The American College of Cardiology and American Heart Association this week published a clinical alert on the FDA’s “black-box warning” concerning use of clopidogrel (Plavix) by patients who could be “poor metabolizers” of the drug and, therefore, may not receive its full benefits. In addition, a study published in the Archives of Internal Medicine (1) has raised concerns about the possibility of increased risk of cancer among patients taking prasugrel (Effient).

SCAI is concerned that an unintended outcome of media attention to these publications is that patients might stop taking prescribed antiplatelet medications or stop taking them as prescribed (e.g., take lower doses than prescribed). Therefore, SCAI is urging all healthcare providers to emphasize to their patients that they should never stop taking a prescribed medication before talking to their healthcare provider, preferably the provider who prescribed the medication. This is the critical take-away message regarding antiplatelet therapies for patients who have undergone PCI with stent placement.

It is also important to note the ACC/AHA clinical alert is not a practice guideline, but rather a summary of the data currently available. SCAI and a number of other organizations have endorsed the clinical alert. To assist members who may be receiving questions from their patients or colleagues, or have questions of their own about whether and how to modify their clinical decision making as a result of either the clinical alert or the Archives paper, SCAI offers the following guidance for members and other healthcare providers:

Q: Are there any patients who should stop taking their antiplatelet medications?

A: Noncompliance with prescribed antiplatelet regimens is the most important modifiable risk factor for adverse events, particularly among patients with coronary stents. Noncompliance results in a far greater number of potential events when compared to poor metabolization of clopidogrel. The vast majority of patients are NOT “poor metabolizers” and have been shown to achieve excellent outcomes with clopidogrel following stent implantation. Any patient whose compliance with antiplatelet regimens is in question should be reminded of the purpose of these medications and the possible ramifications of discontinuing them. Every possible effort should be taken to address any concerns or questions. In terms of cancer risk, the data are inconclusive; any decision-making based on this concern should be carefully considered in the context of the patient’s overall health and risk.

Q: Which patients should undergo a genetic test to determine if they are receiving, or will receive, the full benefit of clopidogrel?

A: The FDA estimates that 2–14 percent of patients are “poor metabolizers” of clopidogrel. As the ACC/AHA clinical alert notes, data from ongoing clinical trials will deliver needed information about the predictive value of genetic testing and will guide efforts toward “personalizing” medicine based on genotyping. In the absence of these clinical trial results, the ACC/AHA clinical alert does not recommend that every patient undergo a genetic test to detect polymorphisms in CYP2C19 or other enzymes responsible for activating clopidogrel. For patients who are at high risk for stent thrombosis or who have had prior thrombotic events, it may be reasonable to consider genetic testing or platelet function testing, as the results might prompt changes in therapy. However, it must be recognized that changing therapy on the basis of these (or other) tests has not definitively been shown to change the risk for subsequent events. There are some preliminary data suggesting that higher loading or maintenance doses of clopidogrel, or the use of alternative medications, such as prasugrel, may be of benefit. No specific recommendation can be made at this time.

Q: Should PCI patients taking clopidogrel be switched to another antiplatelet medication?

A: There are very limited data concerning switching a patient from one antiplatelet agent to another, particularly in the absence of an event. For new patients or patients who are taking clopidogrel but are very concerned that they may be “poor metabolizers,” providers may consider ordering a platelet-function assay in order to assess responsiveness to clopidogrel. As stated in the ACC/AHA clinical alert, there are several different platelet-function tests that can be used to assess the platelet response to clopidogrel, and the clinician should use the method with the greatest reliability and reproducibility at his or her specific facility. If the test demonstrates a low level of responsiveness, options include continuing the current dosing of clopidogrel, or using a higher dose of clopidogrel or another agent, such as prasugrel, in order to achieve greater levels of platelet inhibition. When a provider is considering either alternative clopidogrel dosing or newer agents such as prasugrel, the balance of potential ischemic benefit with the known increased risk of bleeding should be considered. In particular, prasugrel is contraindicated in patients with stroke and TIA. Again, because there are no definitive studies on this topic, no specific recommendations can be made except for strict compliance with prescribed medications.

Q: Are there symptoms that patients can watch for that might signal they are not receiving the full benefit of their clopidogrel?

A: Unfortunately, there are no specific signs or symptoms that can help patients determine whether he or she is at risk. Compliance remains the major factor that each patient should focus on. Although most patients on dual antiplatelet agents describe increased bruising or prolonged bleeding from even minor cuts, the absence of these findings does not signal increased risk for stent thrombosis. Although it is beneficial to be aware of these common side effects of antiplatelet therapy, patients should accept this as normal and not stop or reduce their dosage in response to this minor bleeding. Unfortunately, the first manifestation of poor response may be stent thrombosis; fortunately, this is a rare event in the compliant patient.

Q: How concerning are the findings on prasugrel and cancer?

A: An analysis of new unpublished data (1) from the TRITON-TIMI 38 trial has suggested there may be an increased risk of new and worsening solid cancers among patients taking prasugrel. There is only speculation regarding potential mechanisms for this possible increase in cancer risk, and the TRITON-TIMI 38 study was not powered to demonstrate this effect. There are no similar concerns with clopidogrel, which is in the same drug class. Other ongoing clinical trials of prasugrel may help to further address this issue. There are not sufficient data to change current recommendations for the use of prasugrel as described in the ACC/AHA/SCAI PCI Guideline Update published in the last year.

Feedback:
SCAI invites your feedback on this communication. Please send your comments to info@scai.org.

Reference:

1. Floyd J, et al "Prasugrel as a potential cancer promoter: review of the unpublished data." Arch Int Med 2010; 170: 1078-80