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Clopidogrel Platelet Function Tests

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December 2011

Beyond Hot Topic is an opportunity for viewers to submit questions to the Hot Topic presenter. The opportunity to submit questions for this topic is now closed.

The following questions were submitted by viewers and answered by the presenter, Gretchen Johns, MD, Laboratory Section Director for Coagulation and Medical Director for the Department of Laboratory Medicine and Pathology at Mayo Clinic in Jacksonville, Florida. 

Questions are presented as submitted (unedited).

  1. Surgeons will order a PT/INR on their patient right before surgery to assess if the patient is a bleeding risk during surgery. Which of the tests discussed should a surgeon order to determine if a patient on Plavix is at risk of a significant bleed during surgery?

    Tests useful for determining if a patient recently on clopidogrel is at risk of bleeding during surgery would include Accumetrics VerifyNow P2Y12 test, TEG platelet mapping, PlateletWorks ADP test, or Chrono-Log Whole Blood /Optical Lumi-Aggregometer (which was not included in the discussion but is FDA approved and available in the US). Light transmission aggregometry (LTA) and flow cytometry are excellent tests but often are not practical for screening due to cost, time, and availability constraints. Multiplate Whole Blood Aggregometry, Impact cone and platelet analyzer and the new P2Y cartridge for the PFA-100 analyzer are not yet FDA approved but would work well when approved. Platelet function experts endorse only the LTA. Since there are many types of platelet function tests available for this task, the choice may depend on which of these instruments is available at your institution.

    At Mayo Clinic Florida, we are using the VerifyNow P2Y12 test for patients on clopidogrel who need to have surgery. While the literature advises waiting 5 to 7 days after stopping clopidogrel, we have tested patients as soon as 3 days to see if their percent inhibition and P2Y12 Reaction Units (PRUs) are within an acceptable range (less than 20% inhibition and greater than 235 PRUs). We do this on patients who need the shortest amount of time off clopidogrel; if they fall within this range, the procedure is performed. Sometimes the procedure must be delayed another couple of days when the values are not acceptable. Bridging antiplatelet therapy may be possible in the future when or if the very short-acting P2Y12 antagonists receive FDA approval.

  2. What is the "generic" test referred to near the end of the presentation?

    I am not exactly sure what this question refers to. For the next to the last slide (the summary slide) of the presentation, I mentioned genetic testing again as a way to identify poor metabolizers of clopidogrel but reminded the listeners that there are additional factors influencing clopidogrel levels. Perhaps I pronounced “genetic testing” badly and it sounded like “generic testing”. I apologize if that is the case for misleading the listener. I also mentioned that the generic form of the medication clopidogrel should be available later this year (May 2012) which will greatly reduce the price.

  3. Additional information on the utilization of the Verify Now >235 PRUs as a measure of resistance. This reference point is being promoted by the vendor as of high importance.

    This is an excellent question to ask when using any test – how were the cutpoints for critical decision making determined and what studies support these cutpoints? The VerifyNow study for the baseline reference range (194-418 P2Y12 Reaction Units or PRUs) was established by testing 147 patients at 4 centers with vascular disease or with 2 of the 8 risk factors for developing vascular disease before administration of clopidogrel. It is apparent from the baseline reference range studies that there is quite a lot of individual variation due to the complex metabolism of clopidogrel.

    Dr. Jackie Coleman from Accumetrics says that the cutoff of over 235-240 PRUs for resistance is supported by the white paper by L Bonello, U Tantry, et al from the Working Group on High On-Treatment Platelet Reactivity in the Journal of the American College of Cardiology (JACC) 2010, vol. 56, no. 12, pp 919-933 which reviewed 4 studies using the VerifyNow P2Y12 test in an attempt to provide consensus on the definition of high on-treatment platelet reactivity to ADP. A meta-analysis of individual patient data by S Brar, J ten Berg, et al in the JACC 2011, vol.58, no. 19 pp 1945-1954 found a strong association of the cutoff value with the clinical endpoints of death, nonfatal myocardial infarction, and stent thrombosis. An analysis of the GRAVITAS data using a cutoff of less than 208 PRUs by J Price, D Angiolillo, et al in Circulation Sept 6, 2011 was also associated with a lower risk for cardiovascular events (death, myocardial infarction, and stent thrombosis).

