Dynamics of bleeding and ischaemic risk in patients with acute coronary syndrome undergoing percutaneous coronary intervention and potential impact of antiplatelet therapy de-escalation.
Dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor inhibitor is the guideline-recommended therapy of patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). Newer antiplatelet drugs, prasugrel and ticagrelor, have a more potent and predictable antiplatelet action and have reduced ischaemic events at the cost of increased bleeding in patients with ACS compared with clopidogrel.[2,3] Bleeding events occurring either peri-procedurally or in the post-discharge period are strongly associated with an increased risk of 1-year mortality.[4,5] Subgroup analyses from the randomized trials of newer antithrombotic drugs in patients with ACS have shown that the greatest benefit of potent DAPT is achieved within the first 30 days after PCI. Notably, these studies showed that the level and trajectory of risk for ischaemic and bleeding events differ with respect to the time interval following PCI, with the thrombotic risk being markedly reduced beyond 30 days after the PCI whereas the risk for bleeding events remains relatively high beyond this time point.[6,7] These studies ushered in the era of DAPT de-escalation strategies with the understanding that these strategies will improve the clinical outcome by reducing the risk for bleeding without an increase in the risk for thrombotic/ischaemic events. DAPT de-escalation consists of two main strategies: a strategy of reduction of the DAPT intensity by switching from potent P2Y12 receptor inhibitors, prasugrel or ticagrelor, to clopidogrel (or a reduced dose of prasugrel); and a strategy of shortening of the DAPT duration followed by single antiplatelet drug therapy. The efficacy and safety of DAPT de-escalation strategies based on the modulation of DAPT intensity have been addressed in several randomized studies and study-level meta-analyses, and have recently been reviewed. Notwithstanding the results of randomized trials and meta-analyses that have assessed the efficacy and safety of DAPT de-escalation strategies based on the modulation of DAPT intensity, many aspects of this strategy remain to be investigated and the current level of knowledge on the safety and efficacy of this strategy may be considered as a work in progress. Although the results of recent research with respect to the use of DAPT de-escalation strategies are encouraging, de-escalation of P2Y12 receptor inhibitor intensity is not supported by a strong recommendation from current guidelines (class IIb, level of evidence A).
In this issue of the European Heart Journal, Kang et al. addressed the efficacy and safety of a DAPT de-escalation strategy based on the modulation of DAPT intensity by switching from potent P2Y12 receptor inhibitors, prasugrel or ticagrelor, to clopidogrel (or a reduced dose of prasugrel) in patients with ACS by performing an individual patient-level data meta-analysis of four randomized controlled trials published between 2017 and 2021. Overall, the meta-analysis pooled together 10 133 patients with ACS. The co-primary endpoints were a composite of ischaemic events (cardiac death, myocardial infarction, or cerebrovascular events) and bleeding events, both analysed up to 1 year after the index event. Briefly, the ischaemic endpoint was significantly lower in patients assigned to the de-escalation strategy compared with patients assigned to the standard DAPT strategy (2.3% vs. 3.0%; P = 0.029). Major and minor bleeding events were also significantly lower in patients assigned to the DAPT de-escalation strategy vs. patients assigned to the standard DAPT strategy (6.2% vs. 8.6%; P < 0.001). However, the incidence of major bleeding (1.2% vs. 1.4%) and all-cause (1.0% vs. 1.1%) or cardiovascular mortality (0.5% vs. 0.7%) was not significantly impacted by the DAPT de-escalation strategy. The reduction of bleeding events was more prominent among patients assigned to an unguided than a guided DAPT de-escalation strategy (P for interaction = 0.007).
The authors recognized several limitations of the meta-analysis including the assessment of only one DAPT de-escalation strategy (P2Y12 inhibitor de-escalation), the differences across the trials in the definition of the outcomes and the time point of initiation of the de-escalation strategy, the clustering of unguided and guided DAPT de-escalation in different geographic regions (East Asia and Europe), and lack of information on the complexity of PCI.
Meta-analyses based on individual patient data represent <5% of the meta-analytic literature and are regarded as the gold standard for meta-analytic or systematic review studies and have many advantages in assessing healthcare. The separate analysis and reporting of bleeding and ischaemic events is a conspicuous strength of this meta-analysis. Since bleeding reduction is a reasonable and expectable outcome of DAPT de-escalation strategies, the designing of bleeding as a primary outcome in previous (or future) trials of DAPT de-escalation is a chronicle of success foretold. Conversely, an eventual increase in the risk for thrombotic/ischaemic events in trials of DAPT de-escalation rather than bleeding reduction should be the main safety concern and the outcome of interest. In this regard, the current meta-analysis is important and reassuring in that it showed a reduction rather than an increase of ischaemic events in patients randomized to DAPT de-escalation.
