Optical Platelet Aggregation drug monitoring for P2Y12 inhibitors (e.g. Plavix or Clopidogrel)

Due to a number of inquiries concerning the monitoring of platelet inhibitors used in cardiovascular procedures, such as percutaneous coronary interventions (PCI), we would like to call your attention to some studies in this area and what we do to answer the concerns of physicians to monitor the effectiveness of the drugs currently used to reduce the incidence of non-responders to the therapy.  Current recommendations for PCI are to use Clopidogrel (Plavix) and Aspirin prior to and post procedurally to inhibit platelets from coagulating in the newly inserted stents. There is a high incidence of  patients who do not respond well to these inhibitors and we can differentiate them from the normal responders using a classical thoroughly validated technique, known as Optical Platelet Aggregation or Platelet Function analysis. Other techniques have been used and their problems have been discussed in the paper cited below along with a comparison with the classical method of Optical Platelet Aggregation (OPA). This paper compares a population study of 530 patients undergoing PCI and studied using the techniques of OPA, Verify Now and PFA-100. It evaluated the parameters that influenced the determination of who responded and who didn’t respond to the therapy (e.g. age, gender, inflammation, BMI, Diabetes and malignancy which are typical aspects seen as variables with OPA). It noted unexpected variables seen with the Verify Now P2Y12 analyzer of hematocrit and hemoglobin levels, while the PFA was influenced by B-blockers.

I would also like to mention that  “P2Y12” is the  name of the membrane glycoprotein that is specifically inhibited by Plavix and affects the platelet’s response to ADP, an agonist used in OPA to monitor platelet aggregation. Aspirin is also monitored in platelet aggregation by using the agonist Arachidonic acid. To confuse the story a little more, the researchers have coined the term “High Responders” referring to the fact that patients are poor responders to the drugs or their platelet are still reactive to the ADP or Arachidonic Acid agonists.

The reference I refer you to is in the Journal of Haemostasis and Thrombosis, 2009,102:719-727.  The Influence of Clinical Characteristics, Laboratory and Inflamatory Markers on “High on Treatment Platelet Reactivity” as Measured with Different Platelet Function Tests.

Ellen H.A.M. Elsenberg, Jochen W van Werkum, Ruud M.A. van de Wal, A.Carla, Zomer, Heleen J. Bouman, Freek W.A. Verheugt, Jurrien M. ten Berg, Christian M. Hackeng.

In conclusion, if anyone asks for P2Y12, Plavix or Clopidogrel monitoring, we do it daily with an order of a Platelet Function Analysis, same day turn around time and the whole blood samples (3-4 Blue top tubes) should be sent with 2 hours of the phlebotomy at room temperature. Please make a note of the type of medications the patient is on so that our comments can be specific as to their response.

Recent Genetic testing at Coagulation Consultants Lab.

Please be advised that our laboratory is able to supply you with the currently available genetic testing for Coumadin( Warfarin) and shortly Clopidogrel (Plavix) which are currently listed and recommended in the drug’s labeling (by FDA mandate) along with dosage recommendations.

 In terms of available population studies for Coumadin, there is a significant reduction in hospitalizations (approximately 30%) for over and under dosages as a result of genetic pharmacologic guidance for this drug (900 patients).  Many other studies were used to derive the specific genetic mutations and how they are involved with metabolism of this drug and the regeneration of Vitamin K(1,2) by the liver enzymes.  The importance of  this type of genetic anaylsis can be circumvented by routine (daily) monitoring of the Prothrombin Times to provide the needed adjustments to achieve a stable dosage that fits with the patients metabolism, drugs and diet. Published articles have established that self monitoring is a satisfactory way to achieve a successful patient routine without having the patient to visit the clinic every day.

 Similarly, diminished antiplatelet  responses to Clopidogrel (Plavix) have been described in 21 studies (4,500 subjects) demonstrating the genetic variables involved with the metabolic conversion of Clopidogrel to its active form (3). Many of the problems associated with Clopidogrel responses can be attributed to its metabolism from the prodrug to its active form, and these can arise from genetic mutations or from drug-drug interactions in the liver enzymes that metabolize the drugs. The genetic testing will anticipate the defects in its metabolism and therefore establish a faster response to the desired dosage. However, the final decision of the desired antiplatelet effect will be assessed by an Optical Platelet Function Analysis and how the platelets respond to ADP agonists. This is especially important when Plavix is combined with Aspirin, which can be associated with a bleeding diathesis in some patients. For more details on the Optical Platelet function analysis see the article entitled Plavix monitoring.

Since we can foresee a new demand for these genetic tests as a result of published reports, we would like to inform you that we can perform these tests in a timely fashion and at a significant cost savings over most alternatives. Please call us for information since our new requisitions are not available yet.

References:

1) Epstein, R., et al. (2010, March 30). Warfarin Genotyping Reduces Hospitalization Rates: Results from the Medco-Mayo Warfarin Effectiveness Study (MM-WES). Retrieved from Journal Of American College Of Cardiology website: http://content.onlinejacc.org/cgi/content/full/jacc;j.jacc.2010.03.009v1

2) Bristol-Myers Squibb Company. (2010, January 22). COUMADIN Tablets (Warfarin Sodium Tablet, USP) Crystalline COUMADIN FOR INJECTION (Warfarin Sodium for Injection, USP). Retrieved from U.S. Food & Drug Administration website: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf

3) Bristol-Myer Squibb/Sanofi Pharmaceuticals Partnership. (2010, March 12). PLAVIX clopidogrel bisulfate tablets. Retrieved from U.S. Food & Drug Administration website:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf