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EDITORIAL COMMENT
Switching FromPrasugrel to ClopidogrelNavigating in Unknown Waters*
Dominick J. Angiolillo, MD, PHD, Fabiana Rollini, MD
Jacksonville, Florida
Dual antiplatelet therapy with aspirin and a P2Y12 receptorantagonist is the cornerstone of treatment to prevent recur-rent atherothrombotic events in patients with acute coro-nary syndrome (ACS) and undergoing percutaneous coro-nary interventions (PCI) (1). Clopidogrel is the most widelyused platelet P2Y12 receptor inhibitor. Despite the clinicalefficacy of clopidogrel, numerous studies have shown abroad inter-individual variability in the response to thisantiplatelet agent (2). Importantly, patients with high
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(HPR) and low (LPR) platelet reactivity while receivingclopidogrel therapy have an increased risk of recurrentischemic events, including stent thrombosis and bleedingcomplications, respectively (3,4). These findings have setthe basis for investigations aimed to define a “therapeuticwindow” of platelet reactivity that defines a range of P2Y12
receptor-mediated antiplatelet effects associated with a re-duced risk of ischemic and bleeding complications (Fig. 1)(5). The broadening of the armamentarium of P2Y12
receptor inhibitors currently available for clinical use, in-cluding prasugrel and ticagrelor, have indeed represented animportant step forward toward reaching such therapeuticgoals (6). These novel generation P2Y12 receptor inhibitorsare characterized by potent antiplatelet effects and a greaterreduction in atherothrombotic recurrences compared withclopidogrel in ACS patients (6). However, despite these
*Editorials published in JACC: Cardiovascular Interventions reflect the views of theuthors and do not necessarily represent the views of JACC: Cardiovascular Interven-ions or the American College of Cardiology.
From the University of Florida, College of Medicine-Jacksonville, Jacksonville,lorida. Dr. Angiolillo reports receiving honoraria for lectures from Bristol-Myersquibb, Sanofi-Aventis, Eli Lilly Company, Daiichi Sankyo, Inc., and AstraZeneca;onsulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co., Daiichiankyo, Inc., The Medicines Company, Portola, Novartis, Medicure, Accumetrics,rena Pharmaceuticals, AstraZeneca, Merck, Evolva, and Abbott Vascular; and
esearch grants from Bristol Myers Squibb, Sanofi-Aventis, GlaxoSmithKline,tsuka, Eli Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola,
ccumetrics, AstraZeneca, and Eisai. Dr. Rollini has reported that she has no
elationships relevant to the contents of this paper to disclose.
benefits, numerous reasons account for the need or desire toswitch a patient from a more potent P2Y12 receptor inhib-itor to clopidogrel. These include the higher risk of bleed-ing, development of side effects, and increased costs of thesenew agents compared with generic clopidogrel. However, todate studies have mostly focused on the effects of switchingfrom clopidogrel to a novel generation P2Y12 receptornhibitor, and despite being broadly performed in clinicalractice, there is a paucity of information on switching fromne of the novel generation P2Y12 receptor inhibitors tolopidogrel (7).
In this issue of JACC: Cardiovascular Interventions, Ker-eis et al. (8) describe the results of an observational studyvaluating the pharmacodynamic (PD) effects of switchingrom prasugrel to clopidogrel. In this study, a total of 300igh-risk ACS patients treated with prasugrel (10 mg/day)ere studied. Platelet reactivity was assessed with multipleD assays after 15 days of treatment. The VerifyNow P2Y12
assay (Accumetrics, San Diego, California) was used todefine the optimal therapeutic window of platelet reactivity,defined as 30 to 208 P2Y12 reaction units (PRU). Patientselow and above these thresholds were identified as havingPR and HPR, respectively. The primary objective of the
tudy was the variation in LPR and HPR rates before andfter the switch. Patients with LPR or those deemed to bet high risk of bleeding were considered for a switch tolopidogrel (75 mg/day) therapy, at the discretion of thereating physician. Platelet reactivity was evaluated again 15ays after switching from prasugrel to clopidogrel. A total of1 (10.3%) prasugrel-treated patients, mostly (93.5%) pre-
Figure 1. Impact of Platelet Reactivity on the Balance Between Safetyand Efficacy
A “therapeutic window” of on-treatment platelet reactivity might delineatethe risk for ischemic and bleeding complications. This can potentially varyaccording to the patient phenotype, such as clinical presentation (acutecoronary syndrome [ACS] vs. stable patient), glucose control (diabetes mel-litus [DM] vs. non-DM patient), renal function (chronic kidney disease [CKD]vs. normal renal function), and age (elderly vs. non-elderly). Adapted, with
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senting with LPR, were switched to clopidogrel. Switchfrom prasugrel to clopidogrel was associated with a signif-icant 10-fold increase in platelet reactivity and a markedreduction (�10%) in LPR rates. However, this was associ-ted with an increase in HPR from null while receivingrasugrel to 29% after switching to clopidogrel. Overall,his led to a greater percentage of patients within theptimal therapeutic window following the switch accord-ng to VerifyNow PRU thresholds. The exploratorylinical observations showed that minor bleeding de-reased after switch from 32.2% to 9.7%; there were noajor bleeding events or ischemic recurrences in this
tudy population.The major strength of this investigation by Kerneis et al.
s that it is the first study in a clinical setting to assess theD effects of switching from prasugrel to clopidogrel.lthough the study was not designed to assess the clinical
mpact of this antiplatelet switching approach, the authorsrovide PD data that in larger investigations have shown toe surrogates of worse outcomes (3,4). Therefore, althougho ascertainments on the safety and efficacy can be made,he data reported can provide some guidance on what toxpect from a PD standpoint when switching from prasu-rel to clopidogrel in a population with characteristicsimilar to that studied in the present investigation (mostlyepresented by patients with LPR while receiving prasug-el). There are, however, some considerations that need toe made that highlight the largely unknown impact ofwitching from prasugrel to clopidogrel in clinical practice.
First, the study reports the results of an observationalegistry in which the decision to switch from prasugrel tolopidogrel was at the discretion of the physician who wasware of the PD results. Therefore, this analysis suffers fromignificant study entry bias. This is further reinforcedecause most patients (93.5%) being switched had LPR, butot all patients with LPR were switched.Second, the observation that after switching to clopdigrelore patients were within the therapeutic window with theerifyNow P2Y12 assay needs to be interpreted with caution.
In fact, as mentioned in the preceding text, most patients beingswitched in this study had LPR while receiving prasugrel, andthus these findings might be a reflection that these patientsmetabolize thienopyridines more efficiently, increasing theirlikelihood of also being good responders to clopidogrel.Whether this can be attributed to any specific clinical charac-teristic or genetic make-up of these patients cannot be extrap-olated from this study. Of note, although the switchingstrategy allowed a higher percentage of patients to be withinthe therapeutic window with the VerifyNow assay, thesepercentages were actually worse with the other PD assays usedin this investigation.
Third, the study does not provide insights on howswitching from prasugrel to clopidogrel affects platelet
reactivity in patients within the optimal therapeutic window
of platelet reactivity while taking prasugrel. This is indeed ofcrucial importance, because these comprised most of thepatients in this study. Prasugrel has been shown to have amore favorable metabolism than clopidogrel, which trans-lates into more consistent PD effects (6). Therefore, thismight raise suspicion that switching patients to clopidogrelwhen they are within the optimal therapeutic window whiletaking prasugrel might account for an increase in plateletreactivity and thus potentially expose them to a higher riskof atherothrombotic events.
