Evidence-based Antiplatelet Pretreatment in Non-ST-elevation Acute Coronary Syndromes

Abstract

Antiplatelet pretreatment in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) is controversial. It is vital that the risk of ischaemia and the risk of haemorrhage are both considered when managing this patient group. Current clinical guidelines do not recommend routine pretreatment in patients presenting with NSTE-ACS who are having coronary angiography within 24 hours. However, a significant portion of these patients will not have coronary angiography until after 24 hours. Pretreatment with antiplatelets may reduce the risk of ischaemic events, but it is associated with bleeding and delays to coronary artery bypass grafting, and it may be deleterious in patients with diagnoses other than NSTE-ACS, such as acute aortic syndromes, pulmonary embolism or intracranial bleeds. This review analyses the most important studies assessing antiplatelet pretreatment in NSTE-ACS.

Acute coronary syndromes (ACS) are usually caused by the rupture of a vulnerable plaque that leads to the activation of platelets and a coagulation cascade, resulting in thrombus formation with consequent compromised coronary blood flow that causes myocardial ischaemia or necrosis. Current evidence recommends dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y₁₂ inhibitor (ticagrelor or prasugrel) as the standard therapy for non-ST elevation acute coronary syndrome (NSTE-ACS) patients, while clopidogrel should be reserved for patients with a high bleeding risk, contraindications for high intensity DAPT or for those with an indication for oral anticoagulation.1,2

A key consideration in the management of antithrombotic therapy in patients with NSTE-ACS is the balance between ischaemic events and bleeding events. Ischaemic events comprise spontaneous MI and device-related MI as defined in the universal definition of MI.3 Percutaneous coronary intervention (PCI)-related MI (type 4a MI) requires an elevation of cardiac troponin (cTn) values more than five times the 99th percentile upper range limit (URL) in patients with normal baseline values or an increase of >20% in patients with elevated cTn before the procedure to an absolute value more than five times the 99th percentile URL with evidence of new myocardial ischaemia, such as ECG changes, imaging evidence or from procedure-related complications. Another subcategory of PCI-related MI is stent/scaffold thrombosis (type 4b MI), as documented by angiography or autopsy using the same criteria as type 1 MI.3

Multiple definitions have been used for bleeding in clinical trials and registries; however, they generally include non-coronary artery bypass grafting (CABG)-related bleeding (classified as major, minor or minimal), as well as bleeding in the setting of CABG. Among the most commonly used classifications in these studies are the Thrombolysis in MI (TIMI) grading system, the Bleeding Academic Research Consortium criteria, and the International Society on Thrombosis and Haemostasis criteria.4

Ischaemic events and bleeding events have a similar prognostic impact; therefore, a comprehensive approach that considers ischaemic and bleeding risk is essential for the management of antiplatelet therapy in patients with NSTE-ACS.5

Pretreatment is defined as the administration of a P2Y₁₂ inhibitor before an invasive coronary angiogram (CAG) is performed.6 It has been associated with increased bleeding events without ischaemic benefit in patients in whom CAG is performed within the first 24 hours of presentation with ACS, and it may be deleterious in patients with misdiagnoses who have acute aortic syndromes, pulmonary embolisms or intracranial bleedings.7,8 Moreover, pretreatment may also delay surgical treatment in patients who require CABG. For these reasons, current guidelines do not recommend routine pretreatment in NSTE-ACS patients when an early invasive strategy is feasible. However, these recommendations are based on the results of randomised controlled trials (RCTs) in which the mean time to CAG is extremely short (2–4 hours), so they do not allow time for a hypothetical benefit of pretreatment and are often not representative of routine clinical practice for these patients, where delays to CAG are longer, especially if the NSTE-ACS occurs during weekends or holidays or in centres where access to the cath lab is not available 24/7, 365 days a year.7,8 Clinicians must decide whether or not to administer pretreatment to NSTE-ACS patients. It is unclear if pretreatment has the same effects across the entire spectrum of NSTE-ACS, such as with non-ST-elevation MI (NSTEMI) and unstable angina (UA) patients.9

The present focused narrative review evaluates the most relevant clinical trials assessing the safety and efficacy of pretreatment in NSTE-ACS patients. Aiming to compare current evidence with our experience, our clinical research group also performed an observational study assessing pretreatment-related outcomes in a cohort of NSTE-ACS patients, in a centre without 24/7 access to a cath lab or access to a local cardiac surgery team. We also devised an algorithm that aims to help clinicians select which patients may benefit from antiplatelet pretreatment.

