Dr. Lundberg is an associate clinical professor of medicine at the David Geffen School of Medicine at the University of California at Los Angeles, the associate program director of the UCLA Emergency Medicine/Internal Medicine Residency, and the director of clinical operations for the emergency department at Olive View-UCLA Medical Center. Luis Lovato, MD, serves as the medical editor of Journal Scan. He is an associate professor at the David Geffen School of Medicine at UCLA, the ED director of clinical practice at Olive View-UCLA Medical Center, and the co-chair for the Emergency Medicine Best Practices Committee for the Los Angeles County Department of Health Services.
Clopidogrel for treating acute coronary syndromes has climbed steadily since the 2001 publication of the landmark CURE trial, but issues that limit the drug's usefulness should rightly give emergency physicians pause before they order that 600 mg load in the ED.
A steady stream of new trials led to new consensus guidelines that call for a loading dose in the ED for patients heading to the catheterization lab for percutaneous coronary intervention and stenting, for patients being treated with fibrinolytics for ST-elevation MI, and for all other patients with high-risk ACS. Despite its documented success in reducing recurrent ischemic events, genetic variations or drug-drug interactions (particularly with proton-pump inhibitors) render the dose ineffective in some patients because clopidogrel is a pro-drug that must be converted by the cytochrome pathway. The drug can be too effective in other patients who have a significant risk of major bleeding, particularly in conjunction with surgical procedures such as coronary artery bypass grafting.
Clopidogrel also binds irreversibly to platelets, and has a long half-life (measured in days), raising the stakes substantially when deciding whether to administer it in the ED. Given its limitations, it is not surprising that other drugs targeting the same platelet receptor (ADP receptor P2Y12) have been studied in search of a superior replacement. Prasugrel is similar to clopidogrel but has less reliance on the cytochrome enzymes for activation. It performs similarly in head-to-head trials with clopidogrel, with perhaps an advantage in some subgroups of patients (such as those on proton-pump inhibitors). (N Engl J Med 2012;367:1297.)
Ticagrelor is structurally distinct from clopidogrel, requires no metabolism to an active form, and has a shorter half-life. Its more consistent efficacy in platelet inhibition has been borne out by reduced ischemic outcomes in recent trials, but it is also associated with higher rates of major bleeding and displays other untoward side effects in clinical use. (N Engl J Med 2009;361:1045.) These circumstances have led to a search for a strategy to identify subgroups of patients who would benefit from more intense platelet inhibition than that provided by clopidogrel without exposing others to increased bleeding risk.
Bedside Monitoring to Adjust Antiplatelet Therapy for Coronary Stenting
Collet JP, Cuisset T, et al
N Engl J Med
The authors of this study describe their novel strategy for studying a real-world application of bedside tests of platelet inhibition in patients undergoing coronary stent placement who are anticipated to receive dual antiplatelet therapy (aspirin and clopidogrel) for at least one year. Bedside assays of the efficacy of inhibition of platelet function have been shown to have prognostic value in identifying patients at higher risk of “failing” the drugs (i.e., having recurrent ischemic events), but no trial evidence that modifying therapy on the basis of these tests mitigates that risk.
The study, called the ARCTIC trial, had half of the study patients undergoing coronary stent placement (monitoring group) to be tested for resistance to aspirin and clopidogrel at the time of the procedure, with intensification of antiplatelet therapy as needed with higher doses of clopidogrel, substitution for prasugrel, or administration of IV glycoprotein IIb/IIIa inhibitors peri-procedurally. A two-week follow-up platelet activity test was conducted in the active group, at which time antiplatelet therapy could be further adjusted. The control group received standard therapy for the one-year course of the study at their treating doctors' discretion, with 94 percent receiving the usual combination of aspirin and clopidogrel.
High platelet reactivity (resistance) with clopidogrel use was common (35% at the time of procedure, 16% at 14 days), and resulted in substantial differences in the treatment given to the two groups. Patients in the monitoring arm were 2.5 times more likely to be reloaded with clopidogrel in the catheterization lab, were five times as likely to receive glycoprotein IIb/IIIa antagonists, and were three times as likely to receive prasugrel or a double dose (150 mg daily) of clopidogrel as maintenance therapy.
After one year, despite this more-intense therapy, no difference was found between the two groups in subsequent death, myocardial infarction, stent thrombosis, stroke or urgent revascularization (monitoring [34.6%] vs. control [31.1%], hazard ratio, 1.13; 95% CI, 0.98 to 1.29; p=0.10). The authors found that routine use of platelet-function testing prior to coronary stenting is not supported by their data.
This result adds another to a long line of laboratory tests that portend adverse outcomes for a subset of patients, but do not yield any improvement in clinical endpoints when targeted for therapy. Like high levels of homocysteine, low HDL, and other such in vitro findings, a high level of platelet reactivity while on clopidogrel (resistance) does not appear to indicate that therapy should be modified based on the results of this study. Instead, the use of alternative P2Y12 antagonists or double-dose clopidogrel should be based on clinical findings of clopidogrel failure, such as stent thrombosis while on standard therapy or on other clinical variables known to limit the efficacy or safety of clopidogrel, such as proton-pump-inhibitor therapy or an anticipated need for urgent CABG. The choice of adjunctive antiplatelet therapy is complex and high-stakes, and is best made in conjunction with your cardiology consultant promptly after the diagnosis of a high-risk acute coronary syndrome.
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