2020 ESC Guidelines on acute coronary syndrome without ST-segment elevation

The 2020 ESC Guideline recommendations are based on the ISAR-REACT 5 trial, which was a comparison of two distinct treatment strategies involving two different drugs [3]. Patients with ACS, including ST-elevation myocardial infarction (STEMI), planned for invasive treatment were randomised to ticagrelor or prasugrel. Patients who were assigned to ticagrelor received the loading dose as soon as possible after randomisation. In the prasugrel group, timing of the initiation of the drug treatment depended on the clinical presentation. In patients with STEMI, prasugrel was administered as soon as possible after randomisation. In patients with NSTE-ACS, the loading dose of prasugrel was postponed until the coronary anatomy was known and before proceeding to percutaneous coronary intervention (PCI). In patients with coronary angiography-confirmed ACS but who were treated conservatively, prasugrel was recommended. Coronary angiography in the NSTE-ACS group was performed within a mean 4 hours after randomisation (personal communication with investigators from the ISAR group).

Although more patients in the ticagrelor group received the study drug initially, at discharge roughly 81% in both groups (STEMI vs non-STEMI (NSTEMI)/unstable angina) were on the assigned P2Y₁₂ receptor inhibitor. Numbers of patients on the study drug in the NSTEMI population were not reported. At 1 year, the ticagrelor-based strategy showed a significantly higher incidence in the composite endpoint of death, MI or stroke (hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.09–1.70, p = 0.006), primarily driven by higher rates of MI. The incidence of major bleeding (Bleeding Academic Research Consortium (BARC) type 3–5) did not differ between the strategies.

The ISAR-REACT 5 trial is a landmark trial and the largest randomised controlled trial (RCT) comparing prasugrel with ticagrelor. However, several comments are to be made on the trial design and results that are relevant for the interpretation of the data. First, instead of a direct comparison between prasugrel and ticagrelor, the comparison is made between treatment strategies including preloading with ticagrelor and no preloading with prasugrel.

Second, approximately 19% of the patients in each strategy group did not receive the randomly assigned trial drug. Of the remaining population, a significant number of patients discontinued study medication: 12.5% in the prasugrel and 15.2% in the ticagrelor strategy group. Such high numbers of discontinuation may have had a major impact on the trial results.

Third, from a pathophysiological view, it is difficult to understand why the ticagrelor treatment led to more ischaemic events when it was given earlier and to more patients than prasugrel. The CHAMPION PHOENIX trial showed that early and potent P2Y₁₂ receptor inhibition results in a significant reduction of stent thrombosis after an intravenous bolus and infusion of cangrelor compared with an oral loading dose of clopidogrel (0.8% vs 1.4%, p = 0.01).[4] The mechanism behind the observed reduction is the swift P2Y₁₂ receptor inhibition with cangrelor, thereby supporting a ‘the sooner, the better’ approach in P2Y₁₂ receptor inhibition. However, this was not the case in the ISAR REACT 5 trial.

In the recent report from the SCAAR database, 64,857 patients were included for analysis. Of these patients, 59,894 received pretreatment consisting mainly of clopidogrel or ticagrelor (1.8% received prasugrel) and 4963 were not pretreated with P2Y₁₂ receptor inhibitors [5]. The analysis showed that pretreatment did not improve survival at 1 month and 1 year but was associated with more in-hospital bleedings (6.0% and 7.5%, respectively, p = 0.02). However, adjusted for age and sex, 30-day mortality was significantly lower with pretreatment (1.4% vs 2.5%, p < 0.001). A policy change in one Swedish region (Västra Götaland County) dictated that pretreatment was not recommended per protocol after 2016. A comparison of the data before and after the policy change showed the same results, albeit a less impressive reduction in in-hospital bleedings (8.5% vs 8.1%, p = 0.006).

Several limitations to the analysis hamper the interpretation of the data. The context is an observational analysis of, nevertheless, an impressive amount of data. Confounding factors and bias are serious concerns despite the fact that the analyses were performed after adjustments for a high number of variables. Furthermore, radial access was significantly lower in patients with pretreatment and could have had a major impact on bleeding events.

With regards to choosing between prasugrel and ticagrelor, the ISAR-REACT 5 trial hints at superiority of prasugrel. However, this is the only large RCT comparing prasugrel and ticagrelor, while in a recent meta-analysis of 12 trials, including all three P2Y₁₂ receptor inhibitors, only ticagrelor was associated with a mortality benefit when compared with clopidogrel [6]. In addition, the recent POPular Age trial showed that patients with NSTE-ACS > 70 years of age who are treated with clopidogrel experience significantly fewer bleeding complications without an increased thrombotic risk compared with ