In patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS), a routine invasive strategy is recommended since it leads to a reduction in the rate of myocardial infarction (MI), refractory angina, rehospitalization and death. Coronary angiography (CA) can confirm the diagnosis and enable coronary revascularization when required.1–4 However, the optimal timing to perform CA remains undetermined because no significant difference regarding clinical outcomes has been observed in several trials comparing early (<24 h) vs. delayed (24-72 h) strategies, except a trend toward fewer recurrent ischemic events and lower mortality with an early strategy (ES) in higher-risk subgroups.1,2 An ES enables rapid revascularization, preventing acute vessel closure and avoiding recurrent ischemic events, while a delayed strategy (DS) enables initiation of medical therapy to stabilize platelets and reduce thrombus burden, facilitating coronary revascularization.1,2,4

Besides CA, dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 antagonist is the standard of care in these patients.5–7 Pre-treatment (PT) is defined as a strategy in which antiplatelet drugs, usually a P2Y12 antagonist, are given before CA when the coronary anatomy is unknown.6–8 PT was widely used in previous studies, in accordance with the guidelines of the time, with the theoretical advantage of providing more ischemic protection. However, the more recent 2020 European guidelines on the management of NSTE-ACS only recommend PT in patients with NSTE-ACS who are not scheduled to undergo an early invasive strategy and do not have a high bleeding risk (class IIb, level of evidence C).8

In this new era, the restriction of PT may influence the choice of timing between an ES and a DS. To the best of our knowledge, only one trial, Early or Delayed Revascularization for Intermediate and High-Risk Non-ST Elevation Acute Coronary Syndromes (EARLY), has investigated the optimal timing of an invasive strategy in this clinical setting without PT with P2Y12-antagonists.1,9 The present study aims to assess the prognostic value of an ES when no loading dose of a P2Y12 antagonist is given as PT in a Portuguese cohort of NSTE-ACS patients regarding all-cause mortality and rehospitalization for cardiovascular causes at one year.

The importance of our study is related to the significant worldwide burden of NSTE-ACS, which arises not only from the index hospitalization but also from patients’ worse mid- and long-term prognosis compared with ST-elevation acute coronary syndrome, with more frequent recurrent ischemic events and a twofold higher death rate at two years.11

In our study, we observed a trend toward an ES in younger patients with lower prevalence of cardiovascular risk factors and cardiovascular disease, lower Killip class, lower creatinine and higher hemoglobin levels. No significant differences were observed between the two groups regarding coronary anatomy burden or complexity (assessed through the number of diseased vessels and the presence of chronic occlusions). There were no significant differences regarding antiplatelet therapy during hospitalization. The major difference observed was a lower percentage of anti-ischemic therapy in the ES, both during hospitalization and at discharge. Despite a trend toward fewer adverse in-hospital outcomes in the ES, only major bleeding was statistically significant, and this did not affect one-year outcomes.

The European guidelines recommend timing coronary intervention depending on the patient's baseline risk.3,8 An earlier approach provides a rapid diagnosis and mechanical revascularization and shorter hospital stays, despite a potential hazard because of unstable plaques with fresh thrombus. Conversely, a delayed strategy may provide benefits through plaque passivation by optimal medical treatment followed by intervention on more stable plaques, despite a higher risk for events while awaiting intervention.3

The initial phase and evolution of NSTE-ACS is marked by activation of blood platelets and the coagulation cascade, so adequate platelet inhibition and anticoagulation is desirable, especially in patients undergoing PCI.8 According to recent literature, routine PT no longer appears to be appropriate in NSTE-ACS due to an unfavorable risk-benefit ratio, so it is not recommended in patients in whom the coronary anatomy is unknown and an ES is planned.8,9,11–15 For patients with a DS, PT with a P2Y12 antagonist may be considered in selected cases according to the patient's bleeding risk.8 The rationale behind PT was to provide maximum inhibition of platelet aggregation while patients are waiting to undergo CA and to reduce thrombotic complications at the time of PCI, given that even the fastest-acting oral P2Y12 antagonists take at least 30-60 min to achieve maximum platelet inhibition, by which time most PCI procedures have already been completed.1,6–8 In fact, in our study, 11.4% patients were proposed for medical therapy, 1.5% for CABG and 6.1% had normal coronary arteries. In cases in which PT is not administered, patients are not protected pending the invasive procedure and may experience recurrent ischemic events and/or complications, so the optimal timing of the invasive strategy in this specific context is unknown. In our study, we excluded all patients with PT, independently of CA timing. There were no significant differences regarding antiplatelet therapies during hospitalization. Of note, the total number of patients taking each of the P2Y12 inhibitors is higher than 100%, as patients may have switched between two agents during hospitalization. Regarding anticoagulant therapies, the only statistically significant difference was that patients proposed for an ES were more often medicated with unfractionated heparin and less often with fondaparinux, which was to be expected due to the need for constant monitoring of therapeutic values of heparin.

