Conundrums of Platelet Function Testing

HomeCirculation: Cardiovascular InterventionsVol. 10, No. 2Conundrums of Platelet Function Testing Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBConundrums of Platelet Function TestingDoes Sex Matter? Amy Sarma, MD and Michelle L. O'Donoghue, MD, MPH Amy SarmaAmy Sarma From the Cardiovascular Division, Massachusetts General Hospital, Boston (A.S.); and TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.L.O.). and Michelle L. O'DonoghueMichelle L. O'Donoghue From the Cardiovascular Division, Massachusetts General Hospital, Boston (A.S.); and TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.L.O.). Originally published13 Feb 2017https://doi.org/10.1161/CIRCINTERVENTIONS.117.004872Circulation: Cardiovascular Interventions. 2017;10:e004872It is well established that there exists significant interpatient variability in the pharmacodynamic response to clopidogrel.1,2 In turn, multiple studies have demonstrated that higher on-treatment platelet reactivity is associated with an increased risk of cardiovascular events.3 Although thresholds for inadequate response have been proposed, the optimal therapeutic window of platelet inhibition for a patient on antiplatelet therapy after percutaneous intervention or an acute coronary syndrome has remained disputed.3,4 In part, this stems from the fact that the relationship between platelet reactivity and the risk of ischemic or bleeding events has not always been shown to be consistent across various patient populations.See Article by Yu et alTo that end, it is intuitive to assume that lower on-treatment platelet reactivity is reliably correlated with a reduced risk of thrombotic events and an increased risk of bleeding. However, studies have not always been consistent in that regard. For example, several analyses have shown that carriers of a loss-of-function CYP2C19 allele (*2, *3) that diminishes the liver's ability to convert clopidogrel to its active metabolite are at increased risk of ischemic events after percutaneous intervention compared with wild-type carriers.5 Yet, fewer studies have been able to demonstrate that this genetic variant reduces the risk of bleeding, despite higher on-treatment platelet reactivity.6 Conversely, patients on clopidogrel who carry a gain-of-function CYP2C19 allele (*17) that confers lower on-treatment platelet reactivity have been shown in some studies to be at increased risk of bleeding but not always at reduced risk of ischemic events.7,8 One could hypothesize that the dose–response curves differ for an individual's risk of bleeding versus their risk of a thrombotic event. Moreover, there may exist a threshold effect rather than a linear relationship between platelet reactivity and outcomes. However, the variable nature of this relationship between study populations has contributed, in part, to the reluctance to routinely adopt platelet function testing into clinical practice.In this issue of Circulation: Cardiovascular Interventions, Yu et al9 explored sex-based differences in on-treatment platelet reactivity and the risk of ischemic or bleeding events in 2163 women and 6285 men enrolled in the ADAPT-DES study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents). The study builds on some previous smaller studies that have suggested that women have higher on-treatment platelet reactivity when treated with clopidogrel compared with men.10 In this current large study of patients undergoing elective or urgent percutaneous intervention, high platelet reactivity after a loading dose of clopidogrel (defined as P2Y12 reaction units [PRU]>208 by Accumetrics VerifyNow) was significantly more common in women than men (51.6% versus 39.6%). High platelet reactivity was associated with approximately a 2-fold higher risk of stent thrombosis in both women and men; albeit the relationship was not significant for women owing to a smaller sample size. In contrast, the relationship between higher platelet reactivity and the risk of MI seemed to be more modest. Unexpectedly, higher platelet reactivity (PRU>208) was associated with a reduced risk of bleeding in women but not in men (P interaction by sex=0.01). It is perhaps less clear how these latter findings should be interpreted. One cannot exclude that the interaction by sex is explained by play of chance, given that multiple outcomes were tested for heterogeneity. Furthermore, the observed imbalance in bleeding events in women was driven almost exclusively by a higher risk of minor bleeding events in women with low platelet reactivity (PRU≤208), whereas one might have expected a more consistent bleeding signal across all bleeding outcomes, including major bleeds. However, it should not be interpreted that lower platelet reactivity is unrelated to bleeding risk in men, given that clopidogrel and more potent antiplatelet drugs have been consistently shown to reduce platelet reactivity and increase bleeding regardless of sex.11,12Nonetheless, the observed findings underscore the complex nature of the relationship between platelet reactivity and subsequent clinical events. No doubt that the cause of thrombotic and bleeding events is multifactorial and not exclusively driven exclusively by platelet activation. As well, the causes of gastrointestinal, access site, intracranial, and other bleeds may be distinct. Moreover, transfusion thresholds that contribute to many bleeding definitions may vary