Elsevier

The Lancet

Volume 396, Issue 10257, 10–16 October 2020, Pages 1079-1089
The Lancet

Articles
Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial

https://doi.org/10.1016/S0140-6736(20)31791-8Get rights and content

Summary

Background

A potent P2Y12 inhibitor-based dual antiplatelet therapy is recommended for up to 1 year in patients with acute coronary syndrome receiving percutaneous coronary intervention (PCI). The greatest benefit of the potent agent is during the early phase, whereas the risk of excess bleeding continues in the chronic maintenance phase. Therefore, de-escalation of antiplatelet therapy might achieve an optimal balance between ischaemia and bleeding. We aimed to investigate the safety and efficacy of a prasugrel-based dose de-escalation therapy.

Methods

HOST-REDUCE-POLYTECH-ACS is a randomised, open-label, multicentre, non-inferiority trial done at 35 hospitals in South Korea. We enrolled patients with acute coronary syndrome receiving PCI. Patients meeting the core indication for prasugrel were randomly assigned (1:1) to the de-escalation group or conventional group using a web-based randomisation system. The assessors were masked to the treatment allocation. After 1 month of treatment with 10 mg prasugrel plus 100 mg aspirin daily, the de-escalation group received 5 mg prasugrel, while the conventional group continued to receive 10 mg. The primary endpoint was net adverse clinical events (all-cause death, non-fatal myocardial infarction, stent thrombosis, repeat revascularisation, stroke, and bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium [BARC] criteria) at 1 year. The absolute non-inferiority margin for the primary endpoint was 2·5%. The key secondary endpoints were efficacy outcomes (cardiovascular death, myocardial infarction, stent thrombosis, and ischaemic stroke) and safety outcomes (bleeding events of BARC grade ≥2). The primary analysis was in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02193971.

Results

From Sept 30, 2014, to Dec 18, 2018, 3429 patients were screened, of whom 1075 patients did not meet the core indication for prasugrel and 16 were excluded due to randomisation error. 2338 patients were randomly assigned to the de-escalation group (n=1170) or the conventional group (n=1168). The primary endpoint occurred in 82 patients (Kaplan-Meier estimate 7·2%) in the de-escalation group and 116 patients (10·1%) in the conventional group (absolute risk difference −2·9%, pnon-inferiority<0·0001; hazard ratio 0·70 [95% CI 0·52–0·92], pequivalence=0·012). There was no increase in ischaemic risk in the de-escalation group compared with the conventional group (0·76 [0·40–1·45]; p=0·40), and the risk of bleeding events was significantly decreased (0·48 [0·32–0·73]; p=0·0007).

Interpretation

In east Asian patients with acute coronary syndrome patients receiving PCI, a prasugrel-based dose de-escalation strategy from 1 month after PCI reduced the risk of net clinical outcomes up to 1 year, mainly driven by a reduction in bleeding without an increase in ischaemia.

Funding

Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Qualitech Korea, and Dio.

Introduction

For patients with acute coronary syndrome after percutaneous coronary intervention (PCI), a potent P2Y12 inhibitor-based dual antiplatelet therapy is recommended for up to 1 year due to the superior effects of these agents in reducing thrombotic outcomes compared with clopidogrel.1, 2 However, these effects are achieved at the expense of an increased risk of bleeding.1, 2, 3 Considering the association of bleeding events with mortality, the trade-off between thrombotic risk and bleeding risk is an integral part of decision making during pharmacotherapy.

In the early phase, the thrombotic risk outweighs the bleeding risk, whereas during the chronic phase, the decrease in thrombotic risk is more pronounced than that of bleeding risk.1, 2, 4 This is one of the reasons why de-escalation of the antiplatelet regimen is quite common in clinical practice.5, 6 However, due to the scarcity of clear clinical evidence, de-escalation strategies are not yet implemented in the guidelines. De-escalation studies have mostly tested switching from prasugrel to clopidogrel4, 7 or stopping aspirin and using a potent antiplatelet agent as monotherapy.8 Because clopidogrel has innate limitations, such as drug-to-drug interaction and a large response variability,9 an alternative de-escalation method could be a dose reduction of the potent P2Y12 inhibitor.

Research in context

Evidence before this study

A potent P2Y12 inhibitor-based dual antiplatelet therapy is recommended for up to 1 year in patients with acute coronary syndrome receiving percutaneous coronary intervention (PCI). De-escalation of the antiplatelet regimen is commonly performed in clinical practice but is not yet implemented in guidelines due to a scarcity of clear clinical evidence. We searched PubMed on Aug 1, 2020, for articles published in English with the search terms “dual antiplatelet therapy”, “de-escalation”, “switching antiplatelet therapy”, “percutaneous coronary intervention”, and “acute coronary syndrome”. Our search identified only a few randomised studies that focused on clinical outcomes. In the TWILIGHT study, de-escalation to ticagrelor monotherapy as compared with aspirin–ticagrelor dual therapy showed a lower incidence of clinical events, especially major bleeding. In the TROPICAL ACS study, de-escalation guided by platelet function testing was non-inferior to standard treatment with prasugrel. However, the multistep protocol of this strategy would be cumbersome and impractical in real-world practice.

