Transcript Effect of Aspirin Dose on Platelet Reactivity in

Effect of Aspirin Dose on
Platelet Reactivity in
Diabetic Patients
Paul A. Gurbel, MD
Director, Sinai Center for Thrombosis Research
Sinai Hospital of Baltimore
Associate Professor of Medicine
Johns Hopkins University School of Medicine
Baltimore, MD
Background
• Diabetes is a “prothrombotic state” characterized by accelerated
atherosclerosis and inflammation.
• Diabetic patients with acute coronary syndromes (ACS) are at higher risk for
recurrent ischemic events compared to non-diabetic ACS patients.1
• Aspirin treatment in diabetic patients is less effective in inhibiting platelet
thromboxane synthesis compared to aspirin treatment in non-diabetics.2
• In the primary prevention project (PPP), a higher cardiovascular risk was
observed in diabetic patients on low dose aspirin compared to non-diabetic
patients, suggesting that the benefits of aspirin therapy may be outweighed
by aspirin insensitive mechanisms of platelet activation.3
• There are limited data quantifying the prevalence of platelet aspirin resistance
in diabetic patients.
• No study has prospectively analyzed the effect of varying aspirin doses on
platelet function in both diabetics and non-diabetics using multiple methods.
•
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and
stroke in high risk patients. BMJ 2002;324:71-86
•
Watala C. Blood platelet reactivity and its pharmacological modulation in people with diabetes mellitus. Current Pharmaceutical Design. 2005;11:2331-2365.
3.
Sacco M et al. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project
(PPP) trial. Diabetes Care. 2003;12:3264-72.
Objectives
• To determine whether diabetic patients with coronary artery
disease during therapy with 81mg daily aspirin will exhibit a
higher prevalence of aspirin resistance and a state of high
platelet reactivity to multiple agonists compared to nondiabetics.
• To determine whether higher daily aspirin doses (162 or
325mg/day) will reduce platelet reactivity to multiple agonists
and decrease the prevalence of aspirin resistance
in diabetic patients.
Methods- Subjects
• Stable CAD outpatients (n=120) from the ASpirin-Induced
Platelet EffeCT (ASPECT) study were examined.
- Random double blind drug treatment sequence of 81,162, and 325mg/day
for 4 weeks each over a 12 week period (Williams design).
- Diabetes (n=30) was defined as fasting glucose 126mg/dL or treatment
with oral hypoglycemic agents  insulin.
• Exclusion Criteria:
- Hx of gastrointestinal bleeding, hemorrhagic stroke, illicit drug or
alcohol abuse, coagulopathy or major surgery within 6 weeks prior
to randomization.
- Plt < 100,000/mm3, Hct< 30%, Cr >4.0 mg/dL.
- Current use of non-steroidal anti-inflammatory drugs, anticoagulants, or
antiplatelet drugs other than aspirin.
Methods-Platelet Testing
• Light Transmittance Aggregometry
- Maximum % change in light transmittance using platelet poor plasma as a
reference.
- Platelets were stimulated with 2 and 5mM arachidonic acid (AA),
5uM adenosine diphosphate (ADP) and 2ug/mL collagen.
• VerifyNow™ (Accumetrics, San Diego, CA)
- Measures platelet aggregation to fibrinogen-coated beads after stimulation
with arachidonic acid and reports this value in aspirin reaction units
(ARU).
• PFA-100 (Dade-Behring, West Sacramento, CA)
- Uses a test cartridge containing a collagen/epinephrine coated
membrane to measure the closure time (seconds) required for platelets
to aggregate and arrest blood flow through an aperture.
• Urinary 11-dehydro-TxB2 (AspirinWorks (Denver, CO)
- Levels were estimated using Enzyme Linked Immunoassay (ELISA)
and reported as pg 11-dehydro-TxB2/mg creatinine.
Methods- Definitions
Aspirin Resistance
 > 20% AA-, > 70% ADP- and > 70% collagen-induced platelet aggregation.1
  550 ARU (VerifyNow).
 < 193 seconds to closure (PFA-100).
 Upper quartile (>420 pg 11-dehydro-TxB2/mg creatinine) during treatment
with 81mg.2
1. Gum PA et al. J Am Coll Cardiol. 2003;41:961-965.
2. Eikelboom JW et al. Circulation 2002;105:1650-1655.
Patient Demographics
649
NonDiabetic
Group
(n=90)
66±11
Diabetic vs.