Fourth, the therapeutic window defining optimal levels ofplatelet reactivity was somewhat arbitrary. In fact, althoughthe threshold of HPR seems to have been validated inseveral studies, there remains large uncertainty on the bestthreshold of LPR. In fact not all studies have been success-ful in identifying a threshold of platelet reactivity associatedwith increased bleeding and it has also varied in those whohave (3). Differences in bleeding definitions, clinical setting,and patient population among other factors can contributeto these findings (Fig. 1) (5). It might also be argued thatthe therapeutic window might also vary over time in ACSpatients, as indirectly reflected by the increase in bleedingcomplications and reduction in ischemic benefit over timewith prasugrel (9). Thus, a switch only after 15 days ofprasugrel treatment in LPR patients might be premature,because the highest risk period for ischemic recurrences—including stent thrombosis—is during the first months afteran acute event, and thus lower levels of platelet reactivitymight be desirable during this time frame.
Ultimately, no conclusions with regard to safety andefficacy should be made on the basis of the clinical findingsfrom this study, which was limited to only 15 days ofobservation in a highly selected population. Of note, moststudies to date have failed to demonstrate that modificationof P2Y12 receptor inhibiting antiplatelet treatment regimenn the basis of the results of platelet function testing canmpact safety and efficacy, underscoring that routine testings still not ready for prime-time (5).
Defining how and when to optimally switch antiplateletherapy remains an unmet clinical need. Further studies areequired to better define PD profiles of switching strategiesf patients with more wide-ranging levels of platelet reac-ivity while receiving a given P2Y12 receptor inhibitor. Mostmportantly, an improved understanding of how switch-ng from newer-generation P2Y12 receptor inhibitors,
which provide more effective anti-ischemic protectionbut increased bleeding potential compared with clopi-dogrel, impacts patient outcomes. Only larger-scale reg-istry and randomized clinical trial data will better delin-eate the safety and efficacy of such switching antiplateletstrategy and thus guide clinicians navigating in these
unknown waters.
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Reprint requests and correspondence: Dr. Dominick J. Angio-lillo, University of Florida College of Medicine-Jacksonville, 655West 8th Street, Jacksonville, Florida 32209. E-mail: [email protected].
REFERENCES
1. Angiolillo DJ. The evolution of antiplatelet therapy in the treatment ofacute coronary syndromes: from aspirin to the present day. Drugs2012;72:2087–116.
2. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability inindividual responsiveness to clopidogrel: clinical implications, manage-ment, and future perspectives. J Am Coll Cardiol 2007;49:1505–16.
3. Bonello L, Tantry US, Marcucci R, et al. Consensus and futuredirections on the definition of high on-treatment platelet reactivity toadenosine diphosphate. J Am Coll Cardiol 2010;56:919–33.
4. Rollini F, Tello-Montoliu A, Angiolillo DJ. Advances in platelet
function testing assessing bleeding complications in patients withcoronary artery disease. Platelets 2012;23:537–51. s
5. Angiolillo DJ, Ferreiro JL. Platelet and genetic testing for clopidogrelhyporesponsiveness perspective: use as a research tool. J Am Coll Cardiol2013. In press.
6. Ferreiro JL, Angiolillo DJ. New directions in antiplatelet therapy. CircCardiovasc Interv 2012;5:433–45.
7. Azmoon S, Angiolillo DJ. Switching antiplatelet regimens: alternativesto clopidogrel in patients with acute coronary syndrome undergoingPCI: a review of the literature and practical considerations for theinterventional cardiologist. Catheter Cardiovasc Interv 2012 May 14.[Epub ahead of print], doi: 10.1002/ccd.24480.
8. Kerneis M, Silvain J, Abtan J, et al. Switching acute coronary syndromepatients from prasugrel to clopidogrel. J Am Coll Cardiol Intv 2013;6:158–65.
9. Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits ofprasugrel in patients with acute coronary syndromes undergoing percu-taneous coronary intervention: a TRITON-TIMI 38 (TRial to AssessImprovement in Therapeutic Outcomes by Optimizing Platelet Inhibi-tioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis.J Am Coll Cardiol 2008;51:2028–33.
