Transcript Aspirin and Clopidogrel Drug Response

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
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.
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
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 aspirinsensitive patients
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Lev et al., JACC 2006 Jan;47(1):27-33.
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).
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
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 AAinduced 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
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Resistance Rates
Clopidogrel Resistance (% of patients)
100
76.0
% patients
80
• Clopidogrel
resistance was
evident in 36
patients (24%).
60
40
24.0
20
0
Clopidogrel-Resistant
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Clopidogrel-Sensitive
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Resistance Rates
Aspirin Resistance (% of patients)
p=0.01
p=0.01
16.0
p=0.02
12.7
% patients
12.0
15.3
9.3
8.0
4.0
n=19
n=14
n=23
2 of the 3
Criteria
Criteria 1 & 2
Criterion 3
0.0
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• Using the primary
definition (having ≥2 of
the criteria), 19 patients
were observed to ASAresistant (12.7%, p=0.01).
• 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%,
p=0.02).
• Under the definition
requiring criterion 3
(RPFA-ASA ARU ≥550), 23
patients were ASAresistant (15.3%, p=0.01).
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Resistance Rates
Clopidogrel resistance among ASA-resistant and ASAsensitive patients (% of patients)
p=0.02
% of patients
60
50
50
40
30
20
20
10
• 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.
0
ASA & Clopidogrel-Resistant
ASA-Sensitive & Clopidogrel Resistant
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Resistance Rates
AA-induced aggregation before and 20-24 hours after witnessed ASA dose in:
ASA-resistant patients (%)
ASA-sensitive patients (%)
p=0.2
p=0.3
20.2 +/- 4.5%
18.8 +/- 2.9%
16
% patients
% patients
25
20
15
10
10.5 +/- 4.7%
10 +/- 3.7%
12
8
4
5
0
0
Pre-PCI
Post-PCI
Pre-PCI
Post-PCI
• 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.
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Patient Characteristics
Dual Drug resistance and ASA resistance
in men and women (%)
%
p=0.02
70
60
50
40
30
20
10
0
67.7
p=0.01
26.9
23.4
7.8
n=8
Dual Drug
Resistance
Men
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n=11
ASA Resistance
Women
• Men were less likely to be
dual-drug resistant
compared with women
(26.9% vs. 67.7%, p=0.02).
• 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 ASAresistant (7.8% vs. 23.4%,
p=0.01).
• No differences were found
between clopidogrelresistant versus
clopidogrel-sensitive
patients.
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Response to Clopidogrel
ADP-induced aggregation in
ASA-resistant vs. ASA-sensitive patients (%)
5 μmol/L
100
%
80
20 μmol/L
p=0.001
78.9
p=0.001
73.4
60
40
20
18.3
19.1
0
ASA-Resistant
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ASA-Sensitive
• Aspirin-resistant patients
had a higher percentage of
post-clopidogrel ADPinduced aggregation than
aspirin-sensitive patients (5
μmol/L ADP: 78.9% vs.
18.3%, p=0.001 and 20
μmol/L ADP: 73.4% vs.
19.1%, p=0.001).
•There was a significant
difference in the change of
ADP-induced aggregation
compared with tertiles of
AA-induced aggregation (5
μmol/L ADP, p=0.006 and
20 μmol/L ADP, p=0.0001).
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Markers of Myonecrosis
CK-MB elevation above the upper limit of normal (%)
p=0.04
% patients with CK-MB elevation
50
45
40
p=0.06
p=0.05
44.4
38.9
32.4
35
30
25
20
15
18.3
17.3
15.8
10
5
0
ASAASAClopidogrel- Clopidogrel- DualDualResistant Sensitive Resistant
Sensitive Resistant Sensitive
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• CK-MB elevation was
present more often in
patients who were ASAresistant than in those
that were ASA-sensitive
(38.9% vs.18.3%, p=0.04)
and in dual-resistant
compared with dual
sensitive patients (44.4%
vs. 15.8%, p=0.05).
• Similarly, CK-MB levels
trended toward more
frequent elevations
among clopidogrelresistant compared with
clopidogrel-sensitive
patients (32.4% vs. 17.3,
p=0.06).
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Limitations
• This study was powered to examine the different responses that aspirinresistant 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.
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
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.
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
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.
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.
Aspirin and Clopidogrel Drug Response:
Summary cont.
• The high occurrence of elevated CK-MB levels found postPCI 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.
www. Clinical trial results.org
Lev et al., JACC 2006 Jan;47(1):27-33.