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Clinical Value of the VerifyNow System

Juan Landrian, RCIS Clinical Science Liaison

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• Evaluate emerging data showing the clinical utility of the VerifyNow system to assess response to and practical impact on antiplatelet therapies

• Recognize commonly used anti-platelet agents, including the

recently approved drugs prasugrel, ticagrelor and the generic form of clopidogrel

• Summarize how these tests are used in the overall assessment

of the patient in multiple clinical scenarios

Program Objectives

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• Anti-platelet medication(s) – 50 million Americans are on chronic aspirin therapy6

– At its peak, over 29 million Plavix prescriptions are written annually7

– Currently over 43 million prescriptions are written in the US for anti platelet therapies of all kind, including aspirin (per IMS data, MAT, November 2012)

• Patient Response to anti-platelet medication(s) varies

– Up to 1 in 3 patients MAY NOT be responding adequately to Aspirin or Plavix8

– These patients may be at significantly greater risk for heart attack, stent thrombosis, or death9-12

Platelet Response?

6. Pignone, et al. Am J Prev Med 2007;32(5):403–407 7. MedAd News. PharmaLive.com. Aug 11 2008. 8. Dupont, et al. Thromb Res. 2009 May;124(1):6- 13. Epub 2009 Mar 25 9. Patti, G. et al. J Am Coll Cardiol. 2008; 52:1128–33. 10. Marcucci, et al. Circulation. 2009;119(2):237-42. 11. Cuisset, et al. Am J Cardiol. 2008 Jun 15;101(12):1700. Epub 2008 Apr 18 12. Price, et al. Eur Heart J. 2008 Apr;29(8):992-1000.

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Testing Rationale

• Physicians routinely test their patient's cholesterol, PT/INR, and blood pressure to verify whether their prescribed medications, such as Lipitor, Coumadin and Norvasc, are producing the desired effect.

A Comprehensive Cardiovascular Approach

Cholesterol Coagulation Blood Pressure Aspirin & Plavix/ Effient / Brilinta

• The VerifyNow System helps assess a patient's response to antiplatelet therapy

• Some of the most commonly prescribed medications to help reduce the risks of heart attack, stroke and death.

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• The first easy, rapid and proven system for measuring individual

platelet response to every major antiplatelet medication − Aspirin

− P2Y12 inhibitors (e.g. clopidogrel, prasugrel, ticagrelor, ticlopidine)

− GP IIb/IIIa inhibitors (e.g. ReoPro® and Integrilin®)

• System Consists of: − Light-Detection Instrument

− Single use Test Devices

− Electronic Quality Controls (EQC)

− Wet Quality Controls (WQC)

The VerifyNow System

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The VerifyNow System is Easy to Use

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Blood Sample Showing Inhibition of Platelet

Reacivity

Blood Sample Showing Normal Platelet Reactivity

• Platelet reactivity is measured as a function of an increase in light transmission through whole blood as platelets are activated by various agonists − If there is low residual platelet reactivity there is decreased light that is

transmitted and detected. − If there is high residual platelet reactivity there is increased light that is

transmitted and detected.

Mechanism of Action

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Benefits of the VerifyNow System

• Uses whole blood directly from closed tube

• No pipetting or sample preparation required

• Factory calibrated reagents

• CLIA Waived (Aspirin Test) - Can be used in a Physician’s Office

• Result available in 2 to 5 minutes after sample introduction

• P2Y12 Test requires 10 minute sample incubation

• ~15 min Turn Around Time from blood draw to result

PROVEN

• Results correlated to Light Transmittance Aggregometry (LTA).

• Most widely studied rapid system to assess response to antiplatelet therapy

• Validated performance in multiple peer-reviewed publications

COST-EFFECTIVE

• Reduces the amount of hands-on time and chance of pre-analytical error.

• Favorable Reimbursement.

• Provides information about antiplatelet therapy that can improve patient management.

EASY RAPID

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Clinical Value of Platelet Reactivity Testing

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VerifyNow Tests: Intended Use

The VerifyNow System, and VerifyNow PRUTest are approved for the following uses for the point-of-care or laboratory setting:

• The VerifyNow PRUTest are approved to measure the level of Platelet P2Y12 receptor blockade

The VerifyNow P2Y12 Assay Reference Range of 194 – 418 PRU that is contained in the FDA approved package insert is the 95% confidence interval in a clinical trial of patients who were to receive PCI prior to exposure to drug. Therefore, this range correlates to the absence of P2Y12 receptor blockade, such as a clopidogrel or prasugrel effect.

