2023 European Society of Cardiology guidelines for the management of acute coronary syndromes

In the Netherlands, patients with STEMI eligible for primary percutaneous coronary intervention (pPCI) are pre-treated with a loading dose of ticagrelor/prasugrel, aspirin and unfractionated heparin by paramedics in the ambulance. However, pre-treatment with a P2Y₁₂ inhibitor received merely a class IIb, level of evidence (LoE) B recommendation in the 2023 ESC guidelines. From our perspective, the use of pre-hospital ticagrelor/prasugrel in STEMI patients, following the design of the PLATO and TRITON trials, appears reasonable given current health care logistics in the Netherlands (with very high use of the radial approach and therefore a lower bleeding risk) and is supported by contemporary evidence that pre-treatment with ticagrelor/prasugrel is a safe approach for these patients.

So far, only the ATLANTIC trial has investigated the different timing regimens of ticagrelor pre-treatment, namely pre-hospital versus in-hospital before pPCI, in STEMI patients [2]. No differences were found in ST resolution or TIMI III flow prior to pPCI, nor in the composite endpoint of mortality, MI, stroke, urgent coronary revascularisations, or stent thrombosis. However, pre-hospital administration of ticagrelor did reduce the occurrence of definite stent thrombosis at 24 h (0% vs 0.8%, p = 0.008) and 30 days (0.2% vs 1.2%; p = 0.02). It is noteworthy that the median time difference between the two timing strategies was only 31 min. Bleeding rates were comparable between the two treatment groups. A comprehensive meta-analysis, encompassing three randomised controlled trials (RCTs) and 14 observational studies, indicated that pre-treatment was not associated with a reduction of overall cardiovascular events. However, within the subgroup of patients receiving pre-hospital P2Y₁₂ inhibition, there was a decreased 30-day risk of MI [3]. In conclusion, there is no evidence that pre-hospital P2Y₁₂ inhibition increases reperfusion, but it does reduce post-PCI thrombotic complications such as stent thrombosis. Currently, the effect of pre-treatment with subcutaneous formulation of novel drugs is being studied as regards the outcome in STEMI patients (CELEBRATE trial, NCT04825743; SOS-AMI trial, NCT04957719).

Unfractionated heparin is recommended as standard of care for patients with STE-ACS and is most often given in the ambulance during transfer to a PCI centre. Fondaparinux (a selective Xa inhibitor) use is not recommended in STEMI patients undergoing pPCI, based on the results of the OASIS-6 trial [4].

The 2023 guidelines state that pre-treatment with a P2Y₁₂ inhibitor is not recommended when the coronary anatomy is unknown (class III, LoE A) and when early (< 24 h) invasive management is planned. This change in recommendation first appeared in the 2020 guidelines following the ISAR-REACT-5 study, demonstrating that prasugrel with no pre-loading was superior to ticagrelor in the context of pre-loading [5]. However, it must be noted that coronary angiography in the NSTE-ACS group was performed within a mean of 4 h after randomisation (personal communication with investigators from the ISAR group), which is not representative for Dutch clinical practice.

The guidelines do offer room for pre-treatment, stating that pre-treatment with P2Y₁₂ inhibitors may be considered (class IIb, LoE C) in patients who cannot undergo an early invasive strategy and who do not exhibit a high bleeding risk, as defined by the Academic Research Consortium on High Bleeding Risk (ARC-HBR) criteria [6].

Several other aspects need to be taken into account when deciding on pre-treatment. Pre-treatment with a P2Y₁₂ inhibitor on top of aspirin and low-molecular-weight heparin imposes a substantial risk of bleeding, especially in older patients or in patients otherwise at high bleeding risk. Second, in patients proceeding to coronary artery bypass grafting the surgical risk is significantly increased. On the other hand, bleeding risk in the Netherlands (with radial access being used in a very high proportion of cases) might be lower than in previous studies investigating the benefits and risks of pre-treatment. Of note is that in the Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention (PCI) or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction (ACCOAST) study, in which pre-treatment resulted in significantly more bleeding, over 50% of patients underwent angiography via femoral access.

Overall, the ACS Working Group supports the class III recommendation not to use pre-treatment routinely. If coronary angiography cannot be performed within 24 h for logistical reasons, it is reasonable to pre-treat those patients deemed to be at high ischaemic risk and low bleeding risk with a P2Y₁₂ inhibitor while they await angiography [1, 7].

The guidelines support the use of a more potent P2Y₁₂ inhibitor and advise the use of clopidogrel only when prasugrel and ticagrelor are not available. In older patients, clopidogrel may be considered (class IIb, LoE B), based on the POPULAR-AGE trial [8]. With respect to which potent P2Y₁₂ inhibitor to choose, the guidelines state that prasugrel should be considered in preference to ticagrelor for ACS patients who proceed to PCI (class IIa, LoE B).

