Elsevier

The Lancet

Volume 398, Issue 10308, 9–15 October 2021, Pages 1305-1316
The Lancet

Articles
Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial

https://doi.org/10.1016/S0140-6736(21)01445-8Get rights and content

Summary

Background

In patients with acute myocardial infarction receiving potent antiplatelet therapy, the bleeding risk remains high during the maintenance phase. We sought data on a uniform unguided de-escalation strategy of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after acute myocardial infarction.

Methods

In this open-label, assessor-masked, multicentre, non-inferiority, randomised trial (TALOS-AMI), patients at 32 institutes in South Korea with acute myocardial infarction receiving aspirin and ticagrelor without major ischaemic or bleeding events during the first month after index percutaneous coronary intervention (PCI) were randomly assigned in a 1:1 ratio to a de-escalation (clopidogrel plus aspirin) or active control (ticagrelor plus aspirin) group. Unguided de-escalation without a loading dose of clopidogrel was adopted when switching from ticagrelor to clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months. A non-inferiority test was done to assess the safety and efficacy of de-escalation DAPT compared with standard treatment. The hazard ratio (HR) for de-escalation versus active control group in a stratified Cox proportional hazards model was assessed for non-inferiority by means of an HR margin of 1·34, which equates to an absolute difference of 3·0% in the intention-to-treat population and, if significant, a superiority test was done subsequently. To ensure statistical robustness, additional analyses were also done in the per-protocol population. This trial is registered at ClinicalTrials.gov, NCT02018055.

Findings

From Feb 26, 2014, to Dec 31, 2018, from 2901 patients screened, 2697 patients were randomly assigned: 1349 patients to de-escalation and 1348 to active control groups. At 12 months, the primary endpoints occurred in 59 (4·6%) in the de-escalation group and 104 (8·2%) patients in the active control group (pnon-inferiority<0·001; HR 0·55 [95% CI 0·40–0·76], psuperiority=0·0001). There was no significant difference in composite of cardiovascular death, myocardial infarction, or stroke between de-escalation (2·1%) and the active control group (3·1%; HR 0·69; 95% CI 0·42–1·14, p=0·15). Composite of BARC 2, 3, or 5 bleeding occurred less frequently in the de-escalation group (3·0% vs 5·6%, HR 0·52; 95% CI 0·35–0·77, p=0·0012).

Interpretation

In stabilised patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events.

Funding

ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.

Introduction

In acute myocardial infarction, adequate platelet inhibition is essential to reduce the risk of recurrent thrombotic events. Thus, the current guidelines preferentially recommend the use of potent P2Y12 inhibitors (such as ticagrelor or prasugrel) over clopidogrel in patients with acute myocardial infarction undergoing percutaneous coronary intervention (PCI).1 However, along with the strong antiplatelet efficacy, a higher risk of bleeding was observed for potent P2Y12 inhibitors compared with clopidogrel in pivotal randomised trials.2, 3 Although the ischaemic benefit was consistent throughout the first year after an index event, the benefit of ticagrelor and prasugrel over clopidogrel for reducing thrombotic risk was prominent in the early period (<30 days) after acute coronary syndrome when the risk of ischaemic complications was the highest,4, 5 whereas most bleeding events occurred predominantly during the maintenance period of treatment.6, 7 These findings have resulted in the development of a stepwise de-escalation of dual antiplatelet treatment (DAPT) that makes use of a potent P2Y12 inhibitor only in the acute phase of treatment and the less potent clopidogrel during the chronic phase of treatment.8 Although data regarding guided de-escalation of antiplatelet therapy to optimise treatment outcomes in the acute phase in patients with acute coronary syndrome undergoing PCI are supported by several large-scale clinical trials,8, 9 and a systematic review and meta-analysis,10 data regarding unguided de-escalating DAPT switching from potent P2Y12 inhibitors to clopidogrel after the acute phase in patients with acute myocardial infarction are based on a small study with important limitations and registry data.11, 12 However, de-escalation commonly occurs in clinical practice owing to a perceived high bleeding risk, side-effects, and for economic reasons, without the guidance of the platelet function test (PFT) or genotyping.12, 13, 14 Moreover, the improved performance of current generation drug-eluting stents compared with earlier generation drug-eluting stents sets the stage for investigating various de-escalating antiplatelet strategies.

Research in context

Evidence before this study

The current guidelines recommend the use of potent P2Y12 receptor inhibitors over clopidogrel for up to 1 year in patients with acute myocardial infarction undergoing percutaneous coronary intervention (PCI). Although the ischaemic risk is greater in the early phase, the bleeding risk remains high during the maintenance phase of acute myocardial infarction. These findings have resulted in the development of a stepwise de-escalation of dual antiplatelet therapy (DAPT) by means of a potent P2Y12 inhibitor only in the acute phase and the less potent clopidogrel during the chronic phase of treatment. We searched PubMed on May 1, 2021, for articles published in English, with the search terms “dual antiplatelet therapy”, “antiplatelet treatment de-escalation”, “switching antiplatelet therapy”, “acute coronary syndrome”, and “percutaneous coronary intervention”. Our search identified only a few relevant randomised, clinical trials that investigated this issue. Unlike ticagrelor monotherapy trials such as TWILIGHT and TICO, and a study using reduced dose of prasugrel, the HOST-REDUCE-POLYTECH-ACS trial, multiple options of de-escalation dual antiplatelet therapy exist: unguided, platelet function test-guided, and CYP2C19 genotype-guided. In the TROPICAL-ACS study, the de-escalation strategy of switching to clopidogrel guided by platelet function test was non-inferior to prasugrel-based DAPT in terms of net clinical benefit. However, the complexity of the testing and protocols are impractical in clinical practice. The POPular Genetics trial adopting CYP2C19 genotype-guided strategy for selection of an appropriate P2Y12 inhibitor showed a lower incidence of bleeding but has similar weakness to that of the TROPICAL-ACS study. Although data on the unguided de-escalation DAPT switching from potent P2Y12 inhibitors to clopidogrel are scarce, unguided de-escalation commonly occurs in clinical practice.

