Should we Monitor Anti-Platelet Treatment? Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular...

Should we Monitor Anti-Platelet Should we Monitor Anti-Platelet Treatment?Treatment?

Rabih R. Azar, MD, MSc, FACCRabih R. Azar, MD, MSc, FACC

Director of Cardiovascular ResearchDirector of Cardiovascular Research

Hotel Dieu de France HospitalHotel Dieu de France Hospital

Associate Professor of MedicineAssociate Professor of Medicine

Saint Joseph University School of MedicineSaint Joseph University School of Medicine

Should we Monitor Anti-Platelet Treatment?Should we Monitor Anti-Platelet Treatment?

1. Is there a reliable test to measure platelet function?

2. Is there a variability in the response to anti-platelet therapy?

3. Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?

4. Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?

How to Measure Platelets Aggregation?

• Platelets function is measured in vitro by light transmission aggregometry

• This method is considered the gold standard

• Disadvantages:

– Limited reproducibility

– Complex sample preparation

– Cannot be routinely performed

WHAT ARE THE ALTERNATIVES WHAT ARE THE ALTERNATIVES TO LIGHT TRANSMISSION TO LIGHT TRANSMISSION

AGGREGOMETRY?AGGREGOMETRY?

Rapid Platelet Function AssayRapid Platelet Function AssayPlateletworksPlateletworks

An alternative to light transmission An alternative to light transmission aggregometryaggregometry

PlateletworksPlateletworks

Excellent Correlation Between Light Transmission Excellent Correlation Between Light Transmission Aggregometry and Plateletworks Test Aggregometry and Plateletworks Test ((Cathet Cardiovasc Intervent Cathet Cardiovasc Intervent

2001;53:346-351)2001;53:346-351)

VERIFYNOW Point of Care Test

It measures the rate and extent of changes in light transmittance caused by platelet aggregation in a pre-set tube in which whole blood in placed

It thus mimics light transmission aggregometry

Samples containing inhibited platelets will produce low level of light transmittance while samples containing normally functioning platelets will aggregate more rapidly, resulting in higher level of light transmittance

The VASP test: A Specific Test to Measure P2Y12 Inhibition

•VASP is not phosphorylated at basal state

•PGE1 activates VASP phosphorylation

•ADP inhhibits VASP phosphorylation via the P2Y12 receptor

•Thus high VASP = active form of P2Y12 receptor

•Low VASP (high VASP-P) = inhibition of P2Y12 receptor






Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

Individual Response Variability to Dual Individual Response Variability to Dual AntiplateletAntiplateletTherapy in the Steady State Phase of TreatmentTherapy in the Steady State Phase of Treatment

% % PlateletPlatelet AggregationAggregation (LTA(LTA--ADP 20ADP 20mol/L)mol/L)

97.597.5

92.592.5

87.587.5

82.582.5

77.577.5

72.572.5

67.567.5

62.562.5

57.557.5

52.552.5

47.547.5

42.542.5

37.537.5

32.532.5

27.527.5

22.522.5

17.517.5

12.512.5

7.57.5

2.52.5

2020

1515

1010

55

00

Nu

mb

er

Nu

mb

er o

f o

f Pati

en

tsP

ati

en

ts

Bleeding riskBleeding risk Ischemic riskIschemic risk

Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or 48% inhibition at 30 days)48% inhibition at 30 days)

Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in aggregation compared to baseline)aggregation compared to baseline)

ACC/AHA Guidelines (2005)ACC/AHA Guidelines (2005)Percutaneous Coronary Interventions: Percutaneous Coronary Interventions:

Oral Antiplatelet TherapyOral Antiplatelet Therapy

Prevalence of inadequate response to Prevalence of inadequate response to clopidogrel 4% to 30%clopidogrel 4% to 30%

Nguyen et al. J Am Coll Cardiol 2005;45:1157-64Nguyen et al. J Am Coll Cardiol 2005;45:1157-64

Cellular FactorsCellular Factors• Accelerated platelet turnoverAccelerated platelet turnover

•• Reduced CYP3A metabolic activityReduced CYP3A metabolic activity•• Increased ADP exposure Increased ADP exposure •• UpUp--regulation of the P2Yregulation of the P2Y1212 pathwaypathway•• UpUp--regulation of the P2Yregulation of the P2Y11 pathway pathway •• UpUp--regulation of P2Yregulation of P2Y––independent pathwaysindependent pathways

(collagen, epinephrine, TXA(collagen, epinephrine, TXA22, thrombin), thrombin)

