The study population consisted of consecutive NSTEMI patients undergoing PCI with stable (variation ≤ 20%) or falling pre-PCI cardiac troponin (cTn) levels, who were prospectively included in the ongoing multicenter AMIPE observational registry (NCT03883711) in centers in the Emilia-Romagna region, metropolitan area of Bologna, Italy, between January 1, 2017 and April 30, 2023.

The diagnosis of NSTEMI was based on the Fourth Universal Definition of Myocardial Infarction, and patients were managed according to existing ESC guidelines at the time of inclusion.1,2,15,16 Until August 2020, NSTEMI patients with an indication for invasive management were recommended to receive a P2Y12 inhibitor as early as possible after diagnosis and prior to CAG.16 From September 2020 onward, updated ESC guidelines on non–ST-elevation acute coronary syndromes (NSTE-ACS) recommended initiating a P2Y12 inhibitor only after the coronary anatomy was defined.1 Consequently, patients enrolled between January 2017 and August 2020 who actually received a P2Y12 inhibitor before CAG were assigned to the pretreatment group, while those enrolled between September 2020 and April 2023 who did not receive pretreatment were assigned to the no pretreatment group.

Exclusion criteria for this analysis included: unavailability of serial cTn measurements; elevated pre-PCI cTn levels with a steadily increasing trend (unstable, variation> 20%); patients already treated with P2Y12 inhibitors before admission; timing of P2Y12 inhibitor administration not aligned with ESC guideline recommendations at the time (eg, patients not pretreated prior to the 2020 NSTE-ACS guidelines or pretreated after their release); and age <18 years.

The study protocol was approved by the institutional review board (registration number: 600/2018/Oss/AOUBo) and adhered to the principles of the Declaration of Helsinki. All patients were informed about their participation and provided consent for the anonymous publication of scientific data. Details regarding data collection and cTn assays can be found in the methods of the supplementary data.

Pretreatment was defined as the administration of a P2Y12 inhibitor prior to CAG, as opposed to administration in the catheterization laboratory after CAG.5,17 Pretreated patients received either clopidogrel (300-600 mg loading dose, followed by 75 mg daily) or ticagrelor (180 mg loading dose, followed by 90 mg twice daily). Based on TRITON-TIMI 38 and ACCOAST trials, prasugrel was not used as part of the pretreatment strategy.6,18 Following PCI, switching from a P2Y12 inhibitor to another was left to clinical judgment and carried out in accordance with guideline recommendations and the Academic Research Consortium consensus on antiplatelet therapy modulation by escalation or de-escalation.1,2,16,19

The primary efficacy endpoint of the study was type 4a MI. According to the Fourth Universal Definition of Myocardial Infarction, type 4a MI was diagnosed in the presence of a post-PCI cTn increase greater than 20%, with an absolute postprocedural value of at least 5 times the 99th percentile upper reference limit, within 48hours of the procedure, in patients with elevated baseline cTn who had stable (variation ≤ 20%) or falling cTn levels, plus one of the following: a) new ischemic electrocardiogram changes; b) development of new pathological Q waves; c) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology; and d) angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, loss of a side branch, slow flow, thrombus, or distal embolization.15

The primary safety endpoint was clinically relevant in-hospital bleeding, defined as Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 (methods of the supplementary data).20

Events were adjudicated by 2 independent experts, who were blinded to the pretreatment group and who reviewed all clinical, laboratory, and instrumental data from the index hospitalization. In cases of disagreement, a third reviewer made the final decision.

The composite secondary endpoints were: a) in-hospital net adverse clinical events (NACE), including all-cause mortality, reinfarction (types 1, 2, and 4), nonfatal ischemic stroke, and BARC types 2, 3, and 5 bleeding; and b) 30-day NACE, including all-cause mortality, reinfarction (type 1, 2, and 4), nonfatal ischemic stroke, hospitalization for heart failure (HF), and BARC types 2, 3, and 5 bleeding.

Patients were followed up after discharge through outpatient visits and/or telephone contact using a standard questionnaire. Only the first event was included in the calculation of NACE. Definitions of each individual component of the secondary endpoints are provided in the methods of the supplementary data.