NonDiabetic
(p-value)
0.38
65 (65)
73 (73)
195±52
18 (60)
22 (73)
210±55
47 (67)
51 (73)
192±50
0.33
1.0
0.11
8 (8)
30 (30)
38 (38)
65 (65)
2 (7)
10 (33)
13 (43)
22 (73)
6 (9)
20 (29)
25 (36)
43 (61)
0.74
0.69
0.51
0.25
Prior Myocardial Infarction
Prior Coronary Artery Bypass Grafting
18 (18)
31 (31)
6 (20)
9 (30)
12 (17)
22 (31)
0.37
0.13
Prior Coronary Angioplasty
Prior Cerebrovascular Accident
Baseline Medications n, (%)
Beta Blockers
ACE Inhibitors
Calcium Channel Blockers
Lipid Lowering Therapy
Laboratory Data
33 (33)
6 (6)
10 (33)
5 (17)
23 (33)
1 (1)
1.0
0.002
56 (56)
52 (52)
19 (19)
76 (76)
18 (60)
19 (63)
5 (17)
23 (77)
38 (54)
33 (47)
14 (20)
53 (76)
0.58
0.15
0.72
0.91
6.4±2.2
225±67
13.3±2.0
40.8±5.1
1.1±0.6
165±41
95±36
50±12
6.3±2.5
208±71
12.8±3.6
38.2±11.1
1.1±0.2
155±43
91±37
45±13
6.4±1.9
229±63
13.6±2.2
41.2±5.2
1.2±0.7
170±44
98±38
51±11
0.82
0.14
0.17
0.09
0.45
0.12
0.40
0.02
Age (years)
Gender and Ethnicity n, (%)
Male
Caucasian
Weight (lbs)
Risk Factors/Past Medical History n,(%)
Current Smoking
Previous Smoking
Family History of Coronary Artery Disease
Hypertension
White Blood Cell Count (x 1000/mm 3)
3
Platelets (x 1000/mm )
Hemoglobin (g/dL)
Hematocrit (%)
Creatinine (g/dL)
Total Cholesterol
Low Density Lipoprotein
High Density Lipoprotein
Total
Group
(n=120)
Diabetic
Group
(n=30)
6510
Results
Platelet Aggregation (%)
100
Resistant pt #1
Resistant pt #2
80
60
40
Resistance
20
0
81 81 162
325
162 325
mgmg mg
mg
mg mg
Diabetic
Diabetic
162
81 81162 325
mg
mg
mg mg mg
325
mg
Non-Diabetic
Non D
- iabetic
2mM AA-Induced
AA -InducedLTA
LTA
81
162
81 162
mg
mg
mg mg
325
325
mg
mg
Diabetic
Diabetic
81 162162325 325
81
mg
mg
mg
mg mg mg
Non-Diabetic
Non
-Diabetic
5mM
5mM
AA AA-Induced
-Induced
LTA
LTA
Results
5uM ADP-Induced LTA
2ug/mL Collagen-Induced LTA
40
81mg ASA
35
162mg ASA
Resistance (%)
30
27
27
23
25
20
325mg ASA
17
14
15
10
10
+
*4
5
*3 3*
+
4
3
0
0
Diabetic
Non-Diabetic
Diabetic
*p0.05 for within group comparison
+p0.05 for between group comparison
Non-Diabetic
Results
VerifyNow Aspirin Assay
20
81mg ASA
162mg ASA
325mg ASA
18
Resistance (%)
16
14
13
12
10
8
6
4
+
3
3
3
4
3
2
0
Diabetic
Non-Diabetic
+p0.05 for between group comparison
Results
PFA-100
70
81mg ASA
162mg ASA
325mg ASA
Resistance (%)
60
50
41
40
40
30
*
20
17
29
27
*
14
10
0
Diabetic
Non-Diabetic
*p0.05 for within group comparison
Results
Urinary Thromboxane
60
81mg ASA
162mg ASA
325mg ASA
Resistance (%)
50
40
37
30
23
20
*
16
+
17
16
13
10
0
Diabetic
Non-Diabetic
*p0.05 for within group comparison
+p0.05 for between group comparison
Comparison Between Groups at Specific Dose
Diabetic
(n=30)
Diabetic
vs.
Non-Diabetic
(p-Value)
Non-Diabetic
(n=90)
81mg
162mg
325mg
81mg
162mg
325mg
81
mg
162
mg
325
mg
2mM AA-LTA (%)
7±18
4±2
5±3
4±1.5
4±6
4±1
NS
NS
NS
5mM AA-LTA (%)
8±22
7±13
5±4
5±8
4±2
5±4
NS
NS
NS
470±66
448±57
426±45
445±48
429±38
428±43
0.02
0.04
NS
5μm ADP-LTA (%)
64±13
60±9
61±3
57±12
57±12
57±9
0.01
NS
0.05
2μg/mL CollagenLTA (%)
54±23
33±21
29±16
31±23
27±20
27±17
<0.001
NS
NS
208±69
251±67
231±73
226±74
257±63
245±65
NS
NS
NS
413±110
332±106
302±112
331±136
315±145
298±148
0.02
NS
NS
AA Stimulated Assays
Accumetrics (ARU)
Other Assays
PFA-100 (sec.)
Urinary Thromboxane
(pg/mg creatinine)
Evaluation of Dose Effect within Groups
Diabetic
(n=30)
Non-Diabetic
(n=90)
81mg
162mg
325mg
81mg
162mg
325mg
2mM AA-LTA (%)
7±18
4±2
5±3
4±2
4±6
4±1
5mM AA-LTA (%)
8±22
7±13
5±4
5±8
4±2
5±4
470±66
448±57
426±45+
445±48
429±38*
428±43+
5μm ADP-LTA (%)
64±13
60±9
61±3
57±12
57±12
57±9
2μg/mL Collagen-LTA (%)
54±23
33±21*
29±16+
31±23
27±20
27±17
PFA-100 (sec,)
208±69
251±67*
231±73
226±74
257±63*
245±65
Urinary Thromboxane
(pg/mg creatinine)
413±110
332±106*
302±112+
331±136
315±145
298±148
AA Stimulated Assays
Accumetrics (ARU)
Other Assays
*p0.02 for 81mg vs 162 mg
+p0.02 for 81mg vs 325 mg
No dose effect observed between 162mg vs 325mg
Conclusion
• Low dose aspirin may not provide adequate platelet inhibition in
diabetic patients.
• In general, increasing the dose of aspirin in the diabetic patient
reduces the prevalence of resistance to a level observed in the nondiabetic patient.
• However, we did not observe a dose dependent effect of aspirin on
resistance measured by ADP-induced aggregation in diabetic
patients suggesting a potential benefit of using ADP receptor
blockers in addition to higher dose aspirin in selected diabetic
patients.
• Future large scale studies are needed to evaluate the clinical
efficacy of higher dose aspirin in diabetic patients.
• The dose dependent effects of aspirin suggest that the
antithrombotic properties of the drug are not all explained by COX-1
inhibition.