De-escalation versus shortening of dual antiplatelet therapy

Despite a relentless effort to shift the paradigm in antiplatelet strategies towards a reduction of bleeding without any trade-off in thrombotic events—known as bleeding reduction strategies—the latest 2023 European Society of Cardiology (ESC) Guidelines have reaffirmed a standard 12-month dual antiplatelet therapy (DAPT) with a potent agent (prasugrel or ticagrelor) as the primary strategy for patients with acute coronary syndrome (ACS), limiting the use of clopidogrel in the cases where prasugrel and ticagrelor are unavailable, contraindicated, or cannot be tolerated, including older patients with high bleeding risk (HBR).^1,2

Bleeding reduction strategies are primarily characterized by shortening DAPT or de-escalating P2Y₁₂ inhibiting therapy.^2–4 Short DAPT may be achieved by stopping aspirin or the P2Y₁₂ inhibitor 1–6 months after ACS.^2,3 On the other hand, de-escalation of P2Y₁₂ inhibiting therapy may be either guided or unguided, depending on the use or not of platelet function or genetic testing to guide clopidogrel administration based on individual patient responsiveness, and can be achieved by switching from a more potent (i.e. prasugrel or ticagrelor) to a less potent (i.e. clopidogrel) P2Y₁₂ inhibitor or by reducing the dose of a potent P2Y₁₂ inhibitor.^2,3

In this regard, the 2023 ESC Guidelines on ACS provide a stronger recommendation for short DAPT (preferably maintaining the P2Y₁₂ receptor inhibitor) 3–6 months after ACS in event-free patients who are not high ischaemic risk [Class IIa, level of evidence (LoE) A] compared with a de-escalation of P2Y₁₂ inhibiting therapy from prasugrel or ticagrelor to clopidogrel 30 days after ACS (Class IIb, LoE A).¹ Curiously, no specific recommendation is provided on a guided de-escalation of P2Y₁₂ inhibiting therapy, although this strategy has shown to improve outcomes compared with standard DAPT in ACS.^1,5 With regards to HBR patients with ACS, according to recent consensus documents, the default approach for ACS-HBR patients should be 1-month DAPT followed by clopidogrel or ticagrelor monotherapy (first-line regimens) or aspirin monotherapy (second-line strategy).^6–8 ESC Guidelines endorse this approach as an alternative stating that aspirin or P2Y₁₂ inhibitor monotherapy after 1-month DAPT may be considered in ACS-HBR patients (Class IIb, LoE B).¹

These ESC recommendations have prompted an intense discussion regarding the residual limitations of bleeding reduction strategies that hinder their recommendation as the preferred option in ACS, as well as on whether or not a short DAPT may represent a better strategy compared with a de-escalation of P2Y₁₂ inhibiting therapy. Unfortunately, given the absence of direct comparisons between short DAPT and de-escalation strategies, no definitive conclusions may be drawn. A recent network meta-analysis, based on frequentist indirect comparisons, suggested that de-escalation may perform best compared with short DAPT for the outcomes of net adverse cardiovascular events (NACE), myocardial infarction (MI), stroke, stent thrombosis, and minor bleeding, while short DAPT may perform best for major bleeding.⁹ However, the fact that this analysis relies on indirect comparisons and the inclusion of different de-escalation or short DAPT strategies prevents from providing robust comparative estimates. Indeed, there is supporting evidence that the specific short DAPT or de-escalation strategy used may significantly affect outcomes in ACS patients.³ Specifically, a short DAPT achieved by discontinuing the P2Y₁₂ inhibitor 3–6 months after ACS has been associated with a numerical increase in MI compared with standard 12-month DAPT.¹⁰ With regards to short DAPT by discontinuing aspirin while maintaining a P2Y₁₂ inhibitor, a significant drug-specific effect has been evidenced.¹¹ Indeed, while a strategy of ticagrelor monotherapy 1 or 3 months after standard DAPT has shown to be safer and equally effective compared with standard 12-month DAPT with ticagrelor,^12,13 a strategy of clopidogrel monotherapy 1–2 months (median of 39 days) after standard DAPT failed to demonstrate non-inferiority to standard 12 months of DAPT in NACE, with a numerical increase in cardiovascular events despite a reduction in bleeding events.¹⁴ Although residual concerns persist due to the selective inclusion of East Asian patients in many trials, a strategy of ticagrelor monotherapy after uneventful short (preferably 3 months) DAPT seems a balanced strategy in ACS, reducing bleeding without any trade-off in thrombotic events. Finally, a prasugrel-only strategy failed to reduce major bleeding and was associated with a numerical excess of ischaemic events compared with standard DAPT in ACS, underlining the need for DAPT in the early months after ACS.¹⁵ With regards to de-escalation strategies, they have been consistently shown to improve outcomes, but a significant difference in the evidence between East Asians and non-East Asians has been evidenced, with the vast majority of trials supporting an unguided de-escalation 1 month after standard DAPT being conducted in East Asians.^4,16,17 On the other hand, guided de-escalation has been primarily tested in non-East Asians.⁴

There are practical issues that need to be taken into account when considering bleeding reduction strategies. Indeed, while a strategy of ticagrelor monotherapy may be advisable up to 12 months after ACS, uncertainty arises about the subsequent course of action. This is because ticagrelor 90 mg b.i.d. is not recommended beyond 12 months after ACS for secondary prevention. Similarly, a de-escalation antiplatelet strategy involving the modulation of P2Y₁₂ intensity by reducing the dose of a potent P2Y₁₂ inhibitor encounters the same limitation 12 months after ACS, as no reduced dose of prasugrel or ticagrelor monotherapy is currently approved for secondary prevention. Moreover, individuals with a history of ACS are likely to undergo subsequent percutaneous coronary intervention (PCI) in their lifetime, necessitating the use of DAPT with clopidogrel. Furthermore, clopidogrel monotherapy is increasingly used in lieu of aspirin for primary or secondary prevention.¹⁸ For all these reasons, clopidogrel, which currently represents the most commonly prescribed P2Y₁₂ inhibitor, is likely to remain the backbone of antiplatelet therapy in the near future, despite the implementation of bleeding reduction strategies. However, in an era where precision medicine is consistently emphasized, it cannot be ignored that clopidogrel is ineffective in nearly 30% of treated patients.¹⁹ Against this backdrop, it becomes crucial to further implement the use of tools allowing for the identification of patients non-responder to clopidogrel, at least until dedicated randomized controlled trials will support the use of low-dose potent P2Y₁₂ inhibitors as an alternative to clopidogrel both monotherapy or as part of DAPT.²⁰ These considerations support the use of a guided de-escalation in ACS.

In conclusion, de-escalation and short DAPT strategies are both important approaches that warrant broader adoption in clinical practice. However, their real-world application should consider the context in which a specific regimen was tested. This includes factors such as high vs. low bleeding and ischaemic risks, the type of P2Y₁₂ inhibitor used (clopidogrel vs. ticagrelor/prasugrel), and differences in patient populations (East Asian vs. non-East Asian). Additionally, practical considerations that extend beyond the antiplatelet therapy required after an ACS episode, such as the individual's long-term response to the antiplatelet agent, control of risk factors, procedural characteristics (i.e. PCI complexity), and concomitant use of other therapies for secondary prevention (i.e. anti-inflammatory agents), should be taken into account.

Conflict of interest: M.G. declares that he has received honoraria from Terumo, outside the present work. F.C. declares that he has received honoraria from Novo Nordisk, outside the present work. E.P.N. reports research grants from Abbott, Amgen, and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the present work.

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