
first 7 days
Am J Cardiol 20091035-10
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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)
lt 0.001
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Secondary end-point TIMI bleeding
Control (n 214)
VASP-guided (n 215)
p
Major bleeding
2 (0.9)
2 (0.9)
1
Minor bleeding
4 (1.9)
6 (2.8)
0.8
All
6 (2.8)
8 (3.7)
0.8
No difference in bleeding complication between
the 2 groups No intra-cerebral bleeding, no fatal
bleeding Majority of patients had PCI through the
radial access (55.6)
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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
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Tailored GP IIb/IIIa Receptor Blockade According
to Clopidogrel Resistance

• 149 Clopidorel resistant patients
• Resistance defined by inhibition lt 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. 20081649-53
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Events According to GPIIb/IIIa Blockade in
Clopidogrel Resistant Patients
P0.006
Cuisset et al. JACC Interventions. 20081649-53
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How Can We Solve the Problem Caused by
Clopidogrel Resistance?

• Is the answer by increasing the dose?

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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)