The stipulated timings for coronary intervention are supported by two large trials. The Timing of Intervention in Patients with Acute Coronary Syndromes (TIMACS) and the Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography (VERDICT) trials showed that an ES was not superior to a DS with regard to composite clinical endpoints in NSTE-ACS patients, except for the highest GRACE risk score tertile.1,2,8 Although the mean GRACE score was similar between groups, patients proposed for an ES were younger, with less CKD, and tended to have lower creatinine levels and Killip class, so we can infer that in the DS group, CA was delayed until clinical stabilization, which is in accordance with an observed trend for higher use of diuretics and ventilatory support in this group, or alternatively to patient optimization to prevent contrast nephropathy. Individual trials and meta-analyses were underpowered to detect individual clinical endpoints such as mortality, non-fatal MI or stroke; only recurrent or refractory ischemia and length of hospital stay have been shown to be improved by an ES.2,8,11,16 The LIPSIA-NSTEMI trial concluded that an immediate invasive approach did not offer an advantage over an early (10-48 h) or a selective invasive approach with respect to infarct size as defined by peak CK-MB levels.17 The RIDDLE-NSTEMI trial showed that an immediate invasive strategy was associated with lower rates of death or new MI compared with a delayed (2-72 h) strategy at 30-day follow-up, mainly due to a decrease in the risk of new MI in the pre-intervention period. In one-year follow-up, the rates of death, new MI and recurrent ischemia were similar. At both 30 days and one year, the rates of major bleeding were similar in both groups.18 In our study, adverse in-hospital outcomes were not significantly different between groups, except for major bleeding, which was less prevalent in the ES. In this group, although not statistically significant, transfemoral access, which is known to be associated with more bleeding complications, was used in a lower proportion of patients.8 Even so, in the ACCOAST trial transfemoral access did not significantly increase major bleeding, but transradial access was associated with a reduction in major or minor bleeding.19 Also, patients proposed for an ES presented lower creatinine and higher hemoglobin levels at admission and during hospitalization. The choice and dose of antithrombotic drugs should be carefully considered in patients with kidney dysfunction, as these patients have an increased risk of bleeding. Anemia is also associated with increased mortality, recurrent MI and major bleeding.8 There was a trend toward worse outcomes in the DS group regarding heart failure, shock, ventricular arrhythmias, cardiac arrest, transfusion need and death, which is not surprising since these complications could be associated with delayed revascularization and a greater need for blood transfusion, since these patients more often presented with major bleeding. These endpoints were not individually assessed in previous studies except for heart failure, which, as in our study, showed a trend toward less heart failure hospitalization in favor of an ES (HR 0.78, 95% CI 0.60-1.01) in the VERDICT trial.4 However, these outcomes were not reflected in the one-year individual or composite endpoints of all-cause mortality and rehospitalization for cardiovascular causes, as also shown in previous studies.1,2 In our study, a major difference was observed regarding the higher percentage of anti-ischemic therapy in the DS, namely calcium-channel blockers and nitrates, since the most important concern related to DS is reinfarction and angina recurrence.1,2,4 No difference was observed in beta-blocker use since in clinical practice they are used more often as a neurohormonal therapy rather than as an anti-ischemic, and were thus used similarly in both groups. Discharge medication followed the above-presented trends. The use of antiplatelet, neurohormonal and secondary prevention therapies did not differ between groups, which is also in accordance with a similar mean LVEF between groups. A higher prescription rate of anti-ischemic therapies was observed, following the trend of hospitalization prescription. Although not statistically significant, a higher percentage of incomplete revascularization was observed in the DS, possibly explaining this higher prescription rate.

In the EARLY trial, the only study comparing the two invasive strategies in patients with intermediate- and high-risk NSTE-ACS without PT, a very early (<2 h) versus delayed (12-72 h) invasive strategy was associated with a lower rate of the composite endpoint of cardiovascular death and recurrent ischemic events requiring urgent revascularization, due to a lower rate of total occlusion of the culprit artery at the time of CA. Both strategies had similar safety in terms of bleeding events.9,11 We recognize that the stipulated CA timings were significantly different from those in our study, but we agree there is no advantage in ES regarding mortality, and we cannot properly assess recurrent ischemia since we did not stipulate this single endpoint. In our study, an ES (<24 h) was favored in less complex patients but was not associated with a reduction in adverse in-hospital outcomes except for major bleeding. We assume this may be related to higher hemoglobin levels at admission and during hospitalization and lower use of transfemoral access, although it did not translate into a greater need for blood transfusion or higher mortality. Based on our results, we cannot suggest that delaying CA might be harmful in our patient cohort.

Our study presents some limitations. First, it is a retrospective observational study and thus susceptible to inherent limitations including missing data, partucilarly related to follow-up. Since this is a voluntary registry, it does not represent all the cardiology centers in the country and, even in the centers that do participate, we cannot guarantee that all patients are included. Second, our sample is not large, since we had to exclude many patients who were medicated with PT, reflecting the guidelines of that time. Third, we do not know the proportion of very high-risk patients in our population who could have benefited from an immediate approach. Fourth, there are confounding factors that guided the timing of CA, especially whether the hospital had a catheterization laboratory and if so, whether it was available. Fifth, there were no data regarding adherence to medical treatment after discharge that could influence outcomes, and we were unable to properly assess recurrence of ischemic events.

In patients with higher-risk NSTE-ACS in the absence of PT with a P2Y12 antagonist, an early invasive strategy was not associated with higher in-hospital adverse outcomes or a reduction in the composite of all-cause mortality and rehospitalization for cardiovascular causes at one year.

The authors have no conflicts of interest to declare.