According to the European Society of Cardiology (ESC) guidelines, patients with myocardial infarction (MI) and ST-segment elevation (STEMI) are eligible for emergency reperfusion therapy, whereas those with non-ST-segment elevation MI (NSTEMI) require further risk stratification; thus, the qualification for invasive diagnosis and treatment is delayed [1]. The STEMI-NSTEMI paradigm is based on the observation that ST-segment elevation (STE) on the electrocardiogram (ECG) in the majority of patients with MI is associated with acute total occlusion (TO) of the infarct-related artery (IRA), while subtotal IRA occlusion leads mostly to ST-segment depression and negative T-waves on the ECG. However, when qualification for emergency reperfusion therapy is based on ECG criteria, we lose approximately 25% of patients with acute TO of the IRA who do not present STE [2]. NSTEMI patients form a very heterogeneous group, and ESC guidelines recommend urgent coronary angiography only for those with life-threatening ventricular arrhythmias, resistant angina pectoris and haemodynamic instability. These conditions may be accompanied by total IRA occlusion, but this is not always the case. Thus, percutaneous coronary intervention (PCI) may be deferred in a substantial subset of NSTEMI patients with TO of the IRA, which may result in delayed myocardial salvage and poor cardiovascular outcomes [3].

This study aimed to identify the key points of clinical characteristics, course of treatment and outcome of patients with NSTEMI with TO of the IRA (NSTEMI_TO) by comparison with the two most outlying groups: patients with NSTEMI and a non-occluded coronary artery (NSTEMI_NTO) and patients with STE and an occluded IRA (STEMI_TO).

We analysed the data of patients with MI assembled within 48 months (2014–2017) into the Polish National Database of Invasive Coronary Procedures (ORPKI), coordinated by Jagiellonian University Medical College and endorsed by the Association of Cardiovascular Interventions of the Polish Cardiac Society [4]. All clinical data were collected by the operator and then uploaded into the database after each procedure. The diagnosis of NSTEMI or STEMI, recognition of the IRA, all clinical decisions during the coronary invasive procedure and definitions of periprocedural complications were left to the uploading ORPKI operators’ experience and knowledge according to current ESC guidelines.

Acute TO of the IRA was defined in our study as Thrombolysis In Myocardial Infarction (TIMI) 0 flow during coronary angiography in patients with MI [5].

To achieve the aim of the study, we compared 3 groups of patients: NSTEMI_TO, NSTEMI_NTO and STEMI_TO and excluded from the analysis patients with STEMI and non-occluded coronary artery (STEMI_NTO), those without significant coronary artery stenosis, those not treated with PCI and those diagnosed with chronic total occlusion of the IRA. To minimize confounding factors influencing the electrocardiographic presentation of MI, we decided to perform angiographic analysis only for patients with PCI of single native vessel disease.

Our study was an observational, non-experimental, retrospective analysis and was performed in accordance with the relevant guidelines and regulations. Only anonymized data were included in the research analysis, and according to Regulation 2016/679 of the European Parliament and of the Council (EU) from 27 April 2016 on the protection of individuals with regard to the processing of personal data and on the free movement of such data and with art. 9 section 2, this study did not require any additional ethics board approval. All subjects in our study gave informed consent for personal data processing by the Association of Cardiovascular Interventions of the Polish Cardiac Society before percutaneous coronary intervention.

The results of 245,869 coronary angiography procedures performed in patients with MI were entered into the ORPKI registry. After exclusion of patients (a) without significant stenosis of coronary arteries, (b) without occlusion of the IRA in STEMI, (c) without PCI treatment; (d) with chronic total occlusion of the IRA and (e) with multivessel PCI treatment, 131,729 patients who underwent single-vessel PCI constituted the study group. Among them, 65,206 (80.09%) patients with NSTEMI had no TO of the IRA (TIMI > 0), while total occlusion of the IRA (TIMI = 0) was found in 16,209 (19.91%) patients with NSTEMI and 50,314 (48.21%) with STEMI. The study flowchart is shown in Fig. 1.

