Transcript Abstract - Clinical Trial Results

ASA Resistance and
Clinical Outcomes
Daniel I. Simon, M.D.
Associate Director, Interventional Cardiology
Brigham and Women’s Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, MA USA
ASA Resistance: Key Questions
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Does a standardized definition exist?
Are there reliable tests to diagnose this
phenomenon?
What are the possible mechanisms and future
implications?
Does it have any clinical significance?
How do we manage patients with Aspirin
resistance?
Established Platelet Function Tests
Platelet
Function Test
Plt Function
Test
Assay
Advantages
Advantages
Disadvantages
Disadvantages
Physiological
Insensitive, invasive & high
variability
Labor intensive & nonphysiological
Bleeding time
In Vivo screening test
Aggregometry-turbidometric
methods
Responsiveness to panel agonists Diagnostic
Aggregometry-impedance
methods
Responsiveness to panel agonists Whole blood test
Insensitive
Aggregometry &
luminescence
Combined aggregation and ADP
release
More information
Semi-quantitative
Adenine nucleotides
Stored and released ADP
Sensitive
Specialized equipment
Thromboelastography (TEG)
Global Hemostasis
Predicts bleeding
Glass filterometer
High shear platelet function
Simple
Measures clot properties
only, insensitive to ASA
Requires blood counter
Platelet release markers
In vivo platelet activation markers
Simple, systemic
Prone to artifact
measure of platelet
activation
Harrison P. Br J Hematology 2000;111:733-744
Newer Platelet Function Tests
Assay
Substrate
Bedside
Principle
Comments
(PFA)-100
Whole blood
+
Primary
hemostasis
(high shear
adhes/aggreg)
Limited range-most pts
after GP IIb/IIIa inhibitors have
closure times >300 sec, so may
not be able to discern diff. Used
to assay ADP antagonist
Clot Signature
Analyzer
Whole blood
+
Adhesion,
aggregation
Large instrument for routine use
and interpretation of results is
complex
Rapid platelet
function assay
Whole blood
+
Aggregation
GP IIb/IIa: baseline sample req.
Clinical outcome data (GOLD)
Aspirin: AA-like agonist
Flow cytometry
Whole blood
-
Platelet GP,
activation markers,
Platelet function
Flexible & powerful. Requires
specialized operator. Expensive
Harrison P. Br J Hematology 2000;111:733-744
Mukherjee D & Moliterno DJ. Clin Pharmacokinet 2000;39(6): 445-458
Prevalence of ASA Resistance
325 patients with stable CVD taking ASA 325 mg >7days
ASA-R: mean aggregation ≥70% with µM 10 ADP & ≥20% with 0.5 mg/ml AA
Gum PA et al. Am J Cardiol 2001;88:230-235
Prevalence of Aspirin Resistance
422 patients presenting to cardiac cath lab on ASA 81-325 mg >7d
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23.4% Aspirin non-responsive
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Accumetrics VerifyNow Aspirin
Definition: ARU > 550
Multivariate analysis: history of CAD associated with
twice the odds of being ASA non-responder (odds
ratio 2.09, 95% CI 1.189-3.411, p=0.009)
No association with gender, DM, smoking, ASA dose
Wang JC et al. Amer J Cardiol 2003;92:1492-4
Clinical Studies
ASA Resistance: Long-term Clinical Studies
Pts
ASA dose
Test
F/U
End-point
Results
Stroke1
(n=180)
1500 mg
Plt Reactivity
24 m
Stroke/MI/
Vascular death
10-fold lower
risk in ASA
responders
PVD2
(n=100)
100 mg
Whole blood
aggregometry
18 m
Arterial
Occlusion
87% higher risk
in ASA-R
>60 m
Recurrent CVA/
TIA
Recurrent CVA 34%
ASA-R vs. 0% no
recurrent events
CVD/CVA3 100 mg
(n=53) TIA
PFA-10
Subgroup 75-325 mg
HOPE4
(n=967)
Urinary 11-dehydro
TX B2
5 yrs
MI/Stroke/
CVDeath
1.8 times
higher risk in
upper vs. lower
quartile
CVD5
(n=326)
Optical platelet
aggregation
679±185
days
Death/MI/CVA
24% ASA-R vs.
