Platelet function test (what is the clinical relevance)

Light Transmission Aggregometry • Current gold standard for assessing platelet function, which measures platelet aggregation in response to a given agonist • Its limitations include the

Platelet Function Test: What Is The Clinical Relevance?

14 th Vietnam National Congress of Cardiology

Da Nang City Vietnam 2014

Dr Tan Huay Cheem

MBBS, M Med(Int Med) MRCP(UK), FRCP(Edinburgh), FAMS, FACC, FSCAI

Director, National University Heart Centre, Singapore Associate Professor of Medicine, Yong Loo Lin School of Medicine

National University of Singapore President, Asia Pacific Society of Interventional Cardiology

National University Heart Centre, Singapore (NUHCS)

Variability in Clopidogrel Response

Change in ADP-Induced platelet

aggregation 75 mg chronic dosing

Time from loading dose to cath (h)

Maximal aggregation 5µmol/L ADP (%) following 600 mg loading dose

Mechanism of Clopidogrel Response Variability

Intestinal Absorption

Highly variable absorption capacity with ceiling effect at 600 mg leading dose

Inactive Carboxylic Acid

CY3A4/5 CYP2C9 CYP2C19

Active Thiol Metabolite

P2Y12 Receptor Genetic Polymorphism

Genetic polymorphisms

Smoking

Clopidogrel is frequently chosen in high risk patients

Yet, it is a highly unpredictable and overall weak antiplatelet agent

How do we rationalise giving this drug blindly to prevent stent thrombosis?

Genetic Testing vs Platelet Function Testing

Platelet function testing

• Continuous so cutpoints needed

• Dynamic

• Less reproducible

• Very sensitive to pre-analytic variables

• Fast turnaround

Platelet Function Tests: Types and Limitations

Platelet Function Tests

• Results unconvincing for:

(1) “ the tests are crude substitutes for the….interactions …… in vivo”

(2) “ failed to satisfy… the minimal criteria to establish

a causal relationship…between the results of the… test and …… a thromboembolic event”

Definitions of Non-/Low Response using LTA

Platelet aggregation 2 standard deviations below mean

Relative change in platelet aggregation from baseline < 40%

(Variable results also depending on the concentration of ADP used)

Platelet Function Tests

• Point-of-care

Ultegra rapid platelet function analyzer (VerifyNow) Thromboelastagraph (TEG)

Plateletworks Cone and plate(let) analyzer (IMPACT)

Angiolillo DJ et al J Am Coll Cardiol 2007

Light Transmission Aggregometry

• Current gold standard for assessing platelet function,

which measures platelet aggregation in response to a given agonist

• Its limitations include the need for skilled technicians and high sample volume, expense and delay in obtaining results due to assay length

• LTA may be subject to several methodological variables that may result in poor reproducibility and thus variance in prevalence of nonresponders These may include the dose of the agonist (5-20 uM), the nature of the anticoagulant (citrate or hirudin/PPACK) and the LTA value

(maximal or late platelet aggregation) used

Flow Cytometry (Eg Vasodilator-Stimulated Phosphoprotein

Point-of-Care VerifyNow ®

Least operator- dependent

Multiplate® Whole Blood Impedance Aggregometry

POPULAR Trial (First head-to-head comparison of Multiple Platelet Function Tests

in Predicting Thrombotic and Bleeding Events)

Consecutive patients on clopidogrel treatment undergoing elective PCI

with stent implantation

n=1069

Measurement of on-treatment platelet reactivity in parallel

LTA 5 μmol/L ADP

PFA-100 COL/ADP n=812

POWER CALCULATION

n=800 per test

Primary Endpoint at one-year

Composite of death, myocardial infarction, stent thrombosis and stroke

Primary Safety Endpoint at one year

TIMI major and minor bleeding

Breet NJ et al JAMA 2010; 303: 754-762

Composite of death, non-fatal myocardial infarction, definite stent thrombosis and stroke

Platelet Function Tests OR (95% CI) P

LTA 5 μmol/L ADP 2.09 (1.34-3.25) 0.0009

LTA 20 μmol/L ADP 2.05 (1.32-3.19) 0.001

INNOVANCE PFA®P2Y* 1.59 (0.85-2.94) 0.15

Clinical risk factors

Clopidogrel Hyporesponsiveness and Stent Thrombosis

Platelet Function in Clopidogrel-Treated Patients and Stent Thrombosis

Angiolillo DJ et al J Am Coll Cardiol 2007

N Functional Parameter Clinical Relevance

Mueller et al

Thromb Hemost 2003

105 ↓Inhibition of platelet aggregation Stent thrombosis

Barragan et al

Cathet Card Intv 2003

36 ↑P2Y12 reactivity ratio Stent thrombosis

EXCELSIOR (Impact of Extent of Clopidogrel-Induced Plt Inhibition During Elective Stent Implantation on Clinical Event Rates)

Hochholzer W et al J Am Coll Cardiol 2006; 48: 1742-1750

802 relatively low-risk pts treated with 600mg clopidogrel followed by maintenance clopidogrel 75mg and ≥100mg aspirin daily

Results:

• Pts in upper quartiles, showing higher degree of 5 uM ADP-induced aggregation before intervention, had higher incidence of MACE over 30-days (p=0.03)

• Multivariable logistic regression analysis identified platelet aggregation as independent predictor of MACE (OR 1.32, 95% CI 1.04 to 1.61; p=0.026)

Overall Resp Non- Resp p value

Low REsponsiveness to CLOpidogrel and Sirolimus- or

Paclitaxel-Eluting StEnt Thrombosis (RE-CLOSE) Trial

Buonamici P et al J Am Coll Cardiol 2007; 49: 2312-17

• 804 pts SES and PES-treated pts were assessed for post-treatment

platelet reactivity after loading dose clopidogrel 600mg and 75mg maintenance

• Nonresponders if platelet aggregation induced by 10 uM ADP using LTA was ≥70%

High On-Treatment Platelet Reactivity (HPR) Predicts Outcomes

After PCI: Pooled Analysis of 17 Trials

How To Overcome Clopidogrel Resistance?

(1) Load Clopidogrel Does Before PCI

 p< 0.05 vs 300 mg LD

ALBION: Faster Onset of Action

and Higher Level of Platelet Inhibition

Montalescot G et al J Am Coll Cardiol 2006; 48: 931-8

Clopidogrel Loading Before Primary PCI:

HORIZONS AMI Outcome to 30 Days

600mg loading dose may safely reduce 30-day ischemic adverse rates

compared with 300mg loading dose

Danga G et al JACC 2009 54:1438-1446

P=0.07 P=0.02

P=0.004

P=0.0007

P=0.0497

P=0.004

CURRENT OASIS 7

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)

 Planned Early (<24 h) Invasive Management with intended PCI

 Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232 (70%)

Angio 24,769 (99%)

No PCI 7,855 (30%)

No Sig CAD 3,616 CABG 1,809 CAD 2,430

Randomized to receive (2 X 2 factorial):

CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d fb75 mg/d) vs Standard dose (300 mg fb 75 mg/d)

ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)

Efficacy Outcomes: CV Death, MI or stroke at day 30

Stent Thrombosis at day 30 Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)

Key Subgroup: PCI v No PCI

Clop in 1st 7d (median) 7d 7 d 2 d 7d

Complete Followup 99.8%

Compliance:

CURRENT OASIS 7: Clopidogrel Double vs Standard Dose

Primary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.85 95% CI 0.74-0.99

P=0.036

15% RRR

CV Death, MI or Stroke

(2) Use of Platelet Function Test to Guide PCI

ADAPT-DES

Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents

Up to 11,000 pts prospectively enrolled

No clinical or anatomic exclusion criteria

11 sites in US and Germany

Clinical FU at 30 days, 1 year and 2 years

Angio core lab assessment all STs w/1:2 matching controls

Assess platelet function after adequate DAPT loading and GPI washout: Accumetrics VerifyNow Aspirin,

VerifyNow P2Y12, and VerifyNow IIb/IIIa assays (results blinded)

PCI with ≥1 non-investigational DES

Successful and uncomplicated

(IVUS/VH substudy; Up to 3000 pts enrolled)

Stone GW et al Lancet 2013; 382: 614-623

ADAPT-DES: Relationship Between VerifyNow P2Y12

% Inhibition and Stent Thrombosis within 30 Days

Definite or Probable Stent Thrombosis

ADAPT-DES: Predictive Accuracy of VerifyNow Testing

Definite or Probable Stent Thrombosis by 30 days (n=39)

VerifyNow test Sensitivity Specificity PPV NPV Accuracy ASA ARU > 550 11.1% 94.4% 0.6% 99.7% 94.1%

ADAPT-DES: Conclusions and Implications

• The absolute and relative levels of platelet inhibition to ADP antagonists

as assessed by the VerifyNow P2Y12 test are powerful independent

predictors of stent thrombosis within 30 days, with a significant

proportion of events independently attributable to clopidogrel

hyporesponsiveness

• However, the modest sensitivity and specificity of platelet function

testing, coupled with the low prevalence of events, implies that testing of platelet ADP antagonist responsiveness is unlikely to provide useful

information to guide clinical decision-making in most individual patients for the prevention of stent thrombosis at 30 days

Stone GW et al Lancet 2013; 382: 614-623

Titration of Clopidogrel to Achieve VASP PRI <50%

Time between first LD and VASP measurement,

hrs

• Each additional bolus of 600 mg of

clopidogrel decreased the number of

patients with low response between

35% to 49%

• Despite 2400mg of clopidogrel, 11(14%)

patients remained low-responders

Bonello L et al J Am Coll Cardiol 2008; 51: 1404-1411

162 patients with clopidogrel resistance undergoing coronary stenting were randomized to a control group or to the VASP-guided group, in which patients received additional bolus clopidogrel to decrease the VASP index below 50%