Added value of this study

The Ticagrelor versus Clopidogrel in Stabilized Patients with Acute Myocardial Infarction (TALOS-AMI) trial investigated the hypothesis that de-escalation DAPT with clopidogrel might be non-inferior to ticagrelor-based antiplatelet therapy in stabilised patients with acute myocardial infarction. In 2697 patients with acute myocardial infarction who had no major ischaemic or bleeding events and tolerated aspirin plus ticagrelor therapy during the first month after an index PCI, a uniform unguided de-escalation antiplatelet therapy switching from ticagrelor to clopidogrel was superior to the ticagrelor-based continuing DAPT in terms of net clinical benefit (a composite of cardiovascular death, myocardial infarction, stroke, and bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months after the index PCI. The de-escalation strategy was associated with a 45% lower risk of net clinical benefits for the next 11 months than the ticagrelor-based dual antiplatelet strategy. The absolute risk reduction was 3·6%, which was mainly caused by a significant decrease in bleeding risk. Additionally, a composite of BARC 3 or 5 bleeding occurred less frequently in the de-escalation group but was marginally significant. Even a composite of ischaemic events and serious bleeding such as BARC bleeding type 3 or 5 showed a significant difference between the two groups. In this study, the incidence of primary ischaemic events from 1 to 12 months after an index event were similar to those of other de-escalation trials including the TROPICAL-ACS, TWILIGHT-ACS, POPular Genetics, and TWILIGHT trials, which might indicate the safety of a uniform unguided de-escalation antiplatelet strategy in stabilised patients with uncomplicated acute myocardial infarction.

Implications of all the available evidence

In stabilised patients with acute myocardial infarction who had no major ischaemic or bleeding events and tolerated aspirin plus ticagrelor therapy during the first month after an index PCI, a uniform unguided de-escalation antiplatelet strategy switching from ticagrelor to clopidogrel was superior to the ticagrelor-based DAPT strategy at preventing net adverse clinical events, including the thrombotic composite and clinically relevant bleeding.

The Ticagrelor versus Clopidogrel in Stabilized Patients with acute myocardial infarction (TALOS-AMI) trial investigated the hypothesis that de-escalation of DAPT with clopidogrel would be non-inferior to ticagrelor-based DAPT in terms of net clinical benefit in stabilised patients who did not have major ischaemic or bleeding events during the first month after an index acute myocardial infarction.15 If the non-inferiority is met, this kind of de-escalating antiplatelet strategy might possibly offer improved safety, better compliance, or reduced economic burden in the stabilised acute myocardial infarction population. Owing to the paucity of clinical evidence for the routine use of PFT and genotyping in stabilised patients with acute myocardial infarction,16 and considering the situation that unguided de-escalation was not uncommon in clinical practice,12, 13, 17 we adopted and tested a uniform unguided de-escalation antiplatelet strategy at the time of randomisation.

Section snippets

Study design

The TALOS-AMI trial was an investigator-initiated, prospective, open-label, multicentre, non-inferiority, assessor-masked, parallel group, randomised trial. Patients were enrolled at 32 institutes in South Korea. The trial rationale and design have been described previously.15 In brief, we assumed that adoption of potent P2Y12 inhibitor-based DAPT in the first month and then de-escalating DAPT thereafter would balance ischaemic and bleeding risks in patients with acute myocardial infarction.

Results

From Feb 26, 2014, to Dec 31, 2018, a total of 2901 patients with acute myocardial infarction who provided informed consent were screened after successful PCI. Of these, 204 patients were excluded before random assignment, and 2697 patients were randomly assigned to receive either clopidogrel plus aspirin (de-escalation group) or ticagrelor plus aspirin (active control group) at 1 month after index PCI (figure 1). Of the 1349 patients assigned to the de-escalation group, 1208 received the

Discussion

The TALOS-AMI trial is the first large-scale randomised, controlled trial investigating the efficacy and safety of a uniform, unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction without major ischaemic or bleeding events during the first month after an index PCI. Key findings from the current study are that the adoption of an unguided de-escalation DAPT strategy of switching from ticagrelor to clopidogrel 1 month after a myocardial

Data sharing

The TALOS-AMI trial plans to continue follow-up for an additional 2 years, which will end in December, 2021. Until then, no participant data will be available. Relevant enquiries should be emailed to the corresponding author ([email protected]).

Declaration of interests

KC has received researched grants from Chongkundang Pharm, Medtronic, Abbott, and Boston Scientific. CJK has received research grants and speaker's fees from Chongkundang Pharm.

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