“Clopidigrel resistance” and management strategies

Overview

• Physiology of platelet function and clopidogrel pharmacology

• Definition of clopidogrel resistance• Clinical significance• Potential mechanisms of resistance• Laboratory tests• Prevention and treatment

Platelet physiology

• Platelets circulate for about 10 days• Platelet activation:

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Activators of plateletsX

ADP mediated plt activation

VASP

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Clopidogrel • Clopidogrel is a thienopyridine

pro-drug, which is converted to its active metabolite by several enzymes of the P450 family, including CYP3A4 and CYP2C19

• The active metabolite combines irreversibly with the platelet membrane P2Y12 ADP receptor, thereby inhibiting this pathway of platelet activation, but leaving the P2Y1 ADP receptor unaffected

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ADP-mediated plt activation

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15% 85%

Defining resistance

Clopidogrel resistance

Biochemical Clinical

Clopidogrel resistance (biochemical)

• There is marked inter-individual variability in platelet inhibition after clopidogrel ingestion.

• Hyporesponders (two standard deviations below the mean)

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5%

Clopidogrel resistance (biochemical)

• Resistance: as baseline aggregation (%) minus post-treatment aggregation (%) ≤ 10% by 5 mol/L ADP.

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63% 31%

15%31%

Defining resistance• Clinical vs Biochemical.• Clinical resistance: In its broadest sense, it refers to the

continued occurrence of ischemic events despite adequate anti-platelet therapy and compliance.

• there is no current definition which unifies the biochemical and clinical expression of failed treatment.

• Rather than attempting to characterize patients as simply resistant or sensitive to a medication, however, therapeutic resistance is more likely a continuous variable similar to blood pressure.

• Disregarding existing uncertainty, the reported rate of Clipidogrel resistance ranges from 5-25%.

Clinical significance of clopidogrel resistance

• Post-stent ischemic events and peri-procedural myocardial infarction.

• Stent thrombosis

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Etiology

In summary so far …

• There is a wide inter-individual variation in platelet response to clopidogrel when measured biochemically.

• Low responders will suffer more stent thrombosis and MACE post stenting.

• Possible aetiologies for clopidogrel resistant include patients’ clinical factors and variations in pharmaco-kinetics and –dynamics.

Laboratory tests

• Light transmittance aggregometry is the current gold standard for determining platelet function.

• VASP phosphorylation analysis• Platelet function analyzer• Verifynow rapid platelet function assay

Pros - Cons

Management...

Prevention...

Loading dose…

• Loading doses of clopidogrel of 300 to 600 mg reach near steady-state levels of platelet aggregation by 4 to 24 hours.

• Daily dosing with 75 mg daily without a preload results in steady-state levels within 4 to 7 days.

ARMYDA-2

•255 patients with NSTEMI/UA•Death, peri-procedural MI•PCI 4-8h•Endpoint: 300mg 12%, 600mg 4%

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•292 patients with NSEMI•All CV events, death•Platelet aggregation •PCI 12h

•Endpoint:•300mg: 12%•600mg:5%

Platelet aggregation –Higher dose of clopidogrel

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ISAR-CHOICE

•60 patients with Stable Angina•Platelet aggregation prior to administration and 20, 40, 60, 120, and 240 minutes after elective PCI 12h

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Reload prn...

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•NSTEMI/UA•VASP index>50% 24h after 600mg For control or till <50% for VASP guided group.•CV events: 10% vs 0%

Control group

VASP guided group

Reload chronic therapy

• ARMYDA-RELOAD ACC 2008:• randomized 436 patients on chronic (>10

days) clopidogrel therapy who presented with stable angina or NSTEMI and going for PCI to reload 600mg vs placebo 30-day MACE :

• (7% vs. 9%, p=0.70) overall• (7% vs. 18%, p=0.035) for NSTEMI• (8% vs. 4%, p=0.23) stable angina

Prasugrel

NEJM november 15, 2007•13608 patients with moderate to high risk ACS•Mortality ,CV events

Cilostazol

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P2Y12 ADP receptor antagonists

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990 patients with NSTEMI

Summary 1)Correct clinically modifiable factors (insulin resistance,

compliance)2)Avoid drug interactions (statins and PPIs)3)Higher dose of Clopidogrel (600 vs 300 mg)4)Individualized dosing based on level of resistance using

biochemical measures.5)Using other ADP receptor antagonists such as

prasugrel, AZD6140..6)Addition of other anti-platelet agents (cilostazol, direct

thrombin inhibitors, ...)

Class IIb:Class IIb: In pts in whom subacute thrombosis may be In pts in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating catastrophic or lethal (unprotected left main, bifurcating left main, or last patent vessel), platelet aggregation left main, or last patent vessel), platelet aggregation studies may be considered and the dose of clopidogrel studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated. platelet aggregation is demonstrated. (Level of Evidence: (Level of Evidence:

Class IIb:Class IIb: In pts in whom subacute thrombosis may be In pts in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating catastrophic or lethal (unprotected left main, bifurcating left main, or last patent vessel), platelet aggregation left main, or last patent vessel), platelet aggregation studies may be considered and the dose of clopidogrel studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated. platelet aggregation is demonstrated. (Level of Evidence: (Level of Evidence:

Level of Evidence C:Level of Evidence C: Consensus opinion of experts, case studies, or standard-of-care. Consensus opinion of experts, case studies, or standard-of-care.

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