Methods

This article includes a narrative review of the available evidence on antiplatelet pretreatment in NSTE-ACS. A structured, non-systematic literature search was performed using PubMed, including studies published up to 2026. Search terms included combinations of “NSTE-ACS”, “pretreatment”, “P2Y₁₂ inhibitors”, “ticagrelor”, “prasugrel” and “clopidogrel”. We prioritised RCTs, meta-analyses and guideline documents and complemented this evidence with selected observational studies reflecting real-world clinical practice. Studies were selected based on their clinical relevance to the timing of antiplatelet therapy and associated ischaemic and bleeding outcomes.

Dual Antiplatelet Therapy in NSTE-ACS

The interpretation of available evidence on antiplatelet pretreatment in NSTE-ACS requires several interrelated but conceptually different factors to be distinguished: the pretreatment strategy, referring to the timing of P2Y12 inhibitor administration relative to CAG; the choice of P2Y12 inhibitor, with different pharmacodynamic profiles; the timing to CAG, which determines the potential window for drug efficacy; and the clinical and procedural context, including differences between earlier PCI-era practices and contemporary management characterised by radial access and early invasive strategies. Failure to differentiate between these aspects may contribute to the heterogeneity of results across clinical trials.

The recommendation for DAPT with aspirin and clopidogrel in patients with ACS was established in the 2002 European Society of Cardiology (ESC) guidelines for the management of ACS in patients presenting without persistent ST-segment elevation, after the publication of the COMMIT and PCI CURE studies, which showed a reduction in ischaemic and cardiovascular events in these patients, with no significant excess risk of bleeding.10,11 Other studies showed a significant increase in bleeding events among patients treated with DAPT.12

However, several studies showed that clopidogrel exhibits variable and dose-dependent platelet inhibition with a maximum inhibitory response to the 300 mg clopidogrel loading dose within 24 hours, with resistance (described as <10% reduction in aggregation in response to 5 μmol/l adenosine diphosphate), and poor response to clopidogrel antiplatelet activity in about 30% of patients, with an associated with a higher risk of stent thrombosis and recurrent ischaemic events.13–16 This concern about clopidogrel resistance led to an investigation of alternative pharmacological strategies with a more effective antiplatelet effect and faster onset of action.

In 2007, the TRITON-TIMI 38 trial compared prasugrel with clopidogrel in 13,608 ACS patients scheduled to undergo PCI.2 The primary efficacy endpoint – a composite of cardiovascular death, non-fatal MI or non-fatal stroke – occurred in 12.1% versus 9.9% in the clopidogrel and prasugrel groups, respectively (HR 0.81; 95% CI [0.73–0.90]; p<0.001). Significant reductions in the rates of MI, urgent target vessel revascularisation and stent thrombosis were observed in the prasugrel group. The key safety endpoint of major bleeding was also observed more frequently in the prasugrel group (2.4% versus 1.8%; HR 1.32; 95% CI [1.03–1.68]; p=0.03).

In 2009, the PLATO trial randomised 18,624 ACS patients to receive ticagrelor (37.5% STEMI patients) or clopidogrel (38% STEMI patients).1 The primary endpoint (cardiovascular mortality, MI or stroke) occurred less frequently in the ticagrelor group (9.8% versus 11.7%; HR 0.84; 95% CI [0.77–0.92]; p<0.001). The rate of stent thrombosis was lower in the ticagrelor group (1.3% versus 1.9%; p=0.009). The benefit of ticagrelor was also observed for the individual components of MI and cardiovascular death, but not for stroke. No significant difference was found in the rates of major bleeding, but ticagrelor was associated with a higher rate of major bleeding not related to CABG (4.5% versus 3.8%; p=0.03) and more episodes of intracranial bleeding (0.3% versus 0.2%; p=0.06).