To the best of our knowledge, we conducted the largest single-study analysis dedicated to the NSTEMI_TO phenomenon (16,209 patients). The previous meta-analyses on this topic included 10,415 patients (7 studies) and 17,212 patients (25 studies) with NSTEMI_TO [6, 7].

Our study results suggest that NSTEMI_TO may be considered an intermediate condition between NSTEMI_NTO and STEMI_TO. However, the following features make the NSTEMI_TO group exceptional:

Numerous studies have shown the differences in the baseline clinical presentation between patients with STEMI and NSTEMI. In the OPERA Registry, correlates of mid- and long-term mortality were similar for NSTEMI and STEMI patients [8]. This leads to the conclusion that we should not consider STEMI and NSTEMI to be two different diseases but rather as an ischaemic continuum due to subtotal or total occlusion of the coronary artery with different ECG manifestations [9, 10]. Total occlusion of the IRA can occur in STEMI and NSTEMI patients. Numerous studies have compared acute total occlusion of the IRA with non-total occlusion of the IRA but mostly within the NSTEMI subset of patients [11, 12]. Our goal was to compare three manifestations of acute MI: NSTEMI_NTO, NSTEMI_TO and STEMI_TO; thus, for the first time, we compared three groups instead of two.

Considering the baseline characteristics, patients with NSTEMI_TO in our study constituted an intermediate group between NSTEMI_NTO and STEMI_TO. In comparison to STEMI_TO patients, NSTEMI_TO patients were older and had a higher prevalence of cardiovascular risk factors and chronic diseases. When comparing NSTEMI_TO to NSTEMI_NTO, the patients were younger and had a lower prevalence of cardiovascular risk factors and chronic diseases. These findings are in accordance with other studies, where patients with NSTEMI, in comparison to STEMI, were older and more often had chronic diseases [13, 14]. According to the baseline characteristics, our NSTEMI_TO group was definitely closer to the STEMI_TO group than to the NSTEMI_NTO group. Patients with STEMI_NTO were excluded due to high group heterogeneity. To summarize the results of pre-hospital management, participants with NSTEMI_TO were generally less frequently considered candidates for direct transportation to the Cath lab than STEMI_TO patients (9.41% vs 25.69%). Additionally, ischaemia time, i.e., time from pain to balloon inflation, as well as time from FMC to balloon inflation, were longer in the NSTEMI_TO group than in the STEMI_TO group. The duration of ischaemia is a major determinant of infarct size and subsequent mortality [3, 15]. In almost all studies included in the meta-analysis of Khan et al., patients with NSTEMI_TO had a mean delay to invasive procedure longer than 24 h and, in comparison to patients with NSTEMI_NTO, an increased risk of both major adverse cardiovascular events and mortality [6]. The mean time from pain to inflation in our study was approximately 30 h (data not presented) and was similar to that presented by Khan et al. [6].

The time from pain to FMC was the longest in the NSTEMI_TO group and was even longer than that in the NSTEMI_NTO group. In the NSTEMI_TO group, patients postponed the decision to seek medical help, probably because of younger age (than in the NSTEMI_NTO group) and a lack of previous experience with stenocardial pain. The longer time delay from pain to FMC in NSTEMI_TO than in STEMI_TO may be explained by the lower severity of symptoms due to the lower degree of ischaemia in the case of LCx occlusion.

The time delay to achieve the opening of the occluded artery in the NSTEMI_TO group in comparison to the STEMI_TO group was amplified during in-hospital management, which was noticeable as the pronounced difference (median time from FMC to balloon inflation was almost three times longer in the NSTEMI_TO group).