The reduction in the risk for bleeding by using regimens of a lower intensity of platelet inhibition as DAPT de-escalation strategies is clinically important and explainable by multiple mechanisms. The reduction of ischaemic events associated with DAPT de-escalation is also important and the most thought-provoking finding of this meta-analysis. The difference in ischaemic events across the DAPT strategies was small (0.7%) and the statistically significant difference reflects the power of large numbers obtained by pooling together a large number of patients in each DAPT strategy. Thus, the clinical benefit of such risk reduction in ischaemic risk by DAPT de-escalation, at best, may be considered as small to moderate. Furthermore, it should be noted that the incidence of overall ischaemic events was low (2.3% vs. 3.0%) which may point to the low risk of patients in whom the DAPT de-escalation strategies were tested. Since the risk for ischaemic and bleeding complications is highest in the first month after PCI—a time interval in which patients are treated with standard DAPT—there is a high probability that any DAPT de-escalation strategy initiated beyond this time point is being tested in patients at low bleeding and ischaemic risk. The inclusion of a sizeable portion of patients of Asian origin, known to be more susceptible to bleeding than ischaemic events compared with Caucasians, may also have contributed to the observed lower incidence of ischaemic events.
A reduction in ischaemic risk by regimens of a lower intensity of platelet inhibition at first seems to be counterintuitive, yet several putative mechanisms may be offered as an explanation. First, reduction in the ischaemic risk may be a consequence of reduced bleeding by DAPT de-escalation. The occurrence of bleeding may increase the risk for thrombotic/ischaemic events via creation of a thrombogenic milieu (mostly due to haemodynamic effects and neuro-endocrine activation by bleeding), which is further potentiated by blood transfusion (if used) and discontinuation of antiplatelet drugs. In the same vein, higher rates of bleeding in the standard DAPT-treated patients may have increased the ischaemic risk despite more intensive platelet inhibition in this group of patients. Furthermore, a poorer adherence to antiplatelet drugs is expected in patients on treatment with more potent antiplatelet drugs (prasugrel and ticagrelor) than in patients assigned to the lower intensity of platelet inhibition in the setting of DAPT de-escalation. This, in turn, will increase the risk for ischaemic events among patients assigned to standard DAPT. A cross-talk interference between bleeding or myocardial infarction and mortality definition may also contribute to reduced numbers of bleeding or myocardial infarction events if the latter events ended fatally. In the latter scenario, they are documented as deaths. Risk prediction analyses in patients with ACS have shown that mortality is the best predicted outcome (and better predicted than bleeding or myocardial infarction), and that bleeding and mortality share many risk factors.
Several other findings of this meta-analysis may deserve comment. First, although bleeding and ischemic events are proven to be prognostically relevant,[4,5] a reduction in bleeding or ischaemic events was not associated with reduced mortality. This finding is not new, but it remains poorly explainable. Second, although overall bleeding was reduced by the DAPT de-escalation strategy, the incidence of major bleeding, the bleeding category most strongly associated with mortality, was not affected. This suggests that the reduction in overall bleeding by DAPT de-escalation was due to a reduction in minor bleeding by this strategy. This finding may help to explain why the reduced risk for bleeding was not associated with lower rates of mortality in patients assigned to DAPT de-escalation. Similar findings have been reported in patients undergoing PCI and treated with bivalirudin vs. unfractionated heparin, suggesting that patients at heightened risk for bleeding will bleed regardless of which bleeding avoidance strategy is used. Third, the finding that a guided de-escalation strategy was less effective in reducing bleeding risk should be considered in the context of the geographic area in which it was applied (Europe vs. East Asia for the unguided de-escalation strategy) and the fact that 40–60% of the patients in the de-escalation arm received the same antiplatelet therapy as those in the control arm.[13,14] This apparent disadvantage of the guided P2Y12 de-escalation should be weighed against its potential of providing individual treatment guidance in the early post-procedural period, much before the time point chosen for starting unguided de-escalation.
Antiplatelet de-escalation strategies still remain the subject of intense clinical research. Yet, DAPT de-escalation strategies such as those assessed in the meta-analysis by Kang et al. are poised to offer a valuable option of modulated platelet inhibition in patients with ACS especially in consideration of the lack of specificity of current bleeding risk scores.
Eur Heart J. 2023;44(15):1371-1373. © 2023 Oxford University Press
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