Aspirin-free strategies: a framework to reassess the role of dual antiplatelet therapy after percutaneous coronary intervention

This commentary refers to the article ‘Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS’ by U. Baber et al., Eur Heart J 2020;41:3533–3545 and the discussion piece ‘Ticagrelor monotherapy following percutaneous coronary intervention for acute coronary syndrome in TWILIGHT patients: still a future for aspirin?’, M Lunardi et al., doi:10.1093/eurheartj/ehab037.

The increasing enthusiasm around aspirin-free strategies in patients undergoing percutaneous coronary intervention (PCI) is now substantiated by a large amount of physiologic studies and randomized clinical evidence. In keeping with the result of the TWILIGHT trial, the 2020 European guidelines on non-ST-segment elevation acute coronary syndrome (ACS) endorse the use of ticagrelor monotherapy in selected patient subsets.¹ Commenting on the TWILIGHT-ACS substudy,² Lunardi et al.  ³ raise two salient points: the optimal timing of aspirin withdrawal after PCI with the possibility of further abbreviating it to <1 month; and the generalizability of the TWILIGHT results to all patients subgroups, including those of different race/ethnicity.

Challenging the existing paradigm of dual antiplatelet therapy (DAPT) as the default strategy after coronary stenting is certainly provocative and ambitious. While pharmacodynamic observations suggesting a marginal antiplatelet effect of aspirin when added to potent P2Y₁₂ inhibitors provide a biological rationale to this approach, the immense body of clinical evidence supporting the use of DAPT after PCI cannot be easily overturned.⁴ The imperative of primum non nocere reminds us that the usefulness of any therapeutic intervention relies on the balance between expected benefits and anticipated risks. Omitting aspirin <1 month after PCI in patients with atrial fibrillation on oral anticoagulant is justified by the expected large reduction in bleeding complications. Similar considerations apply to patients with clinical and comorbid conditions that may shift the risk-benefit calculus for DAPT towards an excess in bleeding risk. However, TWILIGHT was designed to enroll patients at high risk for both bleeding and ischaemic events, a patient cohort ideally suited to demonstrate the bleeding-related benefits of withdrawing aspirin without compromising antithrombotic efficacy upon continuation of ticagrelor alone.⁵ Whether truncating the timing of aspirin withdrawal closer to PCI would translate into an improved net benefit is unknown, and likely dependent on the specific population being tested.

Thus far, all trials evaluating P2Y₁₂ monotherapy started 1 month after PCI were either underpowered for ischaemic endpoints or failed to show any benefit with such strategy. Other studies on high bleeding risk patients used 1-month DAPT as background therapy to compare different stent platforms, thereby leaving questions on the optimal DAPT duration unanswered. It must also be remembered that the first month post-PCI represents the most vulnerable period for thrombotic events. The endothelial damage associated with the intravascular procedure along with the foreign metallic stent material mandate adequate levels of platelet inhibition during the early post-PCI phase. Furthermore, the pro-thrombotic state and high-risk coronary plaque phenotype of ACS patients tend to stabilize over time after the acute event. Altogether, these observations constitute the rationale of a number of antiplatelet regimens that fall under the umbrella term of de-escalation. De-escalation can also be achieved by lowering the drug dose or switching to a less potent agent. The so-called ‘Asian paradox’ of increased bleeding despite higher levels of on-treatment platelet reactivity render Asian patients the ideal candidates for such approaches. Decreasing the potency of DAPT with prasugrel (from 10 mg to 5 mg) after 1 month of PCI was recently shown effective in reducing bleeding without increasing ischaemic events in a large-scale trial of Asian patients with ACS.⁶ Similar results have been reported with platelet function test or genotype-guided de-escalation from potent P2Y₁₂ inhibitors to clopidogrel.⁷ To conclude, aspirin withdrawal, in the context of other de-escalation strategies, is an emerging approach for the treatment of high-risk patients. Extrapolating these findings to a broader population than the one being studied, however, needs confirmation by ongoing and future investigations. Additional considerations related to drug resistance, patient preference, therapy non-compliance, and side effects, must play a role in the selection of the best treatment for the individual patient.

Funding

The TWILIGHT trial was supported by an investigator-initiated grant from AstraZeneca.

Conflict of interest: R.M. reports grants from Abbott Laboratories, AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich; personal fees from Abbott Laboratories, Boston Scientific, Medscape/WebMD, Siemens Medical Solutions, PLx Opco Inc/dba PLx Pharma Inc, Roivant Sciences, Sanofi, Medtelligence (Janssen Scientific Affairs), Janssen Scientific Affairs; other from Abbott Laboratories, other from Abiomed, other from Bristol Myers Squibb, other from Claret Medical, other from Elixir Medical, other from The Medicines Company, other from Spectranetics/Philips/Volcano Corp, other from Watermark Research Partners; non-financial support and other from Regeneron Pharmaceuticals, Idorsia Pharmaceuticals Ltd. U.B. has received honoraria from AstraZeneca, Boston Scientific, and Amgen; and has received a grant from AstraZeneca. D.C. has no disclosures to report.

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