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Using PRU to Measure P2Y12 Receptor Blockade

• A patient with a PRU greater than or equal to 194 indicates that there is no specific evidence of a pharmacodynamic antiplatelet effect from a P2Y12 inhibitor. This is an on-label claim for the VN P2Y12 assay.

• Values less than 194 indicate the presence of P2Y12 receptor blockade. This is an on-label claim for the VN P2Y12 assay.

• These values were from the clinical trial described in the P2Y12 package insert. There is no bleeding or other outcome information available for the participants in this trial.

• Later studies, some with outcome information, that contain additional information about PRU target values have been published in peer-reviewed literature.

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Goal of Antiplatelet Therapies

Maintain Hemostasis Prevent Thrombosis

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• Antiplatelet therapies reduce the potential for thrombus formation through their antiplatelet effect. − Reduce platelet reactivity

• Effects of antiplatelet therapy on thrombosis and bleeding are dissociated − Reducing platelet reactivity reduces thrombosis risk but increases bleeding risk.

Balance Between Thrombosis and Bleeding Risks

Thrombosis Bleeding

Platelet Reactivity High Low

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• There are several ways to cause platelet activation.

• Platelet activation can cause thrombosis. − Platelet is directly involved in

thrombus formation. − Obvious therapeutic target.

• Bleeding is not caused by the platelet.

• High levels of platelet inhibition can prolong/exacerbate bleeding.

Thrombosis vs. Bleeding

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P2Y12 Inhibitors + Aspirin Reduce Thrombosis Rates vs. Aspirin Alone

Events = composite of CV death/MI/stroke;

PCI-CURE events = composite of CV death/MI

Study (Clopidogrel) N Population

Event Rate (Placebo)

Event Rate (Clopidogrel)

Absolute Risk

Reduction

CURE 12,562 NSTE-ACS 11.4% 9.3% 2.1%

→ CURE-PCI 2658 NSTE-ACS +PCI 12.6% 8.8% 3.8%

CREDO 2,116 UA/Recent MI (2/3) 11.5% 8.5% 3.0%

CLARITY 3,491 STEMI 10.9% 9.1% 1.8%

COMMIT 45,852 STEMI 10.1% 9.2% 0.9%

CHARISMA 15,603 Stable 7.3% 6.8% 0.5%

< 4% of Patients With Improved Outcomes

Helton et al, Am J Cardiovasc Drugs 2007

Low Risk & High Risk

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• Not possible to tell which patients will benefit from taking clopidogrel. → Solution: give clopidogrel to all, so that the patients

that benefit are not missed.

• But there is significant variability in response to clopidogrel. → What if the patients that would benefit from taking a

an antiplatelet drug are not getting the expected effect?

The Problem with One Size Fits All

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• Platelet reactivity reported as P2Y12 Reaction Units (PRU)

• Platelets activated through same pathway being inhibited

• Drug effect associated with less thrombosis, more bleeding

The VerifyNow PRUTest Accurately Measures the Effect of P2Y12 Inhibitors

PRU = DRUG EFFECT

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Diagnostic Tests: Sensitivity and Specificity

Condition

+ – Total

Test + TP FP Tot P

– FN TN Tot N

Total C NC POP

• Sensitivity = ability of the test to correctly classify those with the condition = True Positives/# with Condition of Interest (TP/C)

• Specificity = ability of the test to correctly classify those without the condition = True Negatives/# without Condition of Interest (TN/NC)

• Sensitivity and specificity are NOT influenced by prevalence of the condition

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Sensitivity & Specificity Considerations for Platelet Reactivity Testing

• Goal: detect presence of drug • Higher cutoff = higher sensitivity, lower specificity • Lower cutoff = higher specificity, lower sensitivity • High specificity is preferred for confirming presence of

the drug effect (fewer false positives)

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50

100

150

200

250

300

350

400

450

500

Baseline PRU On-Drug PRU

PRU

PRU Sensitivity and Specificity for Detecting P2Y12 Inhibitor Effect1

1. Patients measured before and after taking clopidogrel. Graph reproduced from VerifyNow PRUTest Package Insert and VerifyNow P2Y12 Test Package Insert (not available in the US)

PRU Cutoff Sensitivity Specificity

170 65% 99%

194 72% 98%

200 76% 97%

210 80% 95%

220 82% 91%

230 86% 89%

240 90% 84%

250 92% 82%

260 94% 78%

275 95% 70%

Higher Sensitivity

Higher Specificity

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Factors Influencing Variability in Response to Clopidogrel

Variability in Clopidogrel

Effect

Concomitant Disease (e.g.

Diabetes)

Genetics (e.g.

CYP2C19)

Non-Compliance

Concomitant Medications

(e.g. PPIs)

Platelet reactivity testing is the only way to directly measure the pharmacodynamic effect

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Confirming the Drug Effect is Important for Many Patient Populations and Procedures

IS THERE AN EFFECT OF A P2Y12 INHIBITOR?

NEUROVASCULAR CARDIOVASCULAR PERIPHERAL

ARTERY DISEASE

+/- INTERVENTIONAL PROCEDURES

REDUCE RISK OF THROMBOSIS

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• A large number of patients are treated with antiplatelet agents to avoid missing the few that will benefit. − These are the patients that have the greatest need for a reduction

in platelet reactivity.

• Testing alone does not improve outcomes. • Physicians improve outcomes.

− Feedback on treatment effect is important for patient management.

• Treatments improve outcomes. − If there is no evidence of the treatment effect, one cannot expect

improved outcomes.

Which Patients to Test?

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Why Not Use More Potent Agents? More Potent … for the Benefit of Few

Study N Population Event Rate

(Clopidogrel) Event Rate

(New Agent) Absolute Risk

Reduction

TRITON 13,608 ACS+PCI 12.1% 9.9% 2.2%

PLATO 18,624 ACS +/- PCI 11.7% 9.8% 1.9%

88% event-free on clopidogrel + aspirin → DID NOT NEED NEW AGENT

10% with event on new agent + aspirin → DID NOT BENEFIT FROM NEW AGENT

2.0% event-free on new agent + aspirin → RECEIVED BENEFIT FROM NEW AGENT

Wiviott et al, NEJM 2007 Wallentin et al, NEJM 2009

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• Contraindications. • Ceiling effect of antiplatelet therapy on reducing

thrombosis. − Receptor can be completely blocked, but thrombosis can still

occur through coagulation activation or platelet activation via alternate unblocked pathways.

• More potent antiplatelet therapy = more bleeding − Less of a ceiling effect. − TRACER trial: aspirin + clopidogrel ± PAR-1 inhibitor

oPrimary efficacy endpoint: 1.4% absolute risk reduction (p = 0.07). oPrimary safety endpoint: 2.0% absolute risk increase in GUSTO Mod/Sev

bleeding (p < 0.001).

Other Challenges with More Potent P2Y12 Inhibitors

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There is Another Side to Knowing the Drug Effect: Bleeding

IS THERE AN EFFECT OF A P2Y12 INHIBITOR?

SURGERY TRAUMA

REDUCE BLEEDING & BLOOD PRODUCT USAGE

NEUROVASCULAR CARDIOVASCULAR PERIPHERAL

ARTERY DISEASE

+/- INTERVENTIONAL PROCEDURES

REDUCE RISK OF THROMBOSIS

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• P2Y12 inhibitor therapy is interrupted prior to surgery to reduce bleeding risk. − When platelet reactivity testing is not used, time is used as an

arbitrary surrogate for return to baseline platelet reactivity.

− Variability in response = different rates of return to baseline platelet reactivity.

− Excess time without P2Y12 inhibitor effect = greater potential for thrombosis.

• Sometimes, patients or their family members cannot remember or cannot communicate P2Y12 inhibitor use (especially TBI patients).

PFT: Important for Surgery/Trauma Because P2Y12 Inhibitors Increase Bleeding Risk

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Platelet Reactivity Testing is Described in Treatment Guidelines

Class IIb

Class IIb

Class IIb (x2)

Class Ib Class IIa

Class IIb (x2)

Class IIb

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• The P2Y12 inhibitor antiplatelet effect reduces risk for thrombosis. − Drug effect = less thrombosis = fewer readmissions, especially in the first

30 days (highest risk period). − Fewer readmissions = less potential for readmission penalties.

• The P2Y12 inhibitor antiplatelet effect increases risk for bleeding. − Drug effect = more bleeding = more blood product usage = more $$$. − Affects pre-surgical length-of-stay while waiting for drug elimination

(return to baseline platelet reactivity).

• There are various P2Y12 inhibitors available. − Clopidogrel is generic inexpensive − More potent P2Y12 inhibitors expensive

The Presence of the Drug Effect Can Influence Healthcare Economics

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Thank You for Your Time

Questions?