In patients experiencing an acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 receptor inhibitor represents the standard of care for the prevention of atherothrombotic events [ ]. Three oral P2Y 12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor) are approved for clinical use in ACS patients. Both prasugrel and ticagrelor are characterized by more potent antiplatelet effects than clopidogrel and have been shown to be associated with a greater reduction in atherothrombotic recurrences, albeit at the expense of increased bleeding [ ]. Accordingly, guidelines recommend the preferential use of prasugrel (only in ACS patients undergoing percutaneous coronary intervention (PCI)) and ticagrelor (in ACS patients irrespective of management) over clopidogrel [ ]. However, despite these recommendations, the availability of three oral P2Y 12 receptor inhibitors has inevitably led to switching among these different agents [ , ]. A number of reasons have been identified to be associated with the need for switching, including side effects (bleeding and non-bleeding), costs, use of concomitant therapies, and patient or physician preference [ , ]. Indeed, the reasons for switching may vary from center to center based on the characteristics of the patient population being treated. Because of the multitude of considerations occurring when switching occurs (e.g., timing from the index event, pharmacodynamic potency of agents, chemical class of agents), an expert consensus was developed providing definitions on switching as well as providing practical recommendations on how to switch if this is needed [ , ].
In this edition of Cardiovascular Revascularization Medicine , Gajanana et al. report the results of a retrospective study evaluating the prevalence of switching during hospitalization or at the time of discharge as well as the factors associated with switching among ACS patients presenting at their center [ ]. In particular, data from January 2011 to December 2017 on a total of 2837 ACS patients were analyzed. The analysis did not include patients treated with prasugrel and was limited to observations on switching that implied either clopidogrel or ticagrelor. Patients were categorized into 4 groups based on whether switching had occurred (either from ticagrelor to clopidogrel or from clopidogrel to ticagrelor) or not (in which patients maintained treatment with either clopidogrel or ticagrelor). The authors observed that overall switching, either de-escalation (i.e., switching from ticagrelor to clopidogrel) or escalation (i.e., switching from clopidogrel to ticagrelor) occurred in 9% of patients. Moreover, important predictors of switching, more precisely for de-escalation, were the need for use of oral anticoagulant therapy or the need to undergo coronary artery bypass grafting (CABG). The study did not reveal clinical findings of concern. These study findings provide additional insights into the topic of switching in real-world clinical practice.
The following observations can be made on this study. First, the overall prevalence of switching during hospitalization or at time of discharge in this study is in line with other registries [ , ]. It is important to note that this does not include out-of-hospital switching, the prevalence of which is as high as or sometimes even higher than that occurring in-hospital [ , ]. Therefore, the results of this study support that switching is rather common in clinical practice and represents an area of investigation that warrants further research, particularly to define its clinical impact as well as its cost implications. Prior investigations have suggested that when de-escalation occurs early, this may be associated with worse clinical outcomes [ ]. This may be attributed to withdrawal of antiplatelet protection in a phase (i.e., soon after the index event) characterized by heightened platelet reactivity, during which clopidogrel is not as efficacious as the more potent P2Y 12 inhibitors [ , ]. Moreover, the potential for a drug-drug interaction when de-escalating from ticagrelor to clopidogrel, which limits the pharmacodynamic efficacy of clopidogrel, has also emerged as a concern [ ]. On the contrary, studies of de-escalation at a later phase (i.e., remote from the index event) have shown more reassuring results [ , ]. Whether this should be guided by functional or genetic testing remains a matter of debate [ ]. Nevertheless, the results of the TROPCAL ACS trial showing that de-escalation of antiplatelet therapy guided by platelet function testing to be non-inferior to maintenance therapy with potent P2Y 12 blockade has had an impact on most recent guidelines on revascularization [ ]. In particular, guidelines now indicate with a class IIb level of evidence that an approach of DAPT de-escalation guided by platelet function testing may be considered in ACS patients as an alternative to 12 months of more potent platelet inhibition, especially for patients deemed unsuitable for maintained potent platelet inhibition [ ]. A number of ongoing studies are currently evaluating the role of genetic testing to guide de-escalation [ ]. Indeed, the results of these studies as well as a number of ongoing registries will provide more insights on this topic.
Second, similar to prior observations, the use of oral anticoagulant therapy was shown to be a factor associated with de-escalation [ , ]. Indeed, this therapeutic approach is in line with recommendations for management of PCI patients treated with oral anticoagulants for whom clopidogrel is the P2Y 12 inhibitor of choice [ , ]. Thus, these observations, which also provide insights into practice patterns of the providers in which the data have been collected, provide a quality assessment on compliance with recommended treatments for this very high risk patient population. Indeed, the findings reported are reassuring for the investigators.
Third, de-escalation as an approach for patients undergoing CABG has typically not emerged from prior registries [ , ]. Nevertheless, it appears to be a reasonable one to occur. In fact, physicians have much more experience with clopidogrel than with ticagrelor [ ]. Thus, managing this drug in patients requiring surgery rather than ticagrelor may be associated with a higher degree of comfort. Moreover, concerns of withdrawing ticagrelor therapy without knowing timing of surgery in ACS patients would leave many patients without antiplatelet protection given its rapid offset of effects [ , ]. The findings may also be reflective of practice patterns of this center in whom patients are pre-treated with ticagrelor per standard of care. However, the value of pre-treatment has often been questioned, particularly if time to diagnostic angiography is rapid [ ]. The advent of intravenous therapies such as cangrelor, which allow for immediate and potent platelet inhibition in patients undergoing PCI if not pretreated with an oral agent, represents an emerging treatment alternative [ ]. Moreover, the opportunity to consider cangrelor given its very rapid offset of effects as a bridging agent until time of surgery if antiplatelet protection is needed also represents an emerging treatment option [ ].
In summary, switching between oral P2Y 12 receptor inhibitors commonly occurs in clinical practice. Defining the safety and efficacy of this approach is of paramount importance. Indeed, the introduction of stent platforms with a better safety profile, and thus less prone to thrombotic complications, has led to a new wave of research assessing de-escalation in antithrombotic potency (e.g., shortening DAPT duration, switching to a less potent P2Y 12 inhibitor, dropping an antiplatelet agent) as a strategy to reduce bleeding complications while preserving efficacy [ , , , ]. Questions do remain on the optimal timing of de-escalation and whether this approach should be guided by platelet function or genetic testing (in light of the variability in effects to clopidogrel) or guided by clinical assessment of the patient‘s bleeding and ischemic risk profile [ ]. Ongoing studies will provide important insights into this topic, which has the ultimate goal of tailoring antiplatelet treatment regimens toward the need of the individual patient.
Disclosures: Dr Angiolillo reports receiving payments as an individual for: a) Consulting fee or honorarium from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; b) Participation in review activities from CeloNova and St. Jude Medical. Institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions; in addition, Dr. Angiolillo is recipient of a funding from the Scott R. MacKenzie Foundation and the NIH/NCATS Clinical and Translational Science Award to the University of Florida UL1 TR000064 and NIH/NHGRI U01 HG007269, outside the submitted work.