The normality of the distribution of continuous variables was assessed using the Shapiro-Wilk test. Variables with a normal distribution are reported as mean±standard deviation (SD), while nonnormally distributed variables are presented as the median [interquartile range]. Comparisons between continuous variables were performed using the Student t-test or Mann-Whitney U test, depending on the distribution. Categorical variables are summarized as counts and percentages, and between-group comparisons were made using the Pearson chi-square test or Fisher exact test, as appropriate.

Unadjusted and adjusted odds ratios (ORs) for the primary efficacy and safety endpoints were calculated using logistic regression analyses. A sensitivity analysis was also performed to compare the primary endpoints among patients undergoing an early (< 24hours) vs delayed (≥ 24hours) invasive strategy. The following variables, selected a priori based on prior studies and clinical relevance, were included for adjustment: age, sex, diabetes mellitus, hypertension, dyslipidemia, smoking history, prior MI, prior PCI, history of cerebrovascular disease, history of peripheral arterial disease, chronic obstructive pulmonary disease, chronic kidney disease, GRACE (Global Registry of Acute Coronary Events) score (categorized as <140 or ≥ 140), complex PCI, complete revascularization, arterial access site (radial or femoral), and hemoglobin at admission. Variables with a P <.1 in univariate analysis were included in multivariable models. No stepwise selection procedure was applied. Collinearity among covariates was assessed using the variance inflation factor, and only variables with a variance inflation factor <2.5 were included in the final models. Kaplan-Meier curves and the log-rank test were used to evaluate survival functions for NACE at the 30-day follow-up.

All statistical analyses were conducted using Stata V.17 (StataCorp, United States)) and R V.4.2.1 (R Foundation for Statistical Computing, Austria). A 2-sided P <.05 was considered statistically significant.

Baseline demographic and clinical characteristics are presented in Table 1. The mean age of the study population was 70.5±11.5 years, with 27% being women. There were no significant differences between the 2 groups in terms of age, sex, cardiovascular risk factors, medical history, clinical presentation, comorbidities, or medications at admission. Pretreatment mostly consisted of clopidogrel (91.2%). The median pretreatment time was 18.3 [11.4-37.7] hours.

Angiographic and procedural characteristics are shown in Table 2. Time from symptom onset to PCI was similar between the groups, and radial access was the most widely used vascular approach in both, with no differences. Patients in the pretreatment group received a higher mean number of stents (≥ 3 stents: 26.8% vs 20.6%; P=.013), although the number of treated atherosclerotic lesions was comparable between groups (≥ 3 lesions: 26.9% vs 22.8%; P=.098). Conversely, patients in the no pretreatment group more frequently underwent PCI with drug-coated balloons (12.6% vs 2.7%; P <.001) and PCI involving plaque modification techniques (5.8% vs 1.9%; P <.001). Additionally, cangrelor was used exclusively in the no pretreatment group (0% vs 4.1%; P <.001). However, there were no significant differences between the groups regarding complex PCI rates or the achievement of complete revascularization at discharge.

Secondary prevention therapies at discharge were comparable between the 2 groups (Table 2). Notably, clopidogrel was more frequently prescribed at discharge in the pretreatment group (79.8% vs 45.7%; P <.001), whereas potent P2Y12 inhibitors were more commonly used in the no pretreatment group (36.7% vs 17.1%; P <.001 for ticagrelor and 16.9% vs 2.3%; P <.001 for prasugrel). During hospitalization, in the pretreatment group, 87 patients (11.8%) underwent escalation from clopidogrel to a potent P2Y12 inhibitor, whereas only 6 patients (0.8%) underwent de-escalation from a potent P2Y12 inhibitor to clopidogrel.

In the overall population, type 4a MI was observed in 191 patients (15.2%). Table S1 presents the angiographic findings associated with type 4a MI. There was no significant difference in the incidence of type 4a MI between patients pretreated with P2Y12 inhibitors and those loaded with P2Y12 after CAG (15.9% vs 14.2%; P=.398).

In contrast, in-hospital bleeding was more common in the pretreatment group than in the no pretreatment group (7.7% vs 3.9%; P=.006) (figure 3A). This difference was mainly due to a higher incidence of BARC type 2 bleeding events, primarily related to the vascular access site (4.5% vs 2.1%; P=.028). No significant differences were observed in BARC type 3 bleeding events (3.2% vs 1.8%; P=.104). No BARC type 5 bleeding events were recorded during hospitalization in the entire study population.

