Transcript Comparison of optical coherence tomography and

Aspirinn doses in diabetics - Angiolillo
Slide 1
Pharmacodynamic Effects of Different Aspirin
Dosing Regimens in Type 2 Diabetes Mellitus
Patients with Coronary Artery Disease
Davide Capodanno, MD, Aasita Patel, MD, Kodlipet
Dharmashankar, MD, José Luis Ferreiro, MD, Masafumi Ueno, MD,
Murali Kodali, MD, Salvatore D. Tomasello, MD,
Piera Capranzano, MD, Naveen Seecheran, MD, Andrew Darlington,
MD, Antonio Tello-Montoliu, MD, PhD, Bhaloo Desai, PhD,
Theodore A. Bass, MD, Dominick J. Angiolillo, MD, PhD
University of Florida, College of Medicine, Jacksonville, USA
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Aspirinn doses in diabetics - Angiolillo
Slide 2
Background
 The reduced life-span and increased turnover rates of
platelets have been suggested to have a contributing
role in the differential pharmacodynamic response
profiles to antiplatelet therapy in type 2 diabetes
mellitus (T2DM) patients.
 Aspirin has only a 20-minute half-life and therefore
the accelerated thrombopoiesis which characterizes
T2DM patients does not allow newly generated
platelets entering the circulation to be sufficiently
exposed to aspirin.
Winocour, et al. Eur J Clin Invest. 1994;24 (Suppl 1):34-7
Di Minno G, et al Blood. 1983;61:1081-5
Patrono C. N Engl J Med. 1994;330:1287-94
Aspirinn doses in diabetics - Angiolillo
Slide 3
Rationale and objective
 It may be hypothesized that an increase in the
frequency, rather than the dose, of aspirin
administration may be a more effective strategy to
inhibit platelet reactivity in diabetic patients as this
may enable COX-1 blockade of newly generated
platelets
 Therefore, the aim of the present pilot investigation
was to evaluate how increasing the frequency of
aspirin administration, remaining within the daily
recommended therapeutic doses, affects antiplatelet
responsiveness in T2DM patients with coronary artery
disease (CAD)
Aspirinn doses in diabetics - Angiolillo
Slide 4
Schematic of circadian release of platelets into bloodstream from
bone marrow and impact of a single daily dose of aspirin on newly
generated platelets in type 2 diabetes mellitus
Platelets from patients with type 2 diabetes mellitus (T2DM) have a reduced life-span and increased turnover rates, leading to
enhanced bone marrow megakaryocyte generation and release of new and hyper-reactive platelets into the bloodstream. Aspirin has
only a 20-minute half-life and therefore the accelerated thrombopoiesis which characterizes T2DM patients does not allow newly
generated platelets entering the circulation to be sufficiently exposed to aspirin if given once daily. This may lead to a considerable
proportion of circulating platelets with uninhibited cyclooxigenase-1 (COX-1) activity that continue to generate high levels of serum
thromboxane and therefore promote activation of circulating platelets (acetylated and non-acetylated) via thromboxane receptors
(TP) on the platelet surface. A twice daily administration of aspirin may allow newly generated platelets released into the bloodstream
to be COX-1 inhibited, thus achieving more optimal blockade of platelet activation processes in T2DM.
Aspirinn doses in diabetics - Angiolillo
Slide 5
Patients modified their aspirin regimen on a
weekly basis according to the following scheme
Screening
phase
run-in
phase
Visit 1
81 mg
od
Visit 2
81 mg
bid
Visit 3
162 mg
od
Visit 4
162 mg
bid
Visit 5
325 mg
od
Pharmacodynamic assessments included:
 light transmittance aggregometry (LTA) following arachidonic
acid, collagen and adenosine diphosphate (ADP) stimuli
 VerifyNow-Aspirin assay;
 serum thromboxane B2 (TXB2) levels
Aspirinn doses in diabetics - Angiolillo
Slide 6
Patient population
* Key exclusion criteria
T2DM patients screened
N = 82
Excluded *
N = 34
Eligible to participate to
the study
N = 48
Agreed to participate to
the study
N = 36
Completed all five treatment
regimens and entered the
final analysis
N = 20
•
active bleeding or bleeding
diathesis
•
concomitant use of other
antithrombotic drugs
•
recent treatment (30 days) with a
glycoprotein IIb/IIIa antagonist
•
•
platelet count 100*106/l
•
•
serum creatinine > 2 mg/dL;
•
HbA1C > 10%
acute coronary or cerebrovascular
event within 3 months;
baseline ALT > 2.5 times the upper
limit of normal
Aspirinn doses in diabetics - Angiolillo
Slide 7
Baseline clinical characteristics
(n = 20)
Age (years±SD)
Male, n (%)
BMI (Kg/m2±SD)
Risk factors, n (%)
Smoking
Hypertension
Dyslipidemia
Insulin-treated
Medical history, n (%)
Prior MI
Prior stroke
Prior CABG
Multivessel CAD
59±7
10 (50)
33±9
6 (30)
19 (95)
17 (85)
8 (40)
1 (5)
0 (0)
2 (10)
6 (30)
Aspirinn doses in diabetics - Angiolillo
Slide 8
Medical therapy
(n = 20)
Beta-blockers
ACE inhibitors
Ca2+ antagonists
Lipid-lowering agents
CYP 3A4 pathway metabolized
Non-CYP 3A4 pathway metabolized
Proton pump inhibitors
11 (55)
18 (90)
11 (55)
8 (40)
0 (0)
5 (25)
Laboratory data
(n = 20)
Platelet count (1,000/mm3±SD)
Hematocrit (%±SD)
HbA1C (%±SD)
Creatinine (g/dl±SD)
241±66
42±4
7.1±1.3
1.0±0.3
Aspirinn doses in diabetics - Angiolillo
Slide 9
Dose comparison in once daily
administration
81 mg od vs.
