Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention

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Aspirin and Clopidogrel Drug Response in Patients
Undergoing Percutaneous Coronary Intervention
Eli I. Lev, MD Rajnikant T. Patel, MD Kelly J.
Maresh, RN, BSN Sasidhar Guthikonda, MD Juan
Granada, MD Timothy DeLao, MLT Paul F. Bray,
MD Neal S. Kleiman, MD
Published in Journal of the American College of
Cardiology 2006
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Aspirin and Clopidogrel Drug Response Background

• Treatment with aspirin and clopidogrel has become
  the standard therapy in patients undergoing PCI
  with stenting yet responses to these drugs vary
  widely among individuals.
• Data concerning the concurrent responses to both
  drugs are limited.
• The objective of this study was to prospectively
  evaluate the response to clopidogrel among
  aspirin-sensitive patients compared with
  aspirin-resistant patients, and to distinguish
  factors that affect the responses to either drug
  in patients undergoing elective PCI.

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Response Study Design
150 patients undergoing elective PCI , who
received aspirin 81-325 mg daily but not
clopidogrel 1 week prior to PCI, no
thienopyridine or GP IIb/IIIa for a week prior to
enrollment and excluding those with acute
myocardial infarction within 1 week
contraindications to aspirin, bivalirudin, or
clopidogrel thrombocytopenia anemia or renal
failure. Prospective.
Elective PCI with Stenting Standard course of
IV bivalirudin bolus (0.75 mg/kg) followed by
infusion (1.75 mg/kg/h) until PCI completion
Post-PCI 300 mg clopidogrel and 325 mg oral
aspirin in cath lab followed by 75 mg clopidogrel
and 325 mg aspirin daily
Aspirin-resistant
Aspirin-sensitive

• Primary Endpoint Response to clopidogrel in
  aspirin-resistant and aspirin-sensitive patients

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Response Methods

• Platelet Aggregation
• -Turbidimetric platelet aggregation in
  platelet-rich plasma with platelet count adjusted
  to 250x103/mm3.
• -Degree of aggregation was defined as the
  maximal light transmission 6 min after agonist
  was added. Platelet-poor plasma used as
  reference.
• Platelet Activation
• -Platelet activation was determined by
  assessing platelet surface expression of
  activated GP IIb/IIIa receptors and P-selectin in
  response to ADP stimulation using flow cytometry.
• Rapid Platelet Function Assay-Aspirin (RPFA-ASA)
• -Results expressed as aspirin reaction units
  (ARU). ARU 550 indicates detection of
  aspirin-induced platelet dysfunction. (RPFA-ASA
  did not use AA as agonist).

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Response Methods cont.

• Definitions
• -Clopidogrel resistance absolute difference
  between baseline and post-treatment aggregation
  10 in response to both 5 and 20 µmol/L ADP.
• -ASA resistance definition (incorporated
  previously used criteria) required two of the
  following three 1) 0.5mg/ml AA-induced platelet
  aggregation 20 2) 5 µmol/L ADP-induced
  platelet aggregation 70 and 3) RPFA-ASA ARU
  550.
• -Additional definitions to allow comparison
  with prior studies
• 1) Criteria 1 2
• 2) Criterion 3
• - Baseline blood samples used to determine ASA
  resistance

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Resistance
Rates
Clopidogrel Resistance ( of patients)

• Clopidogrel resistance was evident in 36 patients
  (24).

patients
Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Resistance
Rates

• Using the primary definition (having 2 of the
  criteria), 19 patients were observed to
  ASA-resistant (12.7, p0.01).
• The definition requiring the presence of criteria
  1 2 (AA induced aggregation and 70 5 µmol/L
  ADP-induced aggregation), 14 patients were ASA
  resistant (9.3, p0.02).
• Under the definition requiring criterion 3
  (RPFA-ASA ARU 550), 23 patients were
  ASA-resistant (15.3, p0.01).

Aspirin Resistance ( of patients)
p0.01
p0.01
p0.02
Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Resistance
Rates
Clopidogrel resistance among ASA-resistant and
ASA-sensitive patients ( of patients)

• Regardless of which ASA resistance definition was
  used, 50 of patients were resistant to both ASA
  and clopidogrel while 20 were sensitive to ASA
  but resistant to clopidogrel.

p0.02
of patients
Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Resistance
Rates
AA-induced aggregation before and 20-24 hours
after witnessed ASA dose in
ASA-sensitive patients () p0.3
ASA-resistant patients () p0.2
10 /- 3.7
10.5 /- 4.7
18.8 /- 2.9
20.2 /- 4.5
patients
patients

• AA-induced aggregation was compared pre- and
  post-PCI among aspirin-resistant and
  aspirin-sensitive patients in order to evaluate
  the affect of previous medication compliance on
  aspirin resistance.
• The differences were insignificant.

