De-Escalation of Dual Antiplatelet Therapy: Will We Ever Get to the Right Method?

I see harm reduction as a way of engaging people as part of that path to recovery Paul R. Ehrlich Percutaneous coronary intervention (PCI) is essential in the treatment of patients presenting with acute coronary syndromes (ACS) or chronic coronary syndromes.1 Antiplatelet treatment has an important role to reduce adverse events, specially avoiding thrombotic events in patients undergoing PCI both during the target hospitalization and during follow-up. In fact, these patients may develop both acute or long-term ischemic events, due to local or systemic thrombotic complications.1,2 The suggested duration of dual antiplatelet therapy (DAPT) according to international guidelines is at least 12 months, including the association of ticagrelor/prasugrel with aspirin, but this does not apply to patients with an increased bleeding risk, in whom clopidogrel appears a favorable therapeutic option.3 Numerous investigators designed several trials trying to find antiplatelet drugs with quicker effect,1,3,4 safer profile, and more efficacy/effectiveness to reduce adverse clinical events. The introduction of new P2Y12 inhibitors in the past decade, with stronger antiplatelet action, implied a new clinical scenario for antithrombotic treatment, especially in patients with ACS.3 The correlation between stronger antiplatelet effects and better outcomes changed the understanding of the prognostic implications associated with bleeding. Indeed, bleedings represent the real Achilles' heel of antithrombotic therapy in general and antiplatelet therapies in particular.1 Moreover, the refinement in stent technologies, leading to safer performance, improved implantation skills, and ensuing reduction of stent thrombosis risk, calls for a new focus on the reduction of bleeding events and related comorbidities. According to this objective, de-escalation of P2Y12 inhibiting therapy was introduced as a safer strategy, aiming to reduce bleeding risk without any major drawback or trade-off in ischemic events.1 De-escalation is applied in patients with ACS who are treated with ticagrelor/prasugrel and aspirin at the time of PCI, with a subsequent switch to clopidogrel, which is evidently a less potent P2Y12 inhibitor than both prasugrel and ticagrelor. In this issue of the Journal, Bai et al5 present a systematic review and a meticulous network meta-analysis including only randomized trials to validate the safety and efficacy profile of switching antiplatelet therapy in patients presented with ACS and treated with PCI. The presented data show that the DAPT de-escalation strategy, pivoting indeed on switching to clopidogrel after an initial treatment with prasugrel or ticagrelor, may improve clinical outcomes by reducing the risk of cumulative events and in particular decreasing the rate of bleeding events. The validity of these conclusions is also corroborated by the lack of evidence of major risk of selection, detection, or attrition bias among included studies, as well as the consistency of findings of exploratory meta-regression. Nonetheless, some caveats need to be considered. Although de-escalation was successfully applied in all patients included in the trials shortlisted by the authors, strategies differed remarkably. Indeed, the de-escalation DAPT strategy can be unguided or guided by platelet assays or genetic investigation for the CYP2C19 loss of function alleles. A guided approach may help to identify patients with a different level of clopidogrel resistance, which is linked with slower and less effective antiplatelet effect of clopidogrel and, consequently, with a higher risk of ischemic events post PCI.6 Instead, the unguided de-escalation approach disregards these tests, leading to a potential increase in the risk of ischemic complications, especially if the switching therapy is close in time to PCI (eg, a few weeks).1 Therefore, a safer strategy for the unguided approach could be waiting a reasonably sufficient time (1 month or more) before taking into consideration such unguided and universal de-escalation. Notably, only in 2 trials of the included trials, TROPICAL-ACS7 and Ueno et al,8 de-escalation was guided by platelet function or genetic tests. The others 4 trials were designed with an unguided approach. In particular, in PRAGUE-18,9 approximately one-half of the patients switched to clopidogrel at any stage throughout the follow-up due to economic motivation after obtaining the treating physician's approval. More than 70% of such economically driven switches were done within the first 30 days post hospital discharge and thus in a clinically sensitive timeframe. Conversely, Ueno et al was basically a pharmacological and pharmacodynamic study in which the timing of de-escalation was planned after 2 weeks of treatment with prasugrel.8 Another reason for caution is that 2 of the 6 studies were designed and developed in East Asians who have a higher bleeding risk compared with other populations. Accordingly, the validity of Bai et al results to non-East Asian patients remains uncertain.10 Furthermore, in these trials, prasugrel was used in 3 different dosages: 10 mg, 5 mg, and 3.75 mg, authorized only in that specific ethnic group. From these trials and meta-analytic pooling, the authors did not conclude in favor of the superiority of de-escalation strategies compared with the potent P2Y12 inhibitors therapy. Yet, de-escalation is not inferior to standard therapy and self-evidently appealing to reduce costs and drug access. However, such de-escalation strategy should follow specific temporal milestones and methodology, which we have tried to summarize in a flowchart illustrated indicated in Figure 1. This could indeed represent a first step to reach a safer and more effective approach to reduce the intensity of DAPT therapy, by switching from a more potent P2Y12 inhibitor to clopidogrel when it is most appropriate.FIGURE 1.: Simplified algorithm for the de-escalation strategy, basing on patient's profile risk according to clinical and angiographic characteristics. A, ASA; CTO, chronic total occlusion; DES, drug-eluting stent; LoF, loss of function; MI, myocardial infarction; P, prasugrel; PCI, percutaneous coronary intervention; T, ticagrelor; ST, stent thrombosis.In conclusion, the meta-analysis by Bai et al and the included studies, as well as other similar trials and meta-analyses on de-escalation strategy, confirm its feasibility, but despite that, larger and more meticulous randomized trials are needed comparing different strategies for de-escalation. Nevertheless, considering the different races and their relative bleeding and ischemic risks, a personalized therapeutic strategy should be addressed to leverage rather than to endure inter- and intrapopulation heterogeneity.