WHAT IS PEER TO PEER?
Med-IQ's new complimentary, certified continuing medical education (CME) activity,
Peer to Peer: A New Model for Improving Guideline- and Evidence-Based ACS Care, is connecting healthcare professionals from across the country. This exciting, first-of-its-kind CME series provides participants with access to acute coronary syndrome (ACS) faculty experts during personalized sessions focusing on improving ACS patient care in their practices. This real-time exchange of ideas has helped address some of the major challenges that clinical practices face in managing ACS cases.

WHAT ARE E-BRIEFS?
Each month, Med-IQ will publish a short e-brief to highlight real-world questions, opportunities for improvement, and front-line perspectives gained from these ACS Peer to Peer teleconferences. Below, you'll find the sixth of these e-briefs; in this installment, our expert faculty examine two practical issues in antiplatelet therapy: the recent Food and Drug Administration (FDA) boxed warning for clopidogrel, and defining a role for prasugrel in patients with ACS.

Interpreting the Boxed Warning on Clopidogrel
Question: What does the new FDA boxed warning on clopidogrel mean for my practice?

Answer: A clear answer to this question does not yet exist. Below is an initial review of the FDA warning and several of the issues that have emerged. Many physicians are looking forward to the cardiology societies reviewing the issues more completely and offering recommendations.

In March 2010, the FDA announced that a boxed warning had been added to clopidogrel's prescribing information about its reduced effectiveness in patients who are poor metabolizers of clopidogrel, determined by a patient's cytochrome P450 19 (CYP2C19) genotype.¹ Specifically, the boxed warning in the drug label includes information to:

• Warn about reduced effectiveness in patients who are poor metabolizers of clopidogrel because poor metabolizers do not effectively convert clopidogrel to its active form in the body
• Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function
• Advise healthcare professionals to consider other antiplatelet medications or alternative dosing strategies for clopidogrel in patients identified as poor metabolizers

The warning notes that poor metabolizers treated with the standard dose of clopidogrel exhibit higher rates of cardiovascular events following ACS or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. In addition, it states that tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. The warning suggests considering alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.¹

The CYP2C19*1 allele is associated with fully functional metabolism, while the CYP2C19 *2 and *3 alleles are nonfunctional and account for the majority of reduced-function alleles. According to the definition used for the FDA boxed warning, "poor metabolizers" are individuals found to have two nonfunctional alleles. Using this criterion, approximately 2% of whites, 4% of blacks, and 14% of Chinese are poor metabolizers.²

It is currently difficult to incorporate this warning into clinical practice for a number of reasons. The warning offers no recommendations for exactly which pharmacogenetic tests are considered acceptable, nor does it address specific alternate therapeutic strategies for poor metabolizers. Furthermore, there are no current guidelines or standards of care for implementing the changes recommended on the boxed warning. In addition, it is unclear whether there are any legal implications for hospitals or physicians if tests are not performed on all patients receiving clopidogrel. Similarly, liability is unclear in cases where a hospital or physician does perform testing, then uses an alternate treatment that may be considered to be off label.

Although FDA approval is not necessary for tests, there is one "FDA-cleared" genetic test for pharmacogenetic analysis of the CYP2C19 gene, and others are available.³ Unfortunately, the tests are expensive, ranging from $250 to $500, which is likely to limit their widespread use. In addition, results are not available immediately and, thus, are likely to be of little use in the emergency care setting. At this time, insurance reimbursement is also uncertain.³

Platelet function testing could be another option to assess individual response to clopidogrel. Previous studies have shown that 4% to 30% of patients will have low levels of platelet inhibition in response to clopidogrel.⁴ Results from a meta-analysis of five published trials presented at American College of Cardiology 2010 i2 Summit indicated that those with a poor response to clopidogrel (as measured by increased platelet reactivity) had a more than 2-fold increased risk of the composite endpoint of myocardial infarction and death.⁵

For patients who have been identified as CYP2C19 poor metabolizers, the boxed warning from the FDA suggests that clinicians consider alternative treatments or treatment strategies. Increasing the dose of clopidogrel has been studied as an option in poor metabolizers, however, the appropriate dosing is unknown (and likely varies between individuals), the most appropriate maintenance doses in these patients is unclear, and there are no outcomes from trials evaluating the long-term use of higher doses of clopidogrel.^6,7 Prasugrel is one alternate agent, but its use is approved only in ACS patients who are managed with PCI; therefore, use in other populations is currently off label. In addition, prasugrel is contraindicated in patients with a history of transient ischemic attacks or stroke, and it has a boxed warning regarding an increased risk of bleeding when used in patients 75 years of age or older or who weigh less than 60 kg.⁸ In patients in whom prasugrel is contraindicated and who are poor metabolizers of clopidogrel, possible alternatives include the use of ticlopidine, another thienopyridine, or the addition of cilostazol, a phosphodiesterase inhibitor that inhibits platelet aggregation, but neither of these strategies has been well tested in this setting.

