System

Interventional Procedure

Patients with inadequate response to their antiplatelet medications may be at significantly greater risk of myocardial

infarction, stent thrombosis and death.1-4

Up to 1/3 of patients on antiplatelet medications may not receive the expected platelet inhibiting effect.5

Numerous factors may cause inadequate response,6 including:

• Drug Interactions

(e.g. Proton Pump Inhibitors)

• Genetic differences

1 2 3 4 5

Residual Clopidogrel Responsiveness Within 3 days, > 50% of patients no longer have antiplatelet effectWithin 3 days, > 50% of patients no longer have antiplatelet effect

20%

40%

60%

80%

% O

F P

AT

IEN

TS

% O

F P

AT

IEN

TS

DAY OF RECOVERYDAY OF RECOVERY

No antiplatelet response

Moderate antiplatelet response

High antiplatelet response

• Pre-existing health

conditions (e.g. diabetes)

• Non-compliance

2

What is Reported?

The lab report may look similar to the following:

PRU reference range is 194-418. Values less than the low end of the reference range are specific evidence of a P2Y12 inhibitor effect.

P2Y12 Reaction Units (PRU) indicate the amount of ADP-mediated aggregation specific to the platelet P2Y12 receptor.

*******************************************************

*******************************************************

Patient Example PRUTest Results Patient A Units Reference Range

P2Y12 Reaction Units 132 PRU (Baseline platelet reactivity to ADP)

25 50 75100

125150

175200

225250

275300

325350

375400

425450

475

Values less than the lower limit (194) are highly specific for a P2Y12 inhibitor e�ectValues less than the lower limit (194) are highly specific for a P2Y12 inhibitor e�ect

Normal ADP Reactivity(No Evidence of P2Y12 Inhibitor E�ect)Normal ADP Reactivity(No Evidence of P2Y12 Inhibitor E�ect)

Supressed ADP Reactivity(Evidence of P2Y12 Inhibitor E�ect)

Supressed ADP Reactivity(Evidence of P2Y12 Inhibitor E�ect)

0

5

10

15

20

25

30

FRE

QU

EN

CY

FRE

QU

EN

CY

PRUPRU

VerifyNow PRUTest Results

VerifyNow PRUTest:Platelet response to P2Y12 inhibitors (e.g clopidogrel, prasugrel , ticlopidine, and ticagrelor).

PRU (P2Y12 Reaction Units)• ADP induced aggregation - extent of platelet aggregation in

the presence of P2Y12 inhibitors

• Residual Platelet Reactivity (RPR) of ADP P2Y12 receptor

Pre-Surgical Application• Studies show that there is patient variability in response to P2Y12

inhibitors7.

• Patients that have been administered P2Y12 inhibitors such as clopidogrel and prasugrel are at risk of perioperative bleeding.

• It has been recommended to discontinue P2Y12 inhibitors for 5 – 7 days prior to surgery8 for platelet function to be restored9, however, 2012 STS Guidelines10 recommend using platelet function testing to aid in timing of surgery, instead of arbitrarily waiting a pre-specified period of time.

To Order this Test:

In patients with high on-treatment reactivity (OTR) after PCI, there was substantial variability over time in the pharmacodynamic responses to study drug.Patients with low levels of OTR after PCI appeared to have few (if any) CV events.

Price MJ, AHA 2010

ADAPT-DES: Relationship Between VerifyNow P2Y12 PRU and Stent Thrombosis within 30 Days Definite or probable stent thrombosis

DE

FIN

ITE

/PR

OB

AB

LE S

T (

%)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

0 5 10 15 20 25 30

0.81%

0.21%

P2Y12 PRU > 208 (n=3607)

P2Y12 PRU ≤ 208 (n=4834)

P <0.001

HR [95% CI]=

3.89 [1.90, 7.98]

DAYS

3607 3540 3534 34824834 4754 4752 4686

Number at risk>208 PRU≤208 PRU

500

400

300

200

100

0

PRU VALUE

Post -PCI 30 d 6 mo Post -PCI 30 d 6 mo

N=1013 N=940N=1105 N=1012 N=944N=1109

P = 0.98P < 0.001

PERSISTENTLY HIGH REACTIVITY @ 30 DAYS: 62% VS40%, P<0.001

500

400

300

200

100

0

PRU 12 -24 HRS POST-PCI

High ResidualReactivity

Not HighResidual Reactivity

N=1105 N= 586

Red dots: patients with CV death, MI, or ST

230 PRU

Brar, S et al J Am Coll Cardiol. 2011 Nov 1;58(19):1945-54.*There are currently no definitive criteria that establish a standard PRU/% inhibition cutoff for ischemic risk

N = 3049

DE

AT

H, M

I, O

R S

T

TIME (DAYS)