Clinical FactorsClinical Factors• Failure to prescribe/poor complianceFailure to prescribe/poor compliance

•• UnderUnder--dosing dosing •• Poor absorptionPoor absorption•• DrugDrug--drug interactions involving CYP3A4drug interactions involving CYP3A4•• Acute coronary syndromeAcute coronary syndrome•• Diabetes mellitus/insulin resistanceDiabetes mellitus/insulin resistance•• Elevated body mass indexElevated body mass index

Genetic FactorsGenetic Factors• Polymorphisms of CYPPolymorphisms of CYP

•• Polymorphisms of Polymorphisms of GPIaGPIa•• Polymorphisms of P2YPolymorphisms of P2Y1212

•• Polymorphisms of Polymorphisms of GPIIIaGPIIIa

Clopidogrel Response VariabilityClopidogrel Response Variability

Angiolillo DJ et al. J Am Coll Cardiol. 2007; 49: 1505-1516 .






Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness

Clinical RelevanceFunctional ParameterN

Stent thrombosis↑shear-induced platelet aggregation49Ajzenberg et al.JACC 2005

Stent thrombosis↑P2Y12 reactivity ratio; ↑platelet

aggregation;

↑stimulated GPIIb/IIIa expression

120Gurbel et al.JACC 2005

Stent thrombosis↑P2Y12 reactivity ratio (VASP-levels)36Barragan et al. CCI 2003

Stent thrombosis↓inhibition of platelet aggregation105Mueller et al.

Thromb Haemost2003

Angiolillo DJ et al. Am J Cardiov Drugs. 2007.

Stent ThrombosisStent Thrombosis

Clinical RelevanceFunctional ParameterN

Post-PCI ischemic events (30 days)

↑ platelet aggregation292Cuisset et al.JACC 2006


Post-PCI ischemic events (3 months)

Post-PCI ischemic events (12 months)

↑ platelet aggregation (3rd & 4th quartiles)

↓ platelet inhibition

↑ platelet aggregation

802

379

100

Hocholzer et al.JACC 2006

Geisler et al.Eur Heart J 2006

Bliden et al.JACC 2007

Post PCI-myonecrosis↑ clopidogrel/aspirin-resistant patients120Lev et al.JACC 2006


↑ platelet aggregation106Cuisset et al.J Thromb Haemost2006

Myonecrosis and inflammation marker release

↑ periprocedrual platelet aggregation 120Gurbel et al.Circulation 2005

Post-PCI ischemic events(6 months)

↑ periprocedrual platelet aggregation 192Gurbel et al.JACC 2005

Post-primary PCI ischemic events (6 months)

↑ platelet aggregation (4th quartile)60Matezky et al.Circulation 2004

Angiolillo DJ et al. Am J Cardiov Drugs. 2007.

PostPost-- Stent Ischemic Events and Stent Ischemic Events and PeriproceduralPeriprocedural InfarctionInfarction

Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness

Platelet Reactivity And Early Drug-Eluting Stent Thrombosis

• 1608 consecutive patients with CAD and planned drug eluting stent implantation

• All received a loading of 600 mg of clopidogrel prior to stenting

• Blood was obtained directly prior to PCI

• ADP induced platelet aggregation was assessed with a point of care assay: Multiple Electrode Platelet Aggregometry (MEA) (principle of impedance aggregometry)

• Poor response to clopidogrel was prospectively defined by a cutoff point at the upper quintile of MEA measurments

Sibbing et al. JACC 2009;53:849-56

Clinical Characteristics Associated With Low Response to Cloopidogrel

normal response Low response p

n = 1285 n = 323

BMI 27.3 + 4.2 28.3 + 4.9 < 0.001

Ejection Fraction 54.9 + 10.9 53.2 + 12.6 0.03

Diabetes mellitus 27.4% 34.1% 0.02

Active smokers 12.1% 18.6% 0.002

ACS 31.4% 39.9% 0.001

Platelet count 213 + 62 236 + 64 < 0.001

Time from loading (h) 4 (2-15.5) 3 (2-7) < 0.001


Clinical Outcome According to Clopidogrel Response


P = < 0.001 0.07 0.02 0.005 0.03






TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET

REACTIVITY MONITORING DECREASE EARLY STENT THROMBOSIS

L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg, P Barragan, F Dignat-George, F Paganelli.

