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