The results of these clinical trials led to the recommendation of DAPT using a potent P2Y₁₂ inhibitor, such as ticagrelor or prasugrel, as the standard therapy for patients with NSTE-ACS, while clopidogrel should be reserved for patients with a high bleeding risk, such as older patients or those with chronic kidney disease or previous bleedings, contraindications for high intensity DAPT (e.g prasugrel is not recommended in patients ≥75 years, ≤60 kg or with a history of cerebrovascular accident) or in those with an indication for oral anticoagulation.1,2 As both ischaemic and major bleeding events have a similar prognostic impact in these patients, an integral approach considering not only ischaemic risk, but also haemorrhagic risk is a key point for the management of NSTE-ACS patients.5

The Academic Research Consortium for High Bleeding Risk criteria are a useful tool to identify high-risk patients who may require DAPT tapering.17 To minimise the risk of bleeding associated with DAPT in patients with ACS, a second antiplatelet agent (prasugrel, ticagrelor or clopidogrel) must be chosen and a decision made on the best time to administer it. The need for pretreatment across the spectrum of ACS has subsequently been questioned. There are severe clinical conditions, such as acute aortic syndromes, pulmonary embolism or stroke, which can be misdiagnosed as an ACS, and the use of DAPT can be deleterious in these cases. For this reason, it is recommended that pretreatment in the prehospital setting is avoided in favour of waiting for a more cautious evaluation and the results of complementary tests, such as blood tests, chest X-ray and echocardiogram, to consider alternative diagnoses.

Perioperative bleeding and surgical delay are major concerns in ACS patients treated with DAPT when CABG is required. In 2025, the RAPID CABG randomised open-label non-inferiority trial enrolled 143 ACS patients and compared early CABG surgery 2–3 days after ticagrelor cessation versus delaying surgery to 5–7 days and found that an early surgical strategy was non-inferior in incurring perioperative bleeding.18 Moreover, it was observed that a reduction in the delay between ticagrelor cessation and CABG surgery may decrease the length of hospital stay.

Despite the benefit of DAPT at the time of PCI in reducing ischaemic events, the net clinical benefit is doubtful when the bleeding risk, the delay to surgery and the use of DAPT in patients with a final diagnosis different to ACS are considered. For these reasons, several trials have evaluated the safety and efficacy of pretreatment in NSTE-ACS.7,8,18–21

Comparative RCTs Assessing Antiplatelet Pretreatment for NSTE-ACS

In the PCI CURE study, 2,658 patients with NSTE-ACS undergoing PCI were randomised to receive pretreatment with a loading dose of 300 mg clopidogrel or placebo.11 The number of patients with the primary endpoint of cardiovascular death, MI or urgent revascularisation was significantly lower in the clopidogrel group than in the placebo group (7.2%; n=73 versus 4.2%; n=41, RR 0.58; 95% CI [0.40–0.85]; p=0.005). This reduction in the primary endpoint was seen from the second day after PCI and maintained until 30 days and after 8 months of follow-up. This benefit of clopidogrel pretreatment was seen in the subgroup of patients who had PCI >72 hours after randomisation, while there were no statistically significant differences in those who had CAG <72 hours after randomisation.

Most patients were treated with a thienopyridine after PCI (>80% in both groups), suggesting that this early postprocedural benefit was due to pretreatment with clopidogrel. There were no significant differences in major bleeding between groups, while minor bleeds were more frequent in the clopidogrel group than the placebo group at the end of follow-up.

The CREDO trial assessed the benefit of pretreatment with a clopidogrel 300 mg loading dose plus aspirin 3–24 hours before PCI.19 Participants had low ischaemic risk (32.8% with stable angina, approximately 53% with UA, and approximately 13–14% with recent MI) and were randomly assigned to clopidogrel (n=1,053) or placebo (n=1,063). After PCI, all patients received 75 mg clopidogrel until day 28. From day 29 to 12 months, patients in the loading dose group received 75 mg clopidogrel and those in the control group received a placebo. Pretreatment with clopidogrel did not reduce ischaemic events in the overall cohort. However, in a prespecified subgroup analysis, patients who received clopidogrel ≥6 hours before PCI presented a relative risk reduction of 38.6% (95% CI [-1.6, 62.9]; p=0.051) in the combined risk of death, MI or urgent target vessel revascularisation at 28 days. No significant differences were found in bleeding events.

The ARMYDA-5 PRELOAD trial did not find statistically significant differences in a 600 mg clopidogrel loading dose 4–8 hours before PCI or a 600 mg loading dose given in the cath lab after CAG, but prior to PCI.20 No differences were found in either ischaemic events or bleeding events between groups. Nevertheless, the study had a small cohort (n=409), and only 40% of participants had ACS (UA or NSTE-ACS).

In 2013, the ACCOAST trial enrolled 4,033 patients with NSTE-ACS and randomised patients to receive pretreatment with prasugrel 30 mg or placebo.8 When PCI was indicated, an additional 30 mg of prasugrel was administered in the pretreatment group, while 60 mg of prasugrel was given in the control group. The TIMI major bleeding rate was increased in the pretreatment group (HR 1.9; 95% CI [1.19–3.02]; p=0.006), but no significant differences were observed in the primary efficacy endpoint (a composite of cardiovascular death, MI, stroke, urgent revascularisation or glycoprotein IIb/IIIa inhibitor bailout up to day 7). It is important to note that femoral access was above 50% and the time from loading dose to CAG was 4.4 hours and 4.2 hours in the pretreatment and the no pretreatment group, respectively.

In 2019, the ISAR-REACT 5 trial compared ticagrelor with prasugrel in 4,108 patients presenting with ACS (59% NSTE-ACS and 41% STEMI).7 In the ticagrelor group, the loading dose was administered as soon as possible, while in the prasugrel group, the timing of the loading dose was dependent on the clinical presentation. In NSTE-ACS patients, the loading dose was postponed until the patient’s coronary anatomy was known but before PCI, while in STEMI patients, 60 mg of prasugrel was administered as soon as possible. The primary endpoint was the composite of death, MI or stroke at 1-year follow-up, and it was observed in 9.3% and 6.9% of the ticagrelor and prasugrel groups, respectively (HR 1.36; 95% CI [1.09–1.70]; p=0.006). The safety endpoint was bleeding events, and no significantly differences were found between groups.

In 2020, the DUBIUS trial randomised 1,449 NSTE-ACS patients (approximately 20% UA and 80% NSTEMI) to receive pretreatment with ticagrelor or no pretreatment.21 Both strategies were associated with a low incidence of ischaemic events and bleeding events, suggesting that one strategy was unlikely to be more effective than the other, leading to premature discontinuation of the study. No differences were also found depending on whether the CAG was performed within the first 24 hours or later after enrolment.

The differing results across trials can be explained by three key factors: timing to CAG, pharmacodynamic profiles of P2Y12 inhibitors and changes in contemporary practice. Early trials, such as PCI-CURE and CREDO, were conducted in an era of longer delays to CAG (>24 hours), where upstream pretreatment allowed sufficient time for clopidogrel, which is characterised by relatively slow and variable platelet inhibition, to achieve therapeutic effect before PCI.11,19 In contrast, more recent studies (ACCOAST, ISAR-REACT 5 and DUBIUS) reflect a paradigm of early invasive management (often within 2–4 hours) in which the pharmacodynamic profile of oral P2Y12 inhibitors may be mismatched with the short interval to PCI.7,8,21 This temporal mismatch is particularly relevant for prasugrel and ticagrelor, whose onset of action, although faster than clopidogrel, may still be insufficient when CAG is performed very early, thereby attenuating any ischaemic benefit of pretreatment while exposing patients to an increased bleeding risk.

Contemporary practice has evolved substantially. Radial access was used in a minority of patients in ACCOAST (approximately 40–45%), compared with a substantially higher adoption in ISAR-REACT 5 (approximately 80– 85%) and DUBIUS (>85%), whereas earlier trials, such as PCI-CURE and CREDO, were conducted predominantly with femoral access.7,8,11,19,21 This progressive shift toward radial access has reduced the bleeding risk associated with pretreatment strategies. Likewise, anticoagulation strategies have shifted from routine use of unfractionated heparin frequently combined with glycoprotein IIb/IIIa inhibitors in earlier trials, toward more contemporary approaches including weight-adjusted unfractionated heparin or bivalirudin, with glycoprotein IIb/IIIa inhibitors largely reserved for bailout situations. Additional sources of heterogeneity include differences in study populations (for example, NSTEMI-only versus mixed cohorts), timing of randomisation, crossover rates and the proportion of patients ultimately undergoing PCI. Overall, the benefit-risk balance of P2Y₁₂ inhibitor pretreatment appears highly dependent on context, with potential benefits in delayed invasive strategies. Key features of previous clinical trials are presented in Table 1. Based on this evidence, current clinical guidelines do not recommend routine administration of pretreatment in patients with NSTE-ACS for whom early CAG (<24 hours) is planned.

Table 1: Randomised Clinical Trials Assessing Antiplatelet Pretreatment.

Study	n	Intervention	Clinical Presentation	Arterial Access	Time to CAG	Outcomes
PCI CURE, 200111	2,658	Clopidogrel pretreatment versus placebo	NSTEMI: 95.33% STEMI: 4.67%	100% femoral	<72 h: 544 >72 h: 2,144	Pretreatment: CV death, MI and revascularisation (RR 0.70; 95% CI [0.50–0.97]; p=0.03) No significant differences in BE (p=0.64)
CREDO, 200219	2,116	Clopidogrel pretreatment and long-term use versus placebo	Recent MI: 14.3% versus 13.1% UA: 52.5% versus 53.1% Stable angina and others: 32.8% versus 32.8%	100% femoral	9–10 h	Pretreatment subgroup >6 h before CAG: death, MI or stroke (RR 0.39; 95% CI[-1.6-62.9%]; p=0.051]) No significant differences in BE (p=0.64)
ARMYDA-5, 201020	409	Clopidogrel pretreatment versus non-pretreatment	Stable angina 64% versus 57% NSTE-ACS 36% versus 43%	Clopidogrel pretreatment (90% femoral vs 10% radial) Clopidogrel non-pretreatment (90% femoral vs 10% radial)	4–8 h	No significant differences in BE and IE
ACCOAST, 20138	4,033	Prasugrel pretreatment versus non-pretreatment	All patients were NSTEMI	Femoral: 56.6% versus 57.3% Radial: 43.2% versus 42.5%	4.2–4.4 h	No significant differences in IE Pretreatment TIMI major BE (HR 1.9; 95% CI [1.19–3.02]; p=0.006)
ISAR-REACT 5, 20207	4,108	Ticagrelor versus prasugrel	UA: 12.4% versus 13.0% NSTEMI: 46.2% versus 46.1% STEMI: 41.4% versus 40.9%	Femoral: 62.2% versus 63.0% Radial: 37.3% versus 36.5% Other: 0.5% versus 0.5%	2 h	Prasugrel: death/MI or stroke (HR 1.36; 95% CI [1.09–1.70]; p=0.006) No significant differences in and BE
DUBIUS, 202021	1,449	Ticagrelor pretreatment versus non-pretreatment	UA: 21.4% versus 20.7% NSTEMI: 78.6% versus 79.3%	Mostly radial (94.5%)	23.3 h	No significant differences in IE and BE Premature trial interruption

BE = Bleeding events; CAG = coronary angiography; CV = cardiovascular; IE = ischaemic events; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; NSTEMI = non-ST-segment elevation MI; STEMI = ST-segment elevation MI; UA = unstable angina.

Gaps in Evidence

In daily clinical practice, a substantial proportion of patients with NSTE-ACS are treated in hospitals that do not have 24/7 access to a cath lab. This subgroup remains underrepresented in large RCTs from which current pretreatment recommendations are derived, resulting in a relative lack of direct evidence to guide antiplatelet strategies in this setting. In this context, available evidence is largely derived from indirect data and observational studies. To contribute to this field, our research group conducted a prospective observational single-centre study from June 2021 to June 2024, including 443 patients with suspected NSTE-ACS undergoing CAG. Patients were monitored during their hospital stay for pretreatment-related bleeding events, ischaemic events and misdiagnosis, with 84.0% of the study group having antiplatelet pretreatment. Ischaemic events, bleeding events and cardiovascular mortality occurred in 5.0%, 4.1% and 1.8%, respectively. Ischaemic events were more frequent in the non-pretreatment group (10.3% versus 4.1%; p=0.030), whereas no differences were found in bleeding events between groups (1.4% versus 4.6%; p=0.216). MI before CAG (defined as a new ischaemic event during hospitalisation, re-MI in patients with NSTEMI or MI in patients with an initial diagnosis of UA) and type 4b MI rate were lower in the pretreatment group (1.6% versus 8.5%; p<0.001 and 0.3% versus 2.8%; p=0.016, respectively). After adjusting for covariates, pretreatment was associated with a lower incidence of ischaemic events (OR 0.35; 95% CI [0.135–0.928]; p=0.035), whereas it was not associated with bleeding events (OR 3.68; 95% CI [0.427–31.651]; p=0.236). In addition, a lower estimated glomerular filtration rate and active malignancy were associated with bleeding events, while chronic ischaemic heart disease was associated with ischaemic events in these patients.22 These findings should be considered exploratory and used to generate hypotheses, and should not be used to inform clinical decision-making without confirmation from RCTs.

In summary, the decision to pretreat patients with NSTE-ACS should be individualised. Real-world practice may also involve treatment delays that are longer than those reported in RCTs, and pretreatment may have a role if the time to CAG is prolonged.23 To support this process, we have identified different patient profiles: those who may benefit, those who may be harmed and situations in which pretreatment should be avoided:

• Patients who may benefit from pretreatment: those presenting with NSTE-ACS without diagnostic uncertainty in whom CAG is planned >24 hours.

• Patients who may be harmed by pretreatment: those with suspected alternative diagnoses, such as acute aortic syndromes, pulmonary embolism or stroke, or who have a high bleeding risk.

• When to avoid pretreatment: patients in whom CAG is planned within <24 hours or who have a high likelihood of requiring cardiac surgery that could be delayed if pretreatment is administered.

We developed an algorithm (Figure 1) to help clinicians select those patients who may benefit from pretreatment administration, depending on CAG accessibility and other clinical features.

Figure 1: Antiplatelet Pretreatment in Non-ST Segment Elevation Acute Coronary Syndrome.

*Consider acute aortic syndrome, pulmonary embolism and stroke. †Diffuse ischaemia in ECG, diabetes and coronary angiography. CABG = coronary artery bypass grafting; CAG = coronary angiography; NSTE-ACS = non-ST-elevation acute coronary syndrome.

Discussion

Clinical guidelines base pretreatment recommendations on the planned timing to undergo CAG, considering antiplatelet pretreatment when early CAG (performed within 24 hours of admission) is not available.24 RCTs have shown a lack of benefit of pretreatment with a P2Y₁₂ inhibitor in reducing ischaemic events in patients presenting with ACS.7,8 However, the time from P2Y₁₂ inhibitor loading dose to CAG was about 2 hours and 4.3 hours in the ISAR-REACT 5 and the ACCOAST trials, respectively. This does not give enough time to assess the hypothetical benefit of pretreatment in reducing ischaemic events and, furthermore, cannot be extrapolated to the usual clinical practice in centres that do not have rapid access to a cath lab.7,8 The DUBIUS trial, with a median time to CAG of 23.3 hours, was prematurely interrupted, showing no differences in ischaemic events and bleeding events between the pretreatment group that was given ticagrelor and the non-pretreatment group.21 In contrast, we found a reduction in the overall ischaemic events in patients who received pretreatment. We observed a significant decrease in the rate of stent thrombosis and a reduction in MI before CAG in the pretreatment group.22

Regarding stent thrombosis, it is a rare but dramatic complication associated with MI and cardiac death. Stent thrombosis mechanisms are related to intracranial pressure techniques, such as stent malapposition and underexpansion. Some authors consider that prevention, including the use of pretreatment with a P2Y₁₂ inhibitor, is the only effective treatment for this severe form of coronary stent failure.23 Our results, showing a significant reduction of stent thrombosis in the pretreatment group, support this hypothesis. Interestingly, the percentage of ischaemic events did not differ depending on whether CAG was delayed beyond 24 hours.

Moreover, we did not find a higher rate of bleeding events in the pretreatment group, except in patients in whom CAG was deferred more than 24 hours. Our results could be explained by the longer times between the diagnosis of NSTE-ACS and the performance of the CAG in our study, where the time from P2Y₁₂ inhibitor loading dose to CAG was over 24 hours in 64.8% of patients. This fact is that this is representative of daily clinical practice, not only in centres that have limited access to the cath lab, but also in many hospitals during weekends and non-working days.22 In fact, in a recently published prospective NSTE-ACS Spanish registry where the pretreatment rate was 69.7%, only 37.8% of the patients had an early CAG, and there was a low level occurrence of cardiovascular and bleeding events.25

The NSTE-ACS ESC clinical guidelines point out that routine pretreatment may delay CABG and may be deleterious for a relevant proportion of patients with diagnoses other than NSTE-ACS, such as acute aortic syndromes, pulmonary embolism or intracranial bleeds.26 On the one hand, in our study, we registered only one case of acute aortic syndrome in the non-pretreatment group. Of note, all patients included in our registry were assessed by a cardiologist and a bedside echocardiogram was performed. This factor may explain our low rate of misdiagnosis of NSTE-ACS with other clinical conditions that may present with chest pain, in which pretreatment may be associated with severe complications. On the other hand, recent data from the RAPID CABG trial show that an early surgical strategy, 2–3 days after ticagrelor cessation, was non-inferior in incurring severe or massive bleeding compared to delaying surgery until 5–7 days.18 In our study, all patients in whom CABG was planned remained stable, and none of them required emergency surgery. We found a median time from CAG to CABG of over 15 days. Surgery delay could not be attributed to the antiplatelet pretreatment but to the need for a pre-surgical study and approval by the reference surgical centre. This surgery delay could be explained by the lack of a local cardiac surgical team in our centre.

Current ACS ESC clinical guidelinesdo not differentiate between UA and NSTEMI in the antiplatelet treatment recommendations.26 Since the era of high-sensitivity cTn, the proportion of patients classified with MI has increased, with a corresponding reduction in the diagnosis of UA.27 Patients with UA generally present with a lower baseline ischaemic risk compared with those with MI. In this context, the effects of antiplatelet pretreatment may differ between these two clinical presentations; however, current evidence is insufficient to support differential treatment strategies. Adequately powered RCTs would be required to clarify whether such differences exist and whether they are clinically relevant.

In contrast to the ongoing controversy surrounding antiplatelet pretreatment, other pharmacological strategies in ACS have shown more consistent benefit when administered early. In particular, high-dose statin loading prior to PCI has been associated with a reduction in periprocedural myocardial injury and improved clinical outcomes. A meta-analysis by Borovac et al. demonstrated that early administration of high-dose atorvastatin or rosuvastatin in ACS patients undergoing PCI significantly reduced the incidence of periprocedural MI, with a favourable safety profile.28 These findings suggest that, unlike antiplatelet pretreatment – where the balance between ischaemic and bleeding risk is highly dependent on context – statin pretreatment may provide more consistent benefit across different clinical scenarios. This contrast underscores the need for a tailored approach to pharmacological pretreatment strategies for patients with NSTE-ACS.