Service de cardiologie, Hôpital Universitaire Nord, Marseille; FRANCELaboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCEService de cardiologie, Hôpital d’aubagne, Aubagne; FRANCEService de cardiologie, Clinique clairval, Marseille; FRANCEService de cardiologie, Clinique Bouchard, Marseille; FRANCEService de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCELaboratoire de statistique, Faculté de la Timone, Marseille; FRANCEService de cardiologie, Polyclinique les Fleurs, Ollioules, FRANCE

Am J Cardiol 2009;103:5-10

DESIGN

Non-emergent PCI : ACS and Stable angina (n= 1122)

Loading dose (LD) -ASA 250mg -Clopidogrel 600mg

VASP ≥ 50%

Randomization(n=429)

CONTROL (n =215) VASP-guided LD (n =214)

Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCIMaintenance dose -ASA 160 mg

-Clopidogrel 75 mg

1° endpoint: Definite stent thrombosis (ARC definition)

2° endpoints: MACE including CV death, MI and U-TVRTIMI major and minor bleeding at 30 days

Platelet reactivity monitoring

VASP after first LD 66 ± 11 67 ± 10

VASP after sensitization 37 ± 12†

17 patients (8%)

† p <0.01

Timing of early stent thrombosis

All early stent thrombosis occured during the first 7 days

Am J Cardiol 2009;103:5-10

Secondary end-point: MACE

Endpoint n, (%) Control (n= 214)

VASP-guided (n= 215)

p

Cardiovascular death 4 (1.8) 0 0.06

Myocardial infarction 10 (4.8) 1 (0.5) 0.01

Urgent revascularization 5 (2.3) 0 0.06

All MACE 19 (8.9) 1 (0.5) < 0.001

M. Valgimigli, MD, PhD

On behalf of 3T/2R

Investigators

Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel

Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel

< 40% platelet inhibition 600 mg clopidogrel LD at least 2 hours before 300 mg clopidgrel LD at least 6 hours before 75 mg clopidogrel MD for at least 7 days

Aspirin reaction units (ARU) >550 ASA orally ≥80 mg for at least 5 days i.v. 500 mg ASA 15 mins or more before

Response evaluationResponse evaluation

Aspirin Poor Response

Clopidogrel Poor Response

And/ Or

Or

Or

Valgimigli et al. Cardiovasc Drugs Ther. 2008 Aug;22(4):313-20

Aspirin + Clopidogrel UFH or Bivalirudin

Aspirin + Clopidogrel UFH or Bivalirudin

Tirofiban*Tirofiban*Tirofiban* PlaceboPlaceboPlacebo

Trial DesignTrial Design

1:11:1

*: 25 g/ kg in 3 mins, followed by an 14-24 hour infusion at 0.15 g/ kg/ min

Blood sampling: Hb, PLT, Tp; CK-MB mass @ 6, 12, 18 or 24 hrs Clinical F-UP: 30-d, 4, 8 and 12 months

Bail-out Tirofiban

Double Blind

Bail-out Placebo

30-Day OutcomesEfficacy Endpoints

(CEC adjudicated)

30-Day OutcomesEfficacy Endpoints

(CEC adjudicated)

-5

1 0

2 5

4 0

MACEMACE DeathDeath MIMI Definite STDefinite ST

P=0.006P=0.006

Placebo Tirofiban

40%

10%

25%

uTVRuTVR

P=0.006P=0.006

37%37%

21%21%

Tailored GP IIb/IIIa Receptor Blockade According to Clopidogrel Resistance

• 149 Clopidorel resistant patients

• Resistance defined by inhibition < 30% using light transmission aggregometry

• Elective PCI

• Randomized to :

– Conventional therapy: 600 mg Clopidogrel

– Active therapy: 600 mg Clopidogrel + GP IIb/IIIa blockade

• Combined end-point of: death, periprocedural MI, stent thrombosis and recurrent ACS at 1 month

Cuisset et al. JACC Interventions. 2008;1:649-53

Events According to GPIIb/IIIa Blockade in Clopidogrel Resistant Patients

P=0.006

Cuisset et al. JACC Interventions. 2008;1:649-53

How Can We Solve the Problem Caused by Clopidogrel Resistance?

Is the answer by increasing the dose?