However, this preference for prasugrel is based on limited evidence, as we previously set out [9]. The ISAR-REACT 5 trial is the only study comparing two antiplatelet strategies (pre-treatment with ticagrelor vs treatment with prasugrel post-PCI) rather than a head-to-head-comparison [5].

The ACS Working Group supports the use of both prasugrel or ticagrelor in NSTE-ACS patients. Factors to be taken into account when choosing a P2Y₁₂ receptor inhibitor include logistical and patient- and drug-related considerations (dosing frequency, side effects, prasugrel contraindicated in stroke patients and no net benefit in the elderly). Of note is that prasugrel should not be used for pre-treatment.

Unfractionated heparin is recommended as standard care for patients with NSTE-ACS during invasive angiography or PCI. In patients not at high bleeding risk who are not undergoing immediate invasive treatment, fondaparinux therapy is recommended while they await angiography, based on the results of the OASIS-5 trial [10].

The 2023 ESC guidelines encourage individualised antithrombotic treatment. Although the default strategy of 12 months of dual antiplatelet therapy (DAPT) with aspirin and a strong P2Y₁₂ inhibitor (prasugrel or ticagrelor) remains unchanged, the guidelines offer guidance on specific clinical scenarios in which the default DAPT duration can be shortened (< 12 months), extended (> 12 months) or modified (de-escalation: i.e. switching from a strong P2Y₁₂ inhibitor to clopidogrel).

In recent years, advancements in stent technology and intracoronary imaging-guided PCI have significantly reduced the risk of stent thrombosis. On the other hand, bleeding events carry a high risk of morbidity and mortality [11]. Therefore, emphasis should be shifted to tailoring treatment based on ischaemic and bleeding risk. The new guidelines advise that single antiplatelet therapy (SAPT) be considered after 3–6 months in patients who are event-free and are not at high ischaemic risk (class IIa, LoE A). If so, SAPT with a P2Y₁₂ inhibitor should be preferred. In patients at high bleeding risk, a SAPT strategy may be considered even after 1 month (class IIb, LoE B). The LEGACY trial is currently evaluating the safety and efficacy of even earlier omittance of aspirin, i.e. immediate P2Y12 monotherapy, in NSTE-ACS patients [12].

In the elderly, especially those at high bleeding risk, the option of starting with clopidogrel instead of a strong P2Y₁₂ inhibitor in order to reduce the bleeding risk may be considered (class IIb, LoE B).

Furthermore, P2Y₁₂ inhibitor de-escalation in ACS patients may be considered as an alternative strategy to the default 12-month regimen, in order to reduce the risk of bleeding events. The guidelines do not recommend de-escalation in the first 30 days after an ACS due to a potentially increased risk of ischaemic events (class III, LoE B).

Interestingly, the POPULAR Genetics trial demonstrated that an early (in-hospital) CYP2C19 genotype-guided de-escalation strategy switching from ticagrelor to clopidogrel reduced bleeding while being non-inferior to standard treatment with respect to thrombotic events [13]. Moreover, this genotype-based strategy led to a significant cost reduction when applied in the Netherlands [14]. As CYP2C19 genotyping is now more widely used and available in many Dutch hospitals, efforts should be made to incorporate genotype-based strategies into clinical practice, especially for ACS patients at high bleeding risk.

In ACS patients with an indication for oral anticoagulation (non-vitamin‑K oral anticoagulant preferred to vitamin‑K antagonist), triple antithrombotic therapy (TAT) with the addition of aspirin and clopidogrel is recommended for up to 1 week, followed by 12 months of dual antithrombotic therapy (DAT; oral anticoagulant plus clopidogrel (class I, LoE A)). Generally, TAT is associated with a two- to threefold increase in bleeding risk [15] and therefore should be kept as short as possible. However, in patients with high ischaemic risk or other anatomical/procedural characteristics that outweigh the bleeding risk, TAT could be prolonged for up to 1 month (class IIa, LoE C). In patients with a very high risk of bleeding, maintenance DAT could be reduced to 6 months (class IIb, LoE B).

In medically managed ACS patients, current data support DAT over TAT, with a single antiplatelet agent (most commonly clopidogrel) for at least 6 months (class IIa, LoE B).

As illustrated by the previous scenarios, patient selection is key. Several risk scores have been developed to identify patients at high risk for bleeding or thrombotic events during follow-up. However, all risk scores are hampered by poor discriminatory abilities.