81 mg
162 md 325 mg
Assay
81 mg od vs.
81 mg od vs.
162 mg od vs.
162 mg od
325 mg od
325 mg od
162 mg od vs
325 mg od
od
od
od
P value
P value
P value
P for trend
Arachidonic acid (1 mmol/L), %
2±0.9
2±0.7
2±0.7
1.000
1.000
1.000
1.000
Collagen (2 µg/mL), %
44±23
39±14
35±15
0.285
0.083
0.374
0.157
ADP (5 µmol/L), %
49±13
54±10
54±11
0.111
0.851
0.612
0.192
ADP (20 µmol/L), %
66±7
71±11
68±7
0.033
0.459
0.145
0.109
455±51
432±62
431±58
0.087
0.126
0.922
0.121
107±143
41±79
22±21
0.008
0.030
0.328
0.008
VN-ASA, ARU
Serum TXB2, pg/ml
Data are expressed as means±SD.
ADP indicates adenosine diphosphate; VN-ASA indicates VerifyNow-Aspirin assay; TXB2 indicates thromboxane B2
Aspirinn doses in diabetics - Angiolillo
Slide 10
Dose comparison in twice daily
administration
Assay
81 mg bid
162 mg bid
P value
Arachidonic acid (1 mmol/L), %
2±0.5
2±1.4
0.106
Collagen (2 µg/mL), %
32±14
33±14
0.895
ADP (5 µmol/L), %
54±13
50±15
0.360
ADP (20 µmol/L), %
69±11
67±14
0.476
VN-ASA, ARU
420±41
423±52
0.777
Serum TXB2, pg/ml
34±50
19±21
0.165
Data are expressed as means±SD.
ADP indicates adenosine diphosphate; VN-ASA indicates VerifyNow-Aspirin assay; TXB2 indicates thromboxane B2
Aspirinn doses in diabetics - Angiolillo
Slide 11
Comparison of single versus staggered
daily administration of the same aspirin
dose
162 mg
Assay
81 mg
bid
Arachidonic acid (1 mmol/L), %
2±0.7
2±0.5
Collagen (2 µg/mL), %
39±14
ADP (5 µmol/L), %
ADP (20 µmol/L), %
Serum TXB2, pg/ml
162 mg
P
od
VN-ASA, ARU
325 mg
P
od
bid
0.772
2±0.7
2±1.4
0.094
32±14
0.060
35±15
33±14
0.490
54±10
54±13
0.857
54±11
50±15
0.273
71±11
69±11
0.343
68±7
67±14
0.751
432±62
420±41
0.345
431±58
423±52
0.551
41±79
34±50
0.716
22±21
19±21
0.579
Data are expressed as means±SD.
ADP indicates adenosine diphosphate; VN-ASA indicates VerifyNow-Aspirin assay; TXB2 indicates thromboxane B2
Aspirinn doses in diabetics - Angiolillo
Slide 12
Comparison of different aspirin regimens by collagen induced light
transmission aggregometry (A) and VerifyNow-ASA (B)
80
80
p = 0.046
70
60
50
50
50
%
60
40
40
30
30
20
20
20
10
10
10
0
0
81 mg od
81 mg bid
2 ug/mL collagen-LTA
B
81 mg od
162 mg bid
2 ug/mL collagen-LTA
600
162 mg od
162 mg bid
2 ug/mL collagen-LTA
600
p = 0.004
600
p = 0.016
p = 0.515
500
500
500
400
400
400
ARU
ARU
40
30
0
p = 0.044
70
60
%
%
70
80
p = 0.015
300
ARU
A
300
300
200
200
200
100
100
100
0
0
81 mg od
81 mg bid
VN-ASA
0
81 mg od
162 mg bid
VN-ASA
162 mg od
162 mg bid
VN-ASA
Aspirinn doses in diabetics - Angiolillo
Slide 13
Changes in thromboxane B2 levels across the
study phases
300
250
p = 0.003
pg/ml
200
150
100
50
0
81 od
81 bid
162 od
162 bid
325 od
Thromboxane B2 levels are expressed as pg/ml. Error bars indicate standard deviations of the mean.
Error bars indicate standard deviations; od indicates once daily administration; bid indicates twice daily
administration.
Aspirinn doses in diabetics - Angiolillo
Slide 14
Conclusions
• Aspirin dosing regimens are associated with
different pharmacodynamic effects in platelets from
T2DM patients and stable CAD.
• In particular, a twice daily low-dose aspirin
administration is associated with greater platelet
inhibition than a once daily administration as
assessed by aspirin sensitive assays, and a dosedependent effect is observed on serum TXB2 levels.
• The clinical implications of a modified aspirin
regimen tailored to T2DM patients warrants further
investigation.
Aspirinn doses in diabetics - Angiolillo
Slide 15
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