Platelet Resistance — Much Known and Much More Unknown

In this issue of the Journal, Drs. El-Atat, Sharma and colleagues present the first pilot study in the United States to evaluate the clinical outcomes of patients with aspirin resistance who were assigned to either double versus triple antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). Although their numbers are small, the results suggest that patients with aspirin resistance had improved clinical outcomes if a glycoprotein IIb/IIIa inhibitor was added to the standard dual-antiplatelet regimen. This study adds to the growing body of evidence that suggests, “One size does not fit all” when it comes to optimal pharmacological platelet inhibition for PCI. Why, with about one million PCIs performed each year in the United States, is there such a paucity of data to guide how we inhibit platelets both acutely and long term in patients who undergo coronary stent implantation? We would like to suggest that there are several reasons — all of which need to be addressed in order for us to optimize patient care. These reasons can be categorized as measurement or definition inconsistencies, pharmacologic and drug interaction issues, clinical event disconnections and perhaps patient-related issues of compliance and/or non-uniform variability. Perhaps foremost is how we define platelet resistance. Several surrogate tests have been developed which evaluate the ex vivo responsiveness of platelets to a variety of inhibitors. These surrogate markers (functional platelet resistance with turbidometric and similar measurements) have generally been associated with worse clinical outcomes in patients who demonstrate high levels of platelet reactivity after treatment with aspirin or thienopyridines. However, uniform and standard definitions do not exist, and differ from assay to assay and drug to drug. Additionally, concern has been raised related to the interindividual variability of platelet function testing, where a single measurement may not fully describe the level of platelet reactivity over time. Complicating matters further are the compelling data from Spertus et al² suggesting that up to a third of patients after a myocardial infarction demonstrate compliance issues within 30 days. Furthermore, the pharmacogenetics of platelet resistance has only recently begun to be understood, as evidenced by patients with certain allele combinations who may not be able to efficiently convert clopidogrel into its active form. Yet despite an FDA black box warning for clopidogrel in relation to cytochrome variants of CYP2C19, the clinical importance of this variant is unlikely for homozygotes, and probably irrelevant for heterozygotes, based on the Parés study.³ This clinical disconnect between the findings of such testing and outcomes have made efforts to formulate a strategy for treating patients based on these test results an exercise in frustration for the practicing cardiologist. In addition, drug-drug interactions may also affect antiplatelet effects (e.g., proton pump inhibitors and clopidogrel) — and yet these studies, too, have inconsistent outcomes, with little or no randomized data to date to support a clinically important effect. Thus, although we are now entering an era where we can easily test platelet reactivity or even genetic polymorphisms, the relationship of these findings to strategies to improve clinical outcomes is generally less clear. In fact, even with the recently reported GRAVITAS results from the 2010 AHA scientific session, a therapeutic approach to address thienopyridine resistance with enhanced clopidogrel dosing was not shown to affect clinical endpoints — enzyme release during PCI, stent thrombosis, myocardial infarction and death. We are also entering into an era in which we have several different stent platforms to choose for PCI. Data suggest that not all stents are created equally with regard to the risk of late stent thrombosis and local endothelial function or healing. Clinical events in patients with different types of stents may confound current research on platelet resistance. Are the stents the problem? Is it the level of platelet inhibition? Both? Newer antiplatelet agents are being tested and becoming available for clinical practice, different dosing regimens of currently available medications are being evaluated and different procedural anticoagulation strategies continue to be studied for PCI. All of these factors and more make understanding how to address platelet resistance in patients undergoing PCI an ongoing and complex clinical conundrum. The current study adds to the growing body of evidence that understanding platelet reactivity may be clinically important, and that to modulate the risk of adverse events with PCI related to enhanced platelet function we will need to continue to develop studies and strategies that focus on these many complex variables, including aspirin resistance. Given the pace of change in this field and the variety of patient, pharmacologic, genetic and treatment strategies involved, it is unlikely that any one study, even the currently ongoing DAPT, will fundamentally address or settle this issue.

References

1. El-Atat F, Sarkar K, Kodali V, et al. A randomized pilot trial for aggressive therapeutic approaches in aspirin resistant patients undergoing percutaneous coronary intervention. J Invasive Cardiol 2011;23:9–13. 2. Decker C, Garavalia L, Garavalia B, Spertus JA. Clopidogrel-taking behavior by drug-eluting stent patients: Discontinuers versus continuers. Patient Prefer Adherence 20082;2:167–175. 3. Paré G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010;363:1704–1714.

———————————————————— From the Departments of ^*Hines VA Cardiology and ^§Interventional Cardiology Research, Loyola University, Stritch School of Medicine, Maywood, Illinois; and ^£Department of Cardiology, Vascular Medicine and Peripheral Interventions, West Virginia University, Charleston, West Virginia. Disclosure: Dr. Dieter: Speakers bureau for Bristol-Myers Squibb and Daiichi Sankyo. Address for correspondence: Robert S. Dieter, MD, RVT, Assistant Professor, Department of Medicine, Loyola University, Stritch School of Medicine and Hines VA, 2160 S First Avenue, Bldg. #110, Rm# 6289, Maywood IL 60153. E-mail: rdieter@lumc.edu