    The choice of using the percent inhibition versus the P2Y12 Reaction Units (PRUs) may be influenced by the purpose for which one runs the test. For example, our neurosurgeons are using the VerifyNow test after giving a loading dose of clopidogrel before placement of a shunt or other neurovascular procedure and are looking for at least 20% inhibition over baseline. Other surgical candidates, who are discontinuing their daily clopidogrel in preparation for their procedures, may be followed by the percent inhibition and/or the P2Y12 Reaction Units (PRUs).

  4. Reference whole blood lumi aggregation: when do you think it will be approved by the FDA?

    There is a whole blood / optical lumi-aggregometer available from the Chrono-Log Corporation located in Havertown, PA, USA with an FDA-approved instrument (Model 700) which has been on the market for some years. It actually incorporates 3 different systems in 1: optical or turbidometric aggregometry (which can be used for measuring platelet or leukocyte aggregation, ristocetin cofactor activity or shape changes of suspended cells, impedance aggregometry (light transmission aggregometry) and luminescence (which can be used for measuring platelet ATP release in patients with storage pool or secretion defects or with heparin-induced thrombocytopenia (HIT) or for leukocyte function studies – looking for aggregation or superoxide generation defects as in chronic granulomatous disease or myeloperoxidase deficiency. It is very flexible and is excellent for research. I am not personally familiar with its use in routine laboratory work and apologize for not including it in the discussion of possible tests for clopidogrel testing.

  5. While understanding there is confusion and controversy regarding the use of genetic testing, providing some practice guidelines or an algorithm for consideration by physicians would be useful. Also, discussion of the affect genetic testing could have on controlling downstream costs.

    As you said, there is no consensus on how to apply genetic testing in the face of FDA boxed warnings, population variations, and genetic mutations in the receptors for absorption from the intestine and the platelet P2Y12 ADP receptors, in addition to the CYP2C19 genes. Genetic testing for all patients placed on clopidogrel would not be cost effective in most patient populations, but may be reasonable for patients from Polynesia/Micronesia. Patients of Asian ethnicity on clopidogrel (because of an approximately 15% incidence of 2 loss of function mutations of the CYP2C19 genes) could be screened with a point-of-care test such as the VerifyNow, PlateletWorks, thromboelastography platelet mapping test or the excellent but less available tests such as light transmission aggregometry or flow cytometry tests. Patients that appear resistant by this screening could then have genetic testing done or be placed on an alternative P2Y12 antagonist (however, with generic clopidogrel becoming available in May 2012, the price difference may make other choices less frequently used by insurance companies and self-pay patients). Patients of any ethnicity with an adverse event while on clopidogrel should be strongly considered for genetic testing and/or a change of medication or dosage.

    Finally, there are some rapid, less labor intensive and probably less expensive genetic tests which may soon be available such as the Verigene CYP2C19 Plavix Metabolism Test from Nanosphere Inc., Northbrook, IL, the INFINITI CYP2C19 assay from AutoGenomics, Vista, CA or the Spartan Rx from Spartan Bioscience, Ottowa, Ontario (not available for sale in the US).

    Nanosphere is submitting more studies and data to the FDA in hopes of getting FDA premarket approval (it was declined in June 2011); Nanosphere does already have FDA clearance for other tests using this same technology. AutoGenomics was granted 510(k) clearance by the FDA but their package insert specifically states that the assay is not indicated for use in predicting drug response (the FDA would require more data before approving it for this use). With the advent of these quicker and hopefully less expensive genetic tests performed on appropriate patients and populations, clopidogrel can be used more judiciously. The newer P2Y12 antagonists will be more costly by comparison than clopidogrel when the generic form of clopidogrel is available and the newer drugs could be reserved for patients who are shown to be poor metabolizers by genetic testing. Because these drugs are often taken by patients for many years, genetic testing could become an important tool in reducing the cost of P2Y12 antagonist therapy while potentially preventing serious adverse events when clopidogrel is prescribed for patients who are poor metabolizers.