Added value of this study

HOST-REDUCE POLYTECH-ACS is the first randomised trial to investigate a prasugrel-based dose de-escalation strategy in patients with acute coronary syndrome receiving PCI. In 2338 patients, prasugrel dose de-escalation was non-inferior to conventional therapy in preventing net adverse clinical events (a composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, clinically driven revascularisation, stroke, and Bleeding Academic Research Consortium grade ≥2 bleeding). Subsequent equality testing showed that de-escalation significantly reduced the occurrence of the primary endpoint. The main driver of the difference was a reduction in bleeding, without an increase in ischaemic outcomes. Post-hoc analysis also showed that the beneficial effect of prasugrel de-escalation was consistent in various subgroups without any significant interaction. By showing non-inferiority of prasugrel de-escalation during the chronic maintenance phase, our trial provides important justification for dose reduction of prasugrel in east Asian patients with acute coronary syndrome receiving PCI.

Implications of all the available evidence

In patients with acute coronary syndrome receiving PCI who are indicated to take the full dose of prasugrel, de-escalation of prasugrel dose to 5 mg might be a feasible alternative strategy during chronic maintenance therapy, especially when the risk of bleeding is a concern.

Prasugrel is a third-generation potent thienopyridine that irreversibly binds to the platelet P2Y12 receptor and inhibits adenosine diphosphate-induced platelet aggregation. Compared with clopidogrel, prasugrel has a faster onset, is more potent, and has less response variability.10 Its efficacy was confirmed in planned PCI patients in the TRITON-TIMI 38 trial,2 whereas in patients treated medically without revascularisation, prasugrel did not significantly improve ischaemic outcomes as compared with clopidogrel.11 Previous pharmacodynamic data have shown that the extent of platelet inhibition achieved by reduced-dose prasugrel (5 mg) is weaker than that of the conventional dose of prasugrel (10 mg), but is stronger than that of 75 mg clopidogrel.12, 13, 14 Therefore, the use of 5 mg prasugrel during the chronic maintenance phase could be an attractive de-escalation strategy to minimise both thrombotic and bleeding events after PCI. In particular, previous consensus documents have suggested that reduced-dose regimens of potent P2Y12 inhibitors are a theoretically plausible option in east Asian people, who are known to have a higher bleeding risk and a larger response variability to clopidogrel.15, 16, 17 One pharmacodynamic study in Asian patients suggested a potential benefit of half-dose versus standard-dose prasugrel treatment in patients with acute coronary syndrome;18 the percentage of patients in the therapeutic target range of antiplatelet therapy was more than two-times higher in the 5 mg group compared with the 10 mg group.18 In the present study, we sought to compare a prasugrel-based de-escalation therapy (5 mg) with the conventional maintenance dose (10 mg) after PCI in patients presenting with acute coronary syndrome.

Section snippets

Study design and participants

The HOST-REDUCE-POLYTECH-ACS trial is an investigator-initiated, randomised, parallel-group, open-label, adjudicator-blinded, multicentre trial done at 35 hospitals in South Korea. The design of the study was described previously.19 Briefly, the study had a 2 × 2 factorial design testing two independent hypotheses and thus had two arms, the dual antiplatelet therapy (DAPT) arm and the drug-eluting stent (DES) arm. The DAPT arm compared prasugrel-based dose de-escalation therapy with

Results

From Sept 30, 2014, to Dec 18, 2018, 3429 eligible patients with acute coronary syndrome from 35 hospitals in South Korea were screened. Among this population, 1075 patients did not meet the core indication for prasugrel and were assigned to the observation group. 2338 patients were randomly assigned to the de-escalation group (n=1170) or the conventional group (n=1168) and 16 patients were excluded due to randomisation error (figure 1). The mean age of patients was 58·8 years and 326 (13·9%)

Discussion

The concept of de-escalation is based on the hypothesis that there is a temporal change of ischaemic and bleeding risks after PCI. Immediately after PCI, especially in patients with acute coronary syndrome, the risk of thrombosis is greatest because the patient has a thrombotic milieu and the culprit coronary artery needs to recover from balloon-induced injury and dissection with exposure of the subendothelial tissue to blood.21 Moreover, a foreign material (the DES) is directly exposed to the

Data sharing

The HOST-REDUCE-POLYTECH-ACS trial is planned to continue follow-up for 3 years, which will end in March, 2022. Until then, no individual participant data will be available. Relevant enquiries should be emailed to the corresponding author or H-SK ([email protected]).

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    The HOST-REDUCE-POLYTECH-ACS investigators are listed in the appendix

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