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Generic clopidogrel As antiplatelet therapy enters a transitional phase to generic clopidogrel, will this change drive more patient-tailored treatment? Since the FDA approved clopidogrel in 1997, this antiplatelet agent has revolutionized interven- tional cardiology and transformed therapy for non-STEMI, STEMI, and PCI-treated patients. Clopidogrel enjoyed a remarkable 15-year “home run” marketed under the name Plavix (Bristol-Myers Squibb/ Sanofi Pharmaceuticals Partnership, New York, NY), amassing tens of billions of dollars in sales and serving an estimated 115 million patients internationally and tors having more predictable pharmacodynamic profiles. 50 million patients in the United States alone. The evolu- In 2005, the important relation of high on-treatment tion continues with the expiration of the Plavix patent platelet reactivity (HPR) to poststenting ischemic risk was last month coupled with the FDA’s swift approval of reported in the single-center PREPARE POST-STENTING generic forms of both the 75-mg daily dose and the study.2 Since then, numerous observational studies involv- ing thousands of patients worldwide have confirmed the One of the largest barriers to patient compliance and seminal findings of PREPARE POST-STENTING.3 long-term therapy with branded clopidogrel was cost. Finally, in 2010, the first genome-wide association Generic versions should substantially lower that barrier study identified a sole single nucleotide polymorphism and may improve compliance and patient outcomes, associated with clopidogrel response variability. This single nucleotide polymorphism is CYP2C19*2. In the same publication, we reported the results of a valida- tion study clearly demonstrating the increased risk of poststenting ischemic event occurrence in CYP2C19*2 Clinicians need to be cautious to avoid allowing cost carriers.4 The roles of genetic and platelet function test- to be the most important factor in selecting a treat- ing in clinical practice are now addressed in the most ment option. Patients taking generic clopidogrel face recent American and European treatment guidelines. the same pharmacodynamic limitations as with Plavix. Thus, in the last 15 years, important strides have been In 2003, we first reported the unpredictable antiplate- made in understanding the role of genetics, drug-drug let response to Plavix therapy and the important fact interactions, and many other factors influencing clopi- that approximately 30% of the PCI population had a dogrel metabolism and its pharmacodynamic effect. A negligible or absent pharmacodynamic effect.1 This strong relation has now been established between HPR report was initially met with disbelief and opposition and poststenting ischemic event occurrence.
by many thought leaders. However, these findings have Arguably, P2Y blockade is the most important and now been validated in thousands of patients studied potentially life-saving pharmacologic strategy that we can provide to a stent patient. However, it may be risky The unpredictable and, in some cases, absent phar- to prescribe generic clopidogrel to patients without macodynamic effect following clopidogrel therapy laid confirming an adequate pharmacodynamic response. the groundwork for the development new P2Y inhibi- Direct confirmation is provided by platelet function May/june 2012 cardiac interventions today 25 testing, whereas genetic testing provides indirect evi- could be variations in potency and consistency from batch to batch. Concerns have also been raised about Payers are now more apt to demand this type of the purity of generics after some clopidogrel pills manu- testing as well. Some progressive insurers are already factured in India were proven to contain significant levels requiring testing to determine the suitability of patients of methyl chloride, a known carcinogen.6 for the more expensive new P2Y inhibitors, prasugrel (Effient, Daiichi Sankyo Company, Limited, Parsippany, NJ; Eli Lilly and Company, Indianapolis, IN) and ticagrelor (Brilinta, AstraZeneca Pharmaceuticals LP, Although clopidogrel will likely remain the most popular nonaspirin antiplatelet agent, the new P2Y Various companies are leading the way in point-of- inhibitors, particularly prasugrel, continue to gain market care platelet function testing. With a defined HPR cut- share. Ticagrelor and prasugrel have more predictable point in place and recommendations in the guidelines, and potent pharmacodynamic profiles and a more rapid more cardiologists are now confirming the response to onset of action than clopidogrel. These pharmacody- clopidogrel rather than relying on blind faith. Exciting namic advantages have translated to fewer ischemic preliminary evidence suggests that there may be a event occurrences but more bleeding in acute coronary syndrome patients who were studied in two large-scale With regard to the role of genetic testing in the trials. For the interventional cardiologist, a reduction in PCI-treated patient, the presence of a homozygote for stent thrombosis is particularly notable. a loss-of-function allele should be a strong indication Clinicians should strive to find an antiplatelet therapy to use an alternative P2Y inhibitor to clopidogrel. that achieves the optimal level of platelet inhibition for Similarly, a heterozygote for the loss-of-function allele the patient, regardless of cost. If generic clopidogrel is may undergo platelet function testing to confirm the indeed pharmacodynamically effective in the patient, adequacy of the response to clopidogrel, and if inade- offering them this less-expensive option appears to be a quate, an alternative P2Y inhibitor can be considered. win/win. The introduction of generic clopidogrel holds Platelet function testing in clopidogrel-treated patients the strong possibility of inducing a change in practice should allow for a maximal pharmacodynamic effect to whereby genetic and platelet function testing are per- occur. Therefore, 5 days of maintenance therapy, or at formed more frequently in patients receiving a stent. least 8 hours after an initial loading dose, would be suit- This will allow the patient’s platelet physiology to decide able times to test, and this strategy has been employed the course of treatment instead of the price tag on the The role of follow-up testing is unresolved and understudied. Essentially, all of the major published Paul A. Gurbel, MD, is the Director of the Sinai Center data linking platelet function to post-PCI event occur- for Thrombosis Research at Sinai Hospital of Baltimore, rence has been based on one measurement of platelet and Associate Professor of Medicine at The Johns Hopkins function performed in-hospital after allowance for University School of Medicine in Baltimore, Maryland. an adequate steady state pharmacodynamic effect to He has disclosed that he has received honoraria and/or occur. The introduction of generic clopidogrel to the grants from Astra Zeneca, Bayer, Bristol Myers Squibb, market could be a catalyst that drives clinicians to Lilly/Daiichi Sankyo, Nanosphere, Iverson Genetics, embrace platelet function testing and genotyping and Accumetrics, and Haemonetics. Dr. Gurbel may be potentially provide improved patient care while at the reached at pgurbel@lifebridgehealth.org. 1. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908-2913.
2. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING study. J Am Coll Cardiol. 2005;46:1820-1826.
It is vital to remember that the pharmacodynamic 3. Bonello L, Tantry US, Marcucci R, et al. Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll response, safety, and efficacy of the generic versions of clopidogrel have not been vetted in clinical trials. There 4. Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849-857.
are potentially serious issues that have yet to be com- 5. Gurbel PA, Tantry US. Do platelet function testing and genotyping improve outcome in patients treated with pletely examined and studied. The lack of longitudinal antithrombotic agents? Platelet function testing and genotyping improve outcome in patients treated with data on these generic medicines is sobering. The reliabil- antithrombotic agents. Circulation. 2012;125:1276-1287.
6. Wahi R, Rao G, Thethi I, Pathak L. Prevalence of free methyl chloride as an impurity in generic clopidogrel ity of generic clopidogrel has not been tested, and there preparations: safety implications in cardiovascular patients. Circulation. 2010;122:A17290. 26 cardiac interventions today May/june 2012

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