P < 0.05 vs. 300 mg LD

A Faster Onset of Action Was Seen with Higher Clopidogrel Loading Regimens

A Faster Onset of Action Was Seen with Higher A Faster Onset of Action Was Seen with Higher ClopidogrelClopidogrel Loading RegimensLoading Regimens

The ALBION trial

0

10

20

30

40

50

1 2 3 4 5 6

300 mg LD600 mg LD900 mg LD

Maximum Inhibition of Platelet Aggregation (5 µM ADP)

Time (h)

(%) Inhibition

Shortened time to reach the highest level of inhibition of the 300 mg LD

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

11

CURRENT – OASIS-7 Study Design

Clopidogrel high-dose group600 mg LD Day 1 followed

by 150 mg from Day 2 to Day 7; 75 mg from Day 8 to 30

Clopidogrel standard-dose group300 mg LD Day 1 followed

by 75 mg from Day 2 to Day 7;75 mg from Day 8 to 30

RANDOMIZE RANDOMIZE

ASA low-dose groupAt least 300 mg Day 1;

75–100 mgfrom D2 to D30

ASA high-dose groupAt least 300mg Day 1;


ASA high-dose groupAt least 300 mg Day 1;


ASA low-dose groupAt least 300 mg Day 1;


14,000 patients with UA/NSTEMI planned for early invasivestrategy, i.e. intended for PCI as early as possible within 24 h

RANDOMIZE

Primary endpoint: CV death, MI, stroke at 30 days

ASA Dose ComparisonPrimary Outcome and Bleeding

ASA

75-100 mg

ASA

300-325 mg

HR 95% CI P

CV Death/MI/Stroke

PCI (2N=17,232) 4.2 4.1 0.98 0.84-1.13 0.76

No PCI (2N=7855) 4.7 4.4 0.92 0.75-1.14 0.44

Overall (2N=25,087) 4.4 4.2 0.96 0.85-1.08 0.47

Stent Thrombosis 2.1 1.9 0.91 0.73-1.12 0.37

TIMI Major Bleed 1.03 0.97 0.94 0.73-1.21 0.71

CURRENT Major Bleed 2.3 2.3 0.99 0.84-1.17 0.90

CURRENT Severe Bleed 1.7 1.7 1.00 0.83-1.21 1.00

No other significant differences between ASA dose groups

GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

Clopidogrel: Double vs Standard DoseMajor Efficacy Outcomes in PCI Patients

Day 30 Clopidogrel

StandardN=8684

%

Double N=8548

%

Hazard Ratio

95% CI P value

Stent Thrombosis 2.3 1.6 0.71 0.57-0.89 0.002

Definite 1.2 0.7 0.58 0.42-0.79 0.001

MI 2.6 2.0 0.78 0.64-0.95 0.012

MI or stent thrombosis 3.7 3.0 0.80 0.68-0.94 0.008

CV Death 1.9 1.9 0.96 0.77-1.19 0.68

Stroke 0.4 0.4 0.88 0.55-1.41 0.59

CV Death/MI/Stroke 4.5 3.9 0.85 0.74-0.99 0.036

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Dose

Clopidogrel Double Dose

42% RRR

HR 0.5895% CI 0.42-0.79

P=0.001

Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)

Clopidogrel Double vs Standard DoseBleeding PCI Population

Clopidogrel

Standard

N= 8684

Double

N=8548

Hazard

Ratio

95% CI P

TIMI Major1 0.5 0.5 1.06 0.70-1.61 0.79

CURRENT Major2 1.1 1.6 1.44 1.11-1.86 0.006

CURRENT Severe3 0.8 1.1 1.39 1.02-1.90 0.034

Fatal 0.15 0.07 0.47 0.18-1.23 0.125

ICH 0.035 0.046 1.35 0.30-6.04 0.69

RBC transfusion ≥ 2U 0.91 1.35 1.49 1.11-1.98 0.007

CABG-related Major 0.1 0.1 1.69 0.61-4.7 0.31

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

Sanofi-aventis-BMS Confidential- For Internal Purposes Only- Not for Further Copying or Distribution

TRITON: Primary Efficacy and Safety Endpoints TRITON: Primary Efficacy and Safety Endpoints in Entire ACS Cohort at 15 Monthsin Entire ACS Cohort at 15 Months

Wiviott SD, et al. N Engl J Med 2007;357:2001-15

0

5

10

15

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

Prasugrel

Clopidogrel1.82.4

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

HR 0.81(0.73-0.90)

P<0.001

138events

NNT = 46

HR 1.32(1.03-1.68)

P=0.03

35events

NNH = 167


FACTS:

1- More potent anti-platelet therapy is associated with better outcome

2- But it is also associated with more bleeding !!!

WHAT TO DO IN PRACTICE:

1- Give all patients potent drugs: double dose clopidogrel, or better: prasugrel. Proven to be better, but risk of bleeding

2- Monitor platelet response and adjust therapy accordingly. Waiting confirmation in large clinical trials (GRAVITAS)

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Should we Monitor Anti-Platelet Treatment? Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular...

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