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Patient
Characteristics
Dual Drug resistance and ASA resistance in men
and women ()

• Men were less likely to be dual-drug resistant
  compared with women (26.9 vs. 67.7, p0.02).
• Aspirin resistant patients were more commonly
  women and had diabetes.
• More specifically, 8 of the 103 men compared with
  11 of the 47 women were ASA-resistant (7.8 vs.
  23.4, p0.01).
• No differences were found between
  clopidogrel-resistant versus clopidogrel-sensitive
  patients.

p0.02

p0.01


n8
n11
Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Response
to Clopidogrel
ADP-induced aggregation in ASA-resistant vs.
ASA-sensitive patients ()

• Aspirin-resistant patients had a higher
  percentage of post-clopidogrel ADP-induced
  aggregation than aspirin-sensitive patients (5
  µmol/L ADP 78.9 vs. 18.3, p0.001 and 20
  µmol/L ADP 73.4 vs. 19.1, p0.001).
• There was a significant difference in the change
  of ADP-induced aggregation compared with tertiles
  of AA-induced aggregation (5 µmol/L ADP, p0.006
  and 20 µmol/L ADP, p0.0001).

20 µmol/L
5 µmol/L
p0.001
p0.001

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Markers
of Myonecrosis
CK-MB elevation above the upper limit of normal
()

• CK-MB elevation was present more often in
  patients who were ASA-resistant than in those
  that were ASA-sensitive (38.9 vs.18.3, p0.04)
  and in dual-resistant compared with dual
  sensitive patients (44.4 vs. 15.8, p0.05).
• Similarly, CK-MB levels trended toward more
  frequent elevations among clopidogrel-resistant
  compared with clopidogrel-sensitive patients
  (32.4 vs. 17.3, p0.06).

p0.04
p0.06
p0.05
patients with CK-MB elevation
Clopidogrel-Resistant
Dual- Resistant
Clopidogrel-Sensitive
ASA-Sensitive
ASA-Resistant
Dual-Sensitive
Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Limitations

• This study was powered to examine the different
  responses that aspirin-resistant and
  aspirin-sensitive patients exhibit while being
  treated with clopidogrel however, the sample
  size was not large enough to estimate the risk of
  myonecrosis associated with dual drug resistance.
• Since the antiplatelet effects of aspirin and
  clopidogrel were only assessed at two time points
  during one 24 hour period, they may not reflect
  the possible temporal fluctuations among
  individual responses.
• Among all patients the first blood sample was
  obtained from an arterial access site whereas,
  the second was from a venous access site.
• The loading dose of clopidogrel was 300 mg, which
  is the dose that most clinical efficacy data have
  been obtained with, but recent studies have
  indicated that a 600 mg loading dose not only
  produces a more rapid and pronounced early
  response, but also reduces the rate of
  clopidogrel resistance.

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Summary

• This is the first study to differentiate the
  response to clopidogrel among aspirin-resistant
  and aspirin-sensitive patients.
• Also, it is the first to study antiplatelet drug
  response among a direct thrombin inhibitor
  instead of unfractionated heparin.
• ASA resistance was present in 9 to 15 of
  patients depending on its definition and there
  was clopidogrel resistance in 24.
• Approiximately half of the patients who were
  ASA-resistant were also resistant to clopidogrel.
• Both aspirin resistance and dual drug resistance
  were more commonly observed in women, which may
  help explain the recently reported failure of ASA
  to produce beneficial primary prevention effects
  in women.

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Summary
cont.

• An additional clinical factor associated with
  aspirin resistance is diabetes and platelets have
  been shown to have a reduced response to aspirin
  in patients with type 2 diabetes.
• Three possible mechanisms may explain the lower
  response to clopidogrel in aspirin-resistant
  patients 1) a global increase in platelet
  reactivity 2) an increase in platelet turnover,
  which may cause the release of young platelets
  that are still able to form thromboxane A2
  through non-cyclooxygenase-1-dependent pathways
  and respond to ADP regardless of ASA and
  clopidogrel treatment, or 3) poor compliance,
  which is not likely since both the clopidogrel
  loading dose and ASA were administered in the
  cath lab.
• Furthermore, as demonstrated by the elevated
  CK-MB levels in ASA-resistant and dual-resistant
  patients and the tendency of clopidogrel-resistant
  patients to have more frequent CK-MB elevation,
  this study extends the evidence of an association
  between adverse clinical events and resistance to
  ASA and clopidogrel.

Lev et al., JACC 2006 Jan47(1)27-33.
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Aspirin and Clopidogrel Drug Response Summary
cont.

• The high occurrence of elevated CK-MB levels
  found post-PCI in the dual drug-resistant group
  suggests these patients may be at high risk for
  thorombotic complications and should be confirmed
  in a larger study.
• The low response to clopidogrel among
  aspirin-resistant patients is clinically
  important since clopidogrel has been suggested as
  an alternative treatment for aspirin-resistant
  patients. This finding suggests that other
  platelet inhibitors that would act on additional
  targets should be developed and evaluated.

Lev et al., JACC 2006 Jan47(1)27-33.