N=30490.20

0.15

0.10

0.05

0.000 100 200 300 400 500 600 700

Q4 15.8% <0.001

Q3 10.9% 0.02

Q2 6.9% 0.97Q1 5.8% -

EventRateQuartile P-value*

CV Events and Post-PCI PRU In Patients With High and Not High Reactivity Treated With Clopidogrel 75-mg Daily

PharmacodynamicsEffect of SD vs HD Clopidogrel

Standard-Dose High-Dose

VerifyNow Meta AnalysisSurvival Analysis of PRU Quartiles*

Stone GW, et al presented at TCT 2011

Chart Tertiary Title or Labels

NON-THERAPEUTIC RANGE

THERAPEUTIC RANGE

POST ASPIRIN INGESTION

AR

U: A

SPIR

IN R

EA

CT

ION

UN

ITS

700

650

600

550

500

450

400

350

NON-THERAPEUTIC RANGE

THERAPEUTIC RANGE

POST ASPIRIN INGESTION

AR

U: A

SPIR

IN R

EA

CT

ION

UN

ITS

700

650

600

550

500

450

400

350

350

300

250

200

150

100

50

PR

U: P

2Y

12 R

EA

CT

ION

UN

ITS

Example PRU’s

Conditions that May Affect Test Results

• Patient’s exposure to GP IIb/IIIa inhibitors within:

– 48 hours of eptifibatide – 14 days of abciximab

• Improper sample collection (platelet activation)

VerifyNow Aspirin Test:Platelet response to aspirin

ARU (Aspirin Reaction Units)• Arachidonic acid induced aggregation

• Reference range: 620-672 ARU (pre-drug administration)

• Measurement range: 350–700 ARU

Result Interpretation:• Recommended cut-off: 550 ARU

VerifyNow Aspirin Results

To Order this Test:

In patients with high on-treatment reactivity (OTR) after PCI, there was substantial variability over time in the pharmacodynamic responses to study drug.Patients with low levels of OTR after PCI appeared to have few (if any) CV events.

Price MJ, AHA 2010

ADAPT-DES: Relationship Between VerifyNow P2Y12 PRU and Stent Thrombosis within 30 Days Definite or probable stent thrombosis

DE

FIN

ITE

/PR

OB

AB

LE S

T (

%)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

0 5 10 15 20 25 30

0.81%

0.21%

P2Y12 PRU > 208 (n=3607)

P2Y12 PRU ≤ 208 (n=4834)

P <0.001

HR [95% CI]=

3.89 [1.90, 7.98]

DAYS

3607 3540 3534 34824834 4754 4752 4686

Number at risk>208 PRU≤208 PRU

500

400

300

200

100

0

PRU VALUE

Post -PCI 30 d 6 mo Post -PCI 30 d 6 mo

N=1013 N=940N=1105 N=1012 N=944N=1109

P = 0.98P < 0.001

PERSISTENTLY HIGH REACTIVITY @ 30 DAYS: 62% VS40%, P<0.001

500

400

300

200

100

0

PRU 12 -24 HRS POST-PCI

High ResidualReactivity

Not HighResidual Reactivity

N=1105 N= 586

Red dots: patients with CV death, MI, or ST

230 PRU

Brar, S et al J Am Coll Cardiol. 2011 Nov 1;58(19):1945-54.*There are currently no definitive criteria that establish a standard PRU/% inhibition cutoff for ischemic risk

N = 3049

DE

AT

H, M

I, O

R S

T

TIME (DAYS)

N=30490.20

0.15

0.10

0.05

0.000 100 200 300 400 500 600 700

Q4 15.8% <0.001

Q3 10.9% 0.02

Q2 6.9% 0.97Q1 5.8% -

EventRateQuartile P-value*

CV Events and Post-PCI PRU In Patients With High and Not High Reactivity Treated With Clopidogrel 75-mg Daily

PharmacodynamicsEffect of SD vs HD Clopidogrel

Standard-Dose High-Dose

VerifyNow Meta AnalysisSurvival Analysis of PRU Quartiles*

Stone GW, et al presented at TCT 2011

Chart Tertiary Title or Labels

NON-THERAPEUTIC RANGE

THERAPEUTIC RANGE

POST ASPIRIN INGESTION

AR

U: A

SPIR

IN R

EA

CT

ION

UN

ITS

700

650

600

550

500

450

400

350

NON-THERAPEUTIC RANGE

THERAPEUTIC RANGE

POST ASPIRIN INGESTION

AR

U: A

SPIR

IN R

EA

CT

ION

UN

ITS

700

650

600

550

500

450

400

350

350

300

250

200

150

100

50

PR

U: P

2Y

12 R

EA

CT

ION

UN

ITS

Example PRU’s

Fibrinogen

GP IIb-IIIa

GP IIb-IIIa

Thrombin Receptors

ADP (P2Y1)

ADP (P2Y12)Epinephrine

Plasmin

CollagenShear Forces

Serotonin Platelet Activating Factor

AA

TXA2 Thromboxane A2

Aspirin

GP IIb/IIIa InhibitorsAbciximabEptifibatide

P2Y12 InhibitorsClopidogrelPrasugrelTicagrelor

Blood SampleShowing Inhibition of

Platelet Function

Red Blood Cells

Fibrinogen-Coated Beads

Low LightTransmittance

Platelet-Bead Aggregates

Blood SampleShowing NormalPlatelet Function

Increased LightTransmittance

Platelets

Agonist

How It Works: Activates Specific Drug Receptor Sites

VerifyNow Aspirin or PRUTest Sample Collection Procedure

5 ml

1 CBC

X5

1

2

3

4

5

2

1 2

2 CBC

X5

1

2

3

4

5

6

5 ml

1 CBC

X5

1

2

3

4

5

2

1 2

2 CBC

X5

1

2

3

4

5

6

Direct Venipuncture Sample collection directly into vacuum collection tubes

1. Use 2 mL Greiner Bio-One partial-fill vacuette tubes with 3.2% sodium citrate (blue top). Greiner #454322.

2. Collect 2 tubes of whole blood using a 21 gauge or larger needle. First, collect a discard tube (at least 2 mL) making sure the discard tube does not contain any platelet inhibiting substance (e.g. EDTA). Butterfly (21 gauge) is OK to use.

3. Fill the second tube (sample tube) to the black line (1/2 tube). Do not under fill. Discard the first tube. Keep the second tube for testing.

4. If drawing blood for a CBC at the same time, fill the CBC tube last

5. Gently invert the tube at least 5 times to ensure complete mixing of the contents. Samples with evidence of clotting should not be used.

6. Label the tube with the patient ID, date and time it was drawn. Do not refrigerate.

Indwelling Catheter

1. Discard the first 5 mL from an indwelling catheter to clear the line. Ensure the catheter is free of clots.

2. Immediately transfer blood to a 2 mL Greiner Bio-One partial-fill vacuette tube with 3.2% sodium citrate (blue top). Greiner #454322. Fill to the black line (1/2 tube). Do not under fill.

3. If drawing blood for a CBC at the same time, fill the CBC tube last

4. Gently invert the tube at least 5 times to ensure complete mixing of the contents. Samples with evidence of clotting should not be used.

5. Label the tube with the patient ID, date and time it was drawn. Do not refrigerate.

Verif

yNow

Te

st

Med

icat

ion(

s)

Test

ed

Dos

e G

iven

Sugg

este

d

Test

Tim

ing

Sam

ple

In

cuba

tion

(M

inut

es)

Run

Tim

e (M

inut

es)

PR

UTe

st

Clopidogrel

75 mg 7 days on maintenance1

10 ~3

300 mg 8 hours post bolus2

600 mg 6 hours post bolus3

Ticlopidine250 mg 2 hours post dose4

250 mg (bid) 21 days (steady state)4

Prasugrel

5 mg 5 days on maintenance5

10 mg 5 days on maintenance5

60 mg 45 minutes post bolus9

Ticagrelor 90 mg (bid)

1 day on maintenance7 (within 8 hours of last dose for maximal effect)

180 mg2 hours post bolus8 (within 8 hours for maximal effect)

Aspirin Aspirin 81 - 325 mg 2 hours post dose 30 ~5

For more details, see the VerifyNow Test package insert.1 Plavix (clopidogrel bisulfate) tablets Prescribing Information. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. 3/2010 Update. 2 Price, MJ et al. Am J Cardiol 2006;98:681-684. 3 Hochholzer W. et al. Circulation. 2005;111:2560-2564. 4 Ticlid (ticlopidine hydrochloride) tablets Prescribing Information. Roche Laboratories Inc. Revised 12/2005. 5 Effient (prasugrel) tablets Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. July 10, 2009. 6 VerifyNow IIb/IIIa Test Package Insert. 14320.K. 2009-06-10. 7 Increased Active Metabolite Formation Explains the Greater Platelet Inhibition With Prasugrel Compared to High-dose Clopidogrel. June 26, 2007 8 Husted S et al. Eur Heart J. 2006;27:1038–1047 9 Brilinta (ticagrelor) tablets prescribing information. AstraZeneca group of companies. July 20, 2011. 10 2012 Update to The Society of Thoracic Surgeons Guideline on Use of Antiplatelet Drugs in Patients having Cardiac and Noncardiac Operations. © 2102 by the Society of Thoracic Surgeons. Published by Elsevier Inc.

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www.accumetrics.com

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PN:148039.F 01/2013