inactive clopidogrel pro-drug nr1i2 inactive clopidogrel 1 ... · 1.1 million 2 antiplatelettherapy...
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11-10-2018
1
Small intestine cell
Inactive
Clopidogrel
Pro-drug
ABCB1CES1
CYP1A2
CYP2C19
CYP2B6
CYP2C19
CYP3A4
CYP3A5
CYP2B6
PON1
CYP2C9Elimination
(urine, feces)
Platelet
Clopidogrel
P2Y12-receptor
NR1I2
Liver cell
++
+
+Inactive
Clopidogrel
Pro-drug
Inactive
metabolite
2-oxo-
Clopidogrel
Active
Clopidogrel
metabolite
Inactive
Clopidogrel
Pro-drug
Iskæmisk apopleksi og clopidogrel non-response
Charlotte Lützhøft Rath
5. Oktober 2018
The size of the problem
21
3
21
3
Most expensive brain disorder
Cause of death
1.1 million
2
Antiplatelet therapy
• Reduces the risk of recurrent stroke
• Early treatment is favoured
• In Denmark: Acetylsalicylic acid + ERDP or clopidogrel
3
Antiplatelet therapy testing
Bleeding time
Optimal Aggregometry
Impedence aggregometry
Aggregometry and Lumiscence
Laser Platelet Aggregometry (PA-200)
Thromboelastograophy (TEG)
Glass Filterometer
Clot Signature Analyzer (CSA)
Haemodyne
HemoSTATUS
Thrombotic Status Analyser (TSA)
Cone & Plate Analyser (CPA)
ICHOR (Plateletworks)
Platelet Function Analyser (PFA-100)
VerifyNow
Multiplate Impedance
Flow Cytometry
Cellix I Diagnose Platform
Serum Thromboxane B2 or Urinary 11-
dehydro-thromboxane B2/Creatinine
ratio
4
Brar et al. J Am Coll Card. 2011
Stone et al. Lancet. 2013
The evidence so far
5
Fiolaki et al. J Neurol Sci. 2017
6
11-10-2018
2
Li et al. Heart. 2014
Godschalk et al. AM J Cardiol. 2017
Xie et al. Int J Cardiol. 2013
Collet et al. NEJM. 2012
Trenk et al. JACC. 2012
Collet et al. Eur J Clon Pharmacol. 2015
Zhou et al. BMC. 2017
Depta et al. Stroke. 2012
Personalised medicine – The evidence so far
Antiplateletfunctiontesting
Antiplateletadjustment
Better
CYP2C19 testing
Antiplateletadjustment
No difference
CYP2C19 testing
Antiplateletadjustment
Better
Antiplateletfunctiontesting
Antiplateletadjustment
No difference
Antiplateletfunctiontesting
Antiplateletadjustment
Worse
7 8
Study I: Methods
Study event
Standard treatment
AP
75
mg
/day
Ho
spit
al a
dm
issi
on
Pla
tele
t fu
nct
ion
test
ing
wit
h V
eri
fyN
ow
Bra
in C
T o
r M
RI
Stro
ke s
ym
pto
m o
nse
t
Clo
pid
og
rel
30
0 m
g
Maximum 48 hours 8-24 hours
Time
Fin
al
dia
gn
osi
s
Stro
ke p
hysi
cia
n
eva
lua
tio
n
Inclusion criteria:
• Clinically suspected TIA or stroke
within the last 48 h
• Treatment with clopidogrel 300 mg
on admission
Exclusion criteria:
• Previous clopidogrel treatment
• Haemorrhage or pathologies other
than IS on brain CT
• Cancer
• Increased bleeding risk or ongoing
bleeding
• Treatment, NOAC or Vit-K antagonists
other ADP-inhibitor or NSAIDs other
than ASA
• Unmet criteria for IS or TIA diagnosis
at discharge
• Abnormal Hct or platelet count
9
Study I:Factors associated with HTPR
28.8 % with HTPR
10
11
Discharge from hospital with stroke
diagnosis
Outpatient clinic visit for information
on study and screening for eligibility
with study doctor
If suspected new stroke or
TIA since last visit either
from medical history or
clinical examination -> stroke
unit evaluation
No new eventNew IS/TIA/AMI/
vascular death
Blood test for clopidogrel HTPR by
study nurse
Outpatient clinic visit every 6 months:
Medical history since last visit
Clinical examination
Evaluation of prescriptions
2 years Follow upStudy completed
Study II: Methods
IS: Ischemic Stroke
TIA: Transient Ischemic Attack
AMI: Acute Myocardial Infarction
Time
Minimum 14 days
2 years
Same
day
12
11-10-2018
3
165
67
18
49 13-15
13
Study II: Results
14
Conclusions
About 1/3 of acute ischemic stroke patients have HTPR in the acute stroke phase, where the risk of recurrent
stroke is highest.
Patients in long-term treatment with clopidogrel do not (hardly ever) have HTPR with af PRU limit at 208.
There is not enough data to suggest function guided long-term
antiplatelet therapy.
15
Future perspectives
• HTPR in the acute phase in 1/3: dual antiplatelet treatment
16
Future perspectives: POINT results
17
Tak for opmærksomheden.
18
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