10% ASA-S [HR
3.12 (95% CI 1.18.9, p=0.03)
1.
2.
3.
4.
5.
325 mg
Grotemeyer KH, et al. Thromb Res 1993; 71:397-403
Mueller MR, et al. Thromb Haemost 1997; 78:1003-1007
Grundmann K, et al. J Neurol 2003; 250: 63-66
Eikelboom JW, et al. Circulation 2002; 105:1650-1655
Gum PA, et al. J Am Coll Cardiol 2003; 41:961-965
ASA Resistance and Clinical
Outcome in CAD Patients
HOPE Trial Substudy: ASA 75-325 mg
Eikelboom JW, et al. Circulation 2002; 105:1650-1655
ASA Resistance and Clinical
Outcome in CVD Patients
326 CVD patients on ASA 325 mg > 7 days
p=0.03
ASA-R: mean aggregation ≥70% with 10 µM ADP & ≥20% with 0.5 mg/ml AA
Gum PA, et al. J Am Coll Cardiol 2003; 41:961-965
ASA Resistance and Clinical
Outcome in PVD Patients
Mueller MR et al. Thromb Haemost 1997; 78:1003-1007
ASA Resistance and Clinical
Outcome in Stroke Patients
Grotemeyer KH et al. Thromb Res 1993; 71:397-403
ASA Resistance and Clinical
Outcome in Stroke Patients
53 CVA pts on ASA 100 mg for secondary prevention > 60 months
Grundmann K et al. J Neurol 2003; 250: 63-66
ASA Resistance in PCI
RPFA-ASA, ASA/clopidogrel (n=151), 19.2% ASA resistant
Chen et al. J Amer Coll Cardiol 2004;43:1122-6
Oral Antiplatelet Agents
clopidogrel bisulfate
Dipyridamole
ADP
ticlopidine HCl
ADP
Phosphodiesterase
ADP
Gp IIb/IIIa
(Fibrinogen
Receptor)
Activation
COX
Collagen
Thrombin
TXA2
TXA2
Aspirin
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Schafer AI. Am J Med 1996;101:199–209.
Clopidogrel in Unstable Angina to
Prevent Recurrent Ischemic Events
Clopidogrel 75mg q.d.
+ ASA 75-325 mg q.d.*
(6259 patients)
Aspirin 75-325mg
Patients with
Non-ST elevation
Acute Coronary
Syndrome
R
3 months  double-blind treatment  12 months
Aspirin 75-325mg
1
3
6
9
Months
12
Placebo + ASA
75-325 mg q.d.*
(6303 patients)
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Primary Endpoint:
MI/Stroke/CV Death
Cumulative Hazard Rate
0.14
11.4%
Placebo
+ ASA*
0.12
9.3%
0.10
0.08
Clopidogrel
+ ASA*
0.06
0.04
20% RRR
P < 0.001
N = 12,562
0.02
0.00
0
3
6
9
Months of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
12
CREDO
N = 2,116 patients undergoing elective PCI
Pretreatment
Clopidogrel 75 QD
PLACEBO
+ ASA *
R
N = 1345
PCI
30 days post
PCI
Clopidogrel 75 QD
CLOPIDOGREL
300 mg
3-24h pre-PCI
N = 1313
+ ASA * Pretreatment
* In combination with standard therapy
End of follow-up
Up to 12 months
after
randomization
CREDO: Primary Endpoint
26.9% relative risk reduction
(CI 3.9-44.4%; P=0.02)
Absolute reduction = 3%
Steinhubl et al. JAMA 2002
Aspirin Resistant Patient Management
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Eliminate interfering substances (ibuprofen)
Increase aspirin dose
Use other anti-platelet medications such as
clopidogrel to prevent recurrent ischemic events
Educate patient on importance of compliance
Conclusions
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ASA use associated with 23% reduction in the
odds of vascular events
Beneficial anti-thrombotic effect of ASA
mediated by irreversible acetylation of COX-1
ASA resistance 5-60%
ASA resistance associated with increased risk
of major adverse cardiovascular events