The 2023 guidelines recommend using either the ARC-HBR criteria or the PRECISE-DAPT (PREdicting bleeding Complications in patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy) score for the assessment of bleeding risk. The presence of one major or two minor ARC-HBR risk factors indicates a high bleeding risk (Tab. 2; [6]). Of note is that the presence of multiple major risk factors is associated with a progressive increase in the bleeding risk. The PRECISE-DAPT is an easier-to-use tool with only five parameters (haemoglobin, age, leukocyte count, creatinine clearance and prior bleeding). A PRECISE-DAPT score of ≥ 25 is regarded as a high bleeding risk [16].

Thrombotic risk and (long-term) ischaemic risk are composed of both clinical (patient) characteristics and technical aspects related to the PCI or the coronary anatomy. High-risk features of stent-driven recurrent ischaemic events can be identified, such as prior stent thrombosis, treatment of bifurcation lesions or diffuse multivessel disease, especially in patients with diabetes. In addition, the DAPT score can be used, which has been validated in order to assess the benefit of DAPT continuation beyond 1 year after stenting [17].

As both bleeding and ischaemic risk are complex, we recommend assessing high bleeding risk and high ischaemic risk in a structured manner, using one of the above tools prior to discharge. In addition, the interventional cardiologist should take the leading role in highlighting any high-risk features of recurrent ischaemic events, related to the PCI procedure or coronary anatomy.

It is noteworthy that high bleeding risk and high ischaemic risk often overlap, as some risk factors (e.g. age, renal failure) pre-dispose to both bleeding and ischaemic risk. In patients with both high bleeding and ischaemic risk, prioritising the bleeding risk and thus abbreviating or de-escalating DAPT should generally be considered. Specifically, bleeding risk should be prioritised in frail older patients, in patients with anaemia or previous bleeding and in patients with active malignancy (all known strong predictors for bleeding).

Finally, the decision to continue DAPT beyond 1 year can be postponed to follow-up in the outpatient clinic. Patients who do not experience any bleeding events during the initial course of DAPT and have a high ischaemic risk should be considered for intensified antithrombotic therapy (DAPT continuation or aspirin plus very low-dose rivaroxaban) [18].

In the Netherlands, extensive efforts have been made to ensure proper pre-hospital diagnosis and treatment of STEMI. In this setting, immediate reperfusion therapy by pPCI should be performed within 120 min of the diagnosis. Therefore, we recommend that all patients presenting with symptoms suggestive of ACS and an electrocardiogram consistent with STEMI be transferred immediately to a PCI centre to undergo urgent invasive coronary angiography (ICA) and, in most cases, pPCI. The clinical benefit of an immediate invasive strategy in patients presenting within 12 h after the onset of symptoms is well established. In late presenters (> 12 h after symptom onset), the evidence for immediate ICA (± PCI) is less robust, although imaging studies have provided evidence of myocardial salvage if PCI is performed [19]. In late presenters (> 12 h and < 48 h), immediate ICA should be considered based on the extent of myocardium at risk, ongoing signs of ischaemia and/or haemodynamic or electrical instability. In patients presenting > 48 h after symptom onset who are clinically stable, PCI of an occluded infarct-related vessel is not recommended (class III, LoE A).

In patients presenting with out-of-hospital cardiac arrest (OHCA) and persistent ST-segment elevation, recommendations are similar to those for STEMI without cardiac arrest. In OHCA without persistent ST-segment elevation, the ESC guidelines provide a revised recommendation regarding the timing of ICA. Immediate angiography is downgraded to class III, LoE A, based on the results of the COACT and TOMAHAWK trials [24, 25]. In both trials, a strategy of immediate versus delayed ICA did not affect all-cause mortality. Meanwhile, a class IIa (LoE C) recommendation was decided upon for immediate transfer to a cardiac arrest centre. This recommendation is based on retrospective data only, while the recently published ARREST trial showed no difference in mortality whether patients were transferred to a cardiac arrest centre or the nearest hospital [26]. Of note is that requirements for cardiac arrest centres included a set of 13 minimum criteria related to ICU care and availability of cardiothoracic facilities, such as immediate coronary angiography and mechanical circulatory support. As such, with regard to the Dutch healthcare system, these arrest centres are most similar to hospitals with cardiothoracic surgery.

Based on the evidence stated above, the Dutch ACS Working Group agrees with the recommendation not to perform ICA < 24 h in patients with OHCA without signs of STEMI. Furthermore, we advise that current regional arrangements for haemodynamically unstable patients without STEMI not be changed.

The 2020 recommendation regarding same-day transfer of all high-risk NSTE-ACS patients to a PCI centre has been rephrased and refers to ‘early inpatient transfer’. As postulated in our previous document, we advise that this recommendation be considered in the context of regional arrangements between PCI centres and referring hospitals. Performing ICA in a centre with PCI capabilities may avoid performing two invasive procedures in the same patient, while angiography in a non-PCI centre relieves the burden on ambulance services and PCI centres, as a substantial number of patients do not undergo PCI.