To further complicate the issue, patients with only one reduced-function allele—approximately 30% of the general population—may also have suboptimal responses to clopidogrel, resulting in poorer clinical outcomes.⁹ A recent analysis of TRITON-TIMI 38 data by Mega et al found that in clopidogrel-treated patients who had at least one reduced-function allele, there was a 53% relative increase in the composite outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with patients with fully functional alleles (P = 0.01).⁹

TOP

Identifying Appropriate Candidates for Prasugrel
Question: Which patients are appropriate candidates for prasugrel? Are there any special issues to consider when prescribing the maintenance dose?

Answer: If clopidogrel has not already been given upstream, prasugrel is an alternative to clopidogrel in patients with ACS who will undergo PCI.^8,10 Prasugrel is particularly useful in the cath lab because of its rapid onset of action—within 30 minutes of administration. Thus, for patients for whom the anatomy is known and who did not receive clopidogrel upstream in the emergency department, prasugrel can be given instead in the cath lab. It should be noted that prasugrel has not yet been studied in the upstream setting, and, therefore, guidelines do not recommend its use prior to arrival in the cath lab. One exception to this recommendation is for patients with acute ST-segment elevation myocardial infarction (STEMI) who are going immediately from the emergency department to the cath lab for planned PCI; in these patients, prasugrel can be given in the emergency department.¹⁰ There are few data, however, to identify the safety profile of prasugrel in patients who have already received clopidogrel in the emergency department, so this remains a gray area.

TRITON-TIMI 38 compared prasugrel (60-mg loading dose, 10-mg daily maintenance dose) with clopidogrel (300-mg loading dose, 75-mg daily maintenance dose) in patients with ACS at the time of PCI.¹¹ At 15 months, patients receiving prasugrel had a 19% relative reduction in the rate of the primary efficacy endpoint (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). In addition, the prasugrel group had a 24% relative risk reduction (RRR) for myocardial infarction, a 34% RRR for urgent target vessel revascularization, and a 52% RRR for stent thrombosis when compared with those receiving clopidogrel. The prasugrel group, however, had a 32% increase in the risk of major hemorrhage (TIMI major bleeding not associated with coronary artery bypass graft surgery). Within the prasugrel group, patients with a history of cerebrovascular events experienced more frequent bleeding (including intracranial hemorrhage) and overall worse clinical outcomes in terms of the primary endpoint. Patients 75 years of age or older or who had a body weight of less than 60 kg had a neutral net benefit from prasugrel.¹¹ Therefore, prasugrel has a boxed warning regarding its use in patients with any of these three risk factors.⁸

TOP

REFERENCES

1. US Food and Drug Administration. FDA announces new boxed warning on Plavix. March 12, 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm204253.htm. Accessed April 28, 2010.

2. Plavix prescribing information. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals partnership; 1997. Updated March 2010.

3. Lakhman K. FDA's new Plavix black-box warning could trigger surge in CYP2C19 testing. Genome Web. www.genomeweb.com/blog/fdas-new-plavix-black-box-warning-could-trigger-surge-cyp2c19-testing. Accessed May 11, 2010.

4. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol. 2005;45(8):1157-1164.

5. Brar SS. Impact of platelet reactivity on clinical outcomes: A patient-level analysis. Presented at the American College of Cardiology Annual Scientific Session/i2 Summit. March 14, 2010, Atlanta, GA.

6. Damani SB, Topol EJ. The case for routine genotyping in dual-antiplatelet therapy. J Am Coll Cardiol. 2010;56.[epub ahead of print]

7. Gurbel PA, Tantry US, Shuldiner AR, et al. Genotyping: one piece of the puzzle to personalize antiplatelet therapy. J Am Coll Cardiol. 2010;56.[epub ahead of print]

8. Effient prescribing information. Indianapolis, IN: Daiichi Sankyo, Inc. and Eli Lilly and Company; 2009.

9. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354-362.

10. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction and ACC/AHA/SCAI guidelines on percutaneous coronary intervention. J Am Coll Cardiol. 2009;54(23):2205-2241.

11. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.

"This was a 5-star activity—over the top!" — Physician Participant, Las Vegas, NV

This activity is supported by an educational grant from sanofi-aventis U.S.

Published by Med-IQ, 5523 Research Park Drive. Suite 210. Baltimore, MD 21228.

Statements of fact or opinion are the responsibility of the authors alone and do not imply an opinion of the publishers or the officers of any sponsoring organization. Materials may not be reprinted without written consent from the publisher.

For reprint or other information, call 866 858 7434. © 2010 Med-IQ. All rights reserved.