MACE; n (%)

Control (n=84)

VASP-guided (n=78)

3 Major Prospective Trials of Personalised Antiplatelet Therapy

Using Platelet Function Test in PCI Patients

• GRAVITAS (n= 2 214)

• TRIGGER PCI (n=423)

• ARCTIC (n= 2 440)

Standard-Dose Clopidogrel

clopidogrel 75mg daily X 6 months

High-Dose Clopidogrel

clopidogrel 600mg, then clopidogrel 150mg daily X 6 months

Elective or Urgent PCI with DES*

VerifyNow P2Y12 Test 12-24 hours post-PCI

PRU ≥ 230

R

GRAVITAS Study Design

Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo

Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo

Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months

All patients received aspirin (81-162mg daily)

*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs

Price MJ et al Circulation 2011; 124: 1132-7

GRAVITAS Primary Endpoint: CV Death, MI, Stent Thrombosis

Observed event rates are listed; P value by log rank test

GRAVITAS does not support a treatment strategy of high-dose clopidogrel in low-risk patients with high reactivity identified by a

single platelet function test after PCI

Price MJ et al Circulation 2011; 124: 1132-7

“Standard Therapy”

Clopidogrel MD 75 mg QD

“Clopidogrel arm”

Placebo LD Clopidogrel MD 75 mg QD + Prasugrel placebo

“Prasugrel arm”

Prasugrel LD 60 mg

Prasugrel MD 10 mg QD

+ Clopidogrel placebo

Successful PCI with DES without major complication and NO GPIIb/IIIa use

Post-PCI VerifyNow P2Y12 Assay (PRU)

2 - 7 hours after MD of clopidogrel 75mg at day 1 post-PCI

Non-Responder

Clinical Follow-up and blinded VerifyNow Assessment at 90 days, 180 days

Primary Endpoint: 6 month CV Death or MI

D Trenk TCT 2011 Late Breaking Trial

TRIGGER-PCI: Summary of Primary and Secondary

CEC-Adjudicated Efficacy Endpoints

Prasugrel N=212

Clopidogrel N=211

p

HR (95% CI)

Days on study treatment (median) 174 174 -

Primary composite efficacy EP:

D Trenk TCT 2011 Late Breaking Trial

1.0 0.8

0.6

0.4 0.2

Platelet Function Test Monitor vs No Monitor

Primary Endpoint: Death, MI, stroke, stent thrombosis, urgent revascularization

TRILOGY ACS Platelet Function Substudy Design

VerifyNow P2Y 12 Assay

At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization

UA/NSTEMI (N = 9326, 52 countries) planned medical management without revascularization

10 mg (< 75 years and ≥ 60 kg) 75 mg (for all)

5 mg (≥ 75 years; < 75 years and < 60 kg)

Aspirin ≤ 100 mg (strongly recommended) for all

PFS: 2690 (28% of total) participants from 25 countries

2564 participants (prasugrel, n = 1286 and clopidogrel, n = 1278)

included in final analysis

126 without valid PRU measurement excluded from analysis

Primary Efficacy Endpoint: Composite of CV death, MI, and stroke through 30 mths Key Secondary Endpoints: All-cause death , MI

Primary efficacy endpoint similar for patients included in the platelet function

substudy compared with those who were not (18.1% vs 19.3%; P = 0.48) and—

despite the differences achieved in high-treatment platelet reactivity—were also

no different between the clopidogrel and prasugrel substudy treatment cohorts

(17.2% vs 18.9%; P = 0.29)

JAMA 2012 epub ahead of print

Platelet Function: Variation Over Time

Ongoing PFT-guided Clopidogrel Dosing RCTs

• AHA late-breaking

Guidelines Recommendations

ESC 2014 Guidelines On Myocardial Revascularisation

ACCF/AHA/SCAI 2011 Guidelines for PCI

Levine et al J Am Coll Cardiol 2011; Volume 58

Class IIB

Platelet function testing may be considered in patients

at high risk for poor clinical outcomes (Level of Evidence C)

Class IIB

In patients treated with clopidogrel with high platelet reactivity,

alternative agents, such as prasugrel aor ticagrelor, might be considered

(Level of Evidence C)

Class III

The routine clinical use of platelet function testing to screen patients

treated with clopidogrel who are undergoing PCI is not recommended

(Level of Evidence C)

(a) increased risk of stent thrombosis

(b) increased risk for catastrophe if stent thrombosis occur

OR

need to know when is the ideal time to perform surgery after antiplatelet therapy cessation

Cutoff Associated With Ischemic Event Occurrenes (References)

Cutoff Associated With Bleeding Event Occurrences (References)

Platelet Reactivity Cutoff Associated With Ischemic and

Bleeding Events (Therapeutic Window)

Udaya S Tantry et al JACC 2013;62: 2261-2273

Udaya S Tantry et al JACC 2013;62: 2261-2273