In contrast, patients with NSTEMI_TO in comparison to those with NSTEMI_NTO were previously considered candidates for invasive management. The potential explanation is the more severe clinical presentation caused by total artery occlusion. The higher frequency of cardiac arrest before admission and more advanced Killip class in the NSTEMI_TO group than in the NSTEMI_NTO group in our study confirm this hypothesis. Similar results were obtained by Shin et al. in the COREA‐AMI Registry [16]. Another commonly used parameter of time delay in MI that influences prognosis is the percentage of patients who undergo PCI within 120 min since the onset of symptoms [3, 15, 17]. In the study of Terkelsen et al., approximately 50% of STEMI patients had balloon inflation within 120 min [17]. In our study, almost 70% of STEMI_TO patients, but only 25% of NSTEMI_TO patients, had PCI within 120 min.

Approximately 20% of our NSTEMI patients had acute coronary artery occlusion, which is less than that previously reported by Khan (25.5%) and Hung (34%) [6, 7]. This difference may be explained by the fact that we used a stricter definition of NSTEMI_TO, analysing only patients with TIMI 0 flow, whereas Khan and Hung included patients with TIMI 0–1. Previous studies examining the distribution of occluded arteries in NSTEMI_TO patients indicated that the RCA or LCx was the artery most responsible for NSTEMI_TO [6, 7]. In our study, we found that the LCx was the most typical localization of the culprit lesion responsible for MI in the NSTEMI_TO group. The distribution of the IRA differs between trials when STEMI cases are compared to NSTEMI, i.e., in STEMI, there is underrepresentation of the LCx as the IRA [18], whereas in NSTEMI_TO, occlusion of the LAD occurs the least often [7, 19]. We must acknowledge that ECG has unsatisfactory sensitivity for diagnosis of coronary artery total occlusion, especially in posterolateral distribution [20].

In our study, patients with NSTEMI_TO demonstrated a more severe clinical condition on admission than those with NSTEMI_NTO (more advanced Killip class, higher prevalence of death and cardiac arrest prior to admission or during an invasive procedure, no-reflow phenomenon), which is in concordance with prior studies showing that the prognosis of patients with total occlusion without ST-segment elevation is worse than that of NSTEMI_NTO patients [6, 7]. We confirmed that the outcome after PCI (lower frequency of achieving TIMI 3 and higher frequency of TIMI 0) in NSTEMI_TO patients is even inferior to that in STEMI_TO patients. A possible explanation is that unrecognized acute coronary artery occlusion is associated with high morbidity and mortality [15], and the outcome in this group is worse than that in the group that received timely revascularization [11, 21].

In summary, we must acknowledge that the identification of NSTEMI_TO patients prior to coronary angiography remains challenging. Among the NSTEMI patients in our study, younger patients with a lower frequency of comorbidities (which is not a typical NSTEMI group characteristic) should be highly suspected of having acute total occlusion of the infarct-related artery if they present severe symptoms on admission (i.e., advanced Killip class, pre-hospital cardiac arrest, long pain duration), which enables us classify them into the very high-risk group according to the most current 2020 ESC NSTEMI guidelines [22]. To select high-risk patients who require urgent coronary intervention, we should exert additional effort and use all available methods, i.e., careful clinical assessment, ECG analysis including additional ECG leads (i.e., V7-V9) and patterns that are highly suggestive of TO of the IRA (extensively described in the supplementary table of 2020 ESC NSTEMI guidelines), specific risk score calculation and echocardiography examination with wall motion and strain analysis [22].

Approximately one-fifth of NSTEMI patients had acute total coronary artery occlusion (NSTEMI_TO). According to the clinical characteristics, NSTEMI_TO seems to be an intermediate condition between NSTEMI_NTO and STEMI_TO. However, it should be emphasized that NSTEMI_TO patients have the longest time delay to PCI and the worst final result of PCI, which can be at least partially explained by the most common location of the culprit lesion in the LCx. Therefore, patients with NSTEMI should undergo strict evaluation for signs indicating possible acute total coronary artery occlusion (e.g., younger age, lower cardiovascular risk, fewer chronic diseases but more severe clinical presentation on admission) and should undergo comprehensive ECG and echocardiographic assessment to prevent a time delay to and improve the results of revascularization.