among physicians, regions, and based on other comorbid conditions. However, clinical trials have demonstrated quite consistently that intensification of antiplatelet therapy reduces the risk of ischemic events but with increased bleeding. If the current findings are confirmed in subsequent studies, it may suggest that the slope of the relationship between platelet reactivity and bleeding risk lies along a different slope for men and women. Furthermore, if there exists a threshold effect with regard to bleeding risk, the cutpoint could differ by patient sex.Irrespective of the relationship between platelet reactivity and bleeding risk, it remains notable that women in the current study had higher on-treatment platelet reactivity than men when treated with clopidogrel. Although one could hypothesize that a differential pharmacokinetic response to clopidogrel in women could contribute to this finding, existing evidence suggests that the concentration of the active metabolite of clopidogrel is similar in men and women.13 Therefore, it is unlikely that there exists differential absorption or metabolism of the drug by patient sex; although the relationship between the concentration of clopidogrel's active metabolite and the extent of P2Y12 inhibition may not be linear.14 Of interest, megakaryocytes and platelets express estrogen β and androgen receptors; therefore, hormonal influences or other factors could contribute to sex differences in platelet reactivity.10,13 However, to date, there is no clear evidence that the clinical efficacy or safety of clopidogrel varies between men and women. Although individual trials have been relatively underpowered to examine sex-specific differences, a meta-analysis of randomized trials of clopidogrel did not suggest any significant heterogeneity across efficacy and safety end points.11 Similarly, we recently demonstrated consistency in the effects of the more potent P2Y12 inhibitors for both men and women, suggesting that patient sex need not be a determining factor when selecting an antiplatelet drug.12If indeed sex-based differences exist in response to clopidogrel, there remain unanswered questions. In particular, the current study did not assess platelet reactivity before administration of clopidogrel, and therefore, it is unknown whether higher on-treatment platelet reactivity on clopidogrel in women reflects diminished pharmacodynamic response to clopidogrel or simply higher baseline platelet reactivity before administration of drug. Therefore, both women and men could have similar percentage platelet inhibition to clopidogrel, but women could exhibit higher on-treatment platelet reactivity owing to higher predrug values. In that regard, women often have a higher prevalence of comorbid conditions, such as diabetes mellitus that have been described to potentiate platelet activity.15 Although the authors tried to adjust for potential confounders, it remains unknown whether observed differences are explained by biological differences between men and women versus other unidentified risk factors that may contribute to enhanced platelet reactivity or diminished drug response. As well, the time between clopidogrel loading dose and subsequent platelet function testing was not documented, which may be of particular interest, given that patients may have received different loading doses of clopidogrel. Furthermore, other factors may delay the platelet effects of therapy, including the presence of ST-elevation myocardial infarction or morphine administration.16,17Overall, the current findings are intriguing and guide us toward future pathways of research. It is plausible that some of the challenges in identifying an optimal therapeutic window in platelet reactivity lie in differences explained by patient sex or other characteristics that alter the slope of the relationship with clinical outcomes. Nonetheless, these findings again highlight the importance of exploring in depth the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of established and novel therapies in both women and men. Although there remains much interest in the concept of applying platelet function testing to help guide therapy, trials to date have been unable to demonstrate that this strategy translates into improved clinical outcomes.18–20 However, it may be that a deeper understanding of predictors of on-treatment platelet reactivity will reveal new insights into platelet biology and improve the utility of platelet function testing to help guide patient care.DisclosuresDr O'Donoghue has received grant funding from AstraZeneca, GlaxoSmithKline, Merck, Eisai, and Janssen. The other author reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Michelle L. O'Donoghue, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, 60 Fenwood Road, 7th Floor, Boston, MA 02115. E-mail [email protected]References1. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM.. 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Bedside monitoring to adjust antiplatelet therapy for coronary stenting.N Engl J Med. 2012; 367:2100–2109. doi: 10.1056/NEJMoa1209979.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 2017Vol 10, Issue 2 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCINTERVENTIONS.117.004872PMID: 28193680 Originally publishedFebruary 13, 2017 Keywordsplatelet function testsEditorialsacute coronary syndromesexplatelet aggregationPDF download Advertisement SubjectsPlatelets