Figure 3.

In-hospital ischemic and bleeding events by pretreatment strategy. A: rates of type 4a MI, in-hospital BARC types 2, 3, and 5 bleeding, and composite NACE during hospitalization. B: in-hospital incidence of individual NACE components. BARC, Bleeding Academic Research Consortium; MI, myocardial infarction; NACE, net adverse clinical events.

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In the multivariable logistic regression model, pretreatment was not associated with a reduced risk of the primary efficacy endpoint (OR, 1.15; 95% confidence interval [95%CI], 0.84-1.58; P=.398; adjusted OR [aOR], 1.08; 95%CI, 0.78-1.51; P=.638). Conversely, pretreatment was associated with an increased risk of the primary safety endpoint (OR, 2.06; 95%CI, 1.24-3.56; P=.007; aOR, 2.17; 95%CI, 1.28-3.82; P=.005) (table 3, tables S1-S3). Among pretreated patients, escalation to a more potent P2Y12 inhibitor did not significantly affect the risk of in-hospital bleeding (table S4).

When the population was stratified according to the timing of the invasive strategy, pretreatment was not associated with a reduction in type 4a MI in either the early (< 24hours) or delayed (≥ 24hours) groups. However, a significant and independent increase in the risk of in-hospital bleeding was observed in both subgroups (tables S5, S6).

Table 4 presents the composite secondary endpoints for the overall study population and the 2 treatment groups. During hospitalization, a total of 8 patients (0.6%) died, 195 (15.5%) experienced reinfarction, predominantly type 4a MI (191 out of 195, 97.9%), 6 (0.5%) had an ischemic stroke, and 77 (6.1%) experienced BARC type 2, 3, or 5 events. The composite rate of NACE occurred in 261 patients (20.8%) during the index hospitalization, with a higher incidence in the pretreatment group than in the no pretreatment group (22.8% vs 17.9%; P=.034), mainly due to BARC type 2 bleeding events (figure 3B).

At 30 days of follow-up, there were 11 (0.9%) deaths, 197 (15.7%) reinfarctions, 7 (0.6%) ischemic strokes, 11 (0.9%) hospitalizations for HF, and 115 (9.2%) BARC type 2, 3, or 5 bleeding events. The cumulative incidence of 30-day NACE is illustrated in figure 4. A significantly higher event rate was observed in the pretreatment group (log-rank test P=.012), mainly due to early in-hospital events. Following this initial period, the event curves remained parallel throughout the remainder of the 30-day follow-up.

Figure 4.

Thirty-day cumulative incidence of NACE by pretreatment strategy. Kaplan-Meier curves show higher early event rates in the pretreatment group, mainly due to in-hospital events, with parallel curves thereafter. NACE, net adverse clinical events.

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This study has some limitations that should be acknowledged. First, due to its observational design, the possibility of residual confounding cannot be excluded, despite adjustment through multivariable analysis. Specifically, we could not account for certain unmeasured variables that may have influenced clinical decision-making and outcomes, and therefore the results should be interpreted as hypothesis-generating. To mitigate this limitation, we excluded patients in whom P2Y12 inhibitor administration did not follow the ESC guideline recommendations in effect at the time, as such cases likely reflected individualized clinical reasoning, often based on a perceived imbalance between ischemic and bleeding risks, which could have biased treatment allocation. Furthermore, the analysis was limited to patients with NSTEMI who underwent PCI. However, in clinical practice, at the time the decision to initiate pretreatment is made, it is not yet known whether the patient will actually undergo PCI or not. Lastly, clopidogrel was the preferred agent in the pretreatment strategy; therefore, our findings primarily reflect its effect and may not fully represent the impact of pretreatment with more potent P2Y12 inhibitors. The low rate of escalation to a more potent agent within the pretreatment group further limits the ability to draw firm conclusions regarding alternative pretreatment strategies. However, our study mirrors real-world clinical practice during the time period when the ESC guidelines (2017-2020) supported pretreatment and clopidogrel remained the predominant agent used in many Italian centers.33 This was largely because major trials investigating ticagrelor in the pretreatment setting were still ongoing during that period. Therefore, the role of pretreatment (particularly with more potent or personalized antiplatelet strategies) remains to be better defined and warrants further investigation in adequately powered randomized trials.