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Plavix Response Testing

Platelet activation and aggregation play a pivotal role in the pathogenesis of cardiovascular disease. Inhibition of platelet function has become a primary therapeutic goal. Several large clinical trials have demonstrated improved risk reduction by dual antiplatelet therapy with aspirin and clopidogrel (Plavix). The latter is a thienopyridine that irreversibly blocks binding of ADP to the platelet P2Y12 receptor. The degree of platelet inhibition by clopidogrel varies from patient to patient in a normal or bell-shaped distribution. Between 4 to 30 percent of patients treated with clopidogrel do not have an adequate antiplatelet response as measured by platelet aggregation. Between 5 and 10% of patients treated with dual antiplatelet therapy still have thrombosis after stent implantation.

Five factors may contribute to this variable response; patient noncompliance, malabsorption, drug to drug interactions, platelet ADP receptor heterogeneity, and differences in the rate of drug metabolism. The last factor is particularly important for clopidogrel because it is a prodrug that is converted in the liver by the cytochrome P450 enzyme system to its active thiol metabolite. A single nucleotide polymorphism in the gene encoding the CYP2C19 enzyme is associated with decreased clopidogrel metabolism. Patients with one or more copies of the variant CYP2C19*2 and/or CYP2C19*3 alleles have reduced conversion of clopidogrel to its active thiol metabolite.

Allele Frequencies of CYP2C19 Variants

Variant

Caucasian

Asians

African American

*2

13-15%

32%

17%

*3

<1%

5-10%

<1%

CYP2C19*2 is the most common variant associated with reduced metabolism in all ethnic groups. Patients of Chinese ancestry have a higher incidence of both the CYP2C19*2 and CYP2C19*3 alleles compared to Caucasian or African-American patients.

Lower active metabolite exposure may result in reduced platelet inhibition and, thus, a higher rate of cardiovascular events following myocardial infarction or stent thrombosis following percutaneous coronary intervention (NEJM 2009;360:1-9). Because of this risk, the FDA added a black box warning to clopidogrel, which informs physicians that tests are available to determine an individual's CYP2C19 genotype and that this knowledge can be used to determine the best therapeutic strategy.

Although the black box warning specifically mentions genotyping, this type of testing is too laborious and expensive to perform on a routine basis. Many laboratories have decided to offer the VerifyNow P2Y12 system (Accumetrics) to measure platelet response to clopidogrel. This system consists of an instrument and a disposable assay cartridge. The instrument uses an optical detection system to measure the increase in light transmittance that accompanies platelet aggregation. A whole blood sample is injected into a cartridge that contains two reaction channels. One channel contains fibrinogen coated polystyrene beads, the platelet agonist ADP and Prostaglandin E1. The latter is added to reduce nonspecific platelet aggregation via a second ADP P2Y1 receptor that is not blocked by clopidogrel. This channel specifically measures the effect of clopidogrel on P2Y12-mediated platelet aggregation. Fibrinogen coated beads aggregate in whole blood in proportion to the number of activated platelets. Results of this channel are reported in P2Y12 Reaction Units (PRU), which is the amount of residual P2Y12 receptor mediated aggregation. Therefore, a lower PRU indicates good response to clopidogrel, while a higher number indicates less than optimal response. Responders usually have PRU <200. PRU values >230 have been associated with an increased risk of ischemic events after PCI including death, MI and stent thrombosis. These patients may benefit from either a higher dose of clopidogrel or alternative antiplatelet therapy such as prasugrel.

The second channel contains fibrinogen coated beads and the platelet agonist, isothrombin receptor activating peptide (TRAP). This channel measures the patient’s baseline platelet aggregation and is not affected by clopidogrel.

When the test was originally introduced in 2010, three values were reported including: P2Y12 Reaction Units (PRU), baseline PRU, and percent inhibition.In July 2012, Accumetrics, the manufacturer of the VerifyNow® P2Y12 test notified laboratories in the United States that a software update would eliminate the baseline and percent inhibition results. Our own data supported this modification because of the poor correlation between PRU and percent inhibition.For example, a PRU value of 230 was associated with percent inhibition values ranging from 5 to 50%.

Previously, percent inhibition was primarily used preoperatively to determine if a patient who was taking Plavix, or another P2Y12 receptor inhibitor, was at increased risk of bleeding. After the update, a PRU value of >230 can be used as an indicator that the patient has sufficient residual platelet reactivity to minimize the risk of bleeding.

Inhibition of platelet aggregation can usually be detected 2 hours after a 300 – 600 mg loading dose of clopidogrel. Peak effect is usually detected 6 hours after treatment. Platelets blocked by clopidrogrel are affected for the remainder of their lifespan, which is 7-10 days.

Preoperative management of patients who are taking Plavix and require an invasive procedure or surgery can be problematic. Operating on patients who are taking Plavix is associated with excessive bleeding, but discontinuing Plavix therapy prior to surgery has been associated with a 20% incidence of ischemic events.

At least 3 clinical practice guidelines provide direction regarding the timing of surgery in patients receiving Plavix. Each of these guidelines recommends discontinuing Plavix for at least 3 to 7 days prior to surgery to allow platelet function to return to normal and decrease the risk of bleeding.

  • The American College of Chest Physicians Evidence Based Clinical Practice Guidelines from 2008 state that platelet function returns to normal 7 days after the last dose of clopidogrel (Chest 2008;133:71S-105S, specifically page 217S)
  • The Society of Thoracic Surgeons Clinical Practice Guidelines, which were updated in 2011, state that previous reports recommended a 5 to 7 day delay after discontinuation of clopidogrel in patients requiring coronary artery bypass graft surgery to lessen bleeding (Ann Thorac Surg 2011;91:944-82, specifically page 951).
  • In between these two sets of guidelines is an update from May 2011 by the American College of Cardiology Foundation/American Heart Association for management of patients with unstable angina/non-ST elevation myocardial infarction. This document recommended withdrawing clopidogrel for at least 5 days prior to coronary artery bypass graft surgery (JACC 2011;57:1920-59).

All of these recommendations are based on the pharmacokinetics of clopidogrel and do not take into account individualized response to drugs. Approximately 40% of patients have suboptimal antiplatelet response to clopidogrel. Patients who are hyporesponders or nonresponders would be expected to normalize platelet function even sooner than 5 to 7 days after discontinuing clopidogrel. An individual’s response to clopidogrel can only be determined by performing platelet function testing. In our experience more than 50% of patients have minimal platelet inhibition within 3 days after discontinuing clopidogrel. Testing may reduce unnecessary surgical delays.

This test has been named P2Y12 Response Assay to avoid confusion with other tests such as the platelet function assay (PFA-100) and platelet aggregation. Also, the use of this test is not limited to clopidogrel. It can be used to measure the effect of other P2Y12 drugs, such as prasugrel.

Blood must be collected in a 2 mL Greiner Bio-One light blue capped vacuette tube using a 21 gauge or larger needle. Two tubes must be collected. The first tube should be discarded and the second tube sent to the laboratory for testing. The tube should be gently inverted 5 times to avoid clotting. If a CBC is ordered at the same time, it should be collected last to avoid contamination with EDTA. Specimens that are clotted, hemolyzed, collected in the wrong tube, incompletely filled or centrifuged are unacceptable for testing. Specimens must be transported at ambient temperature and tested within 4 hours after collection. This test should not be ordered on patients treated with GPIIb/IIIa inhibitors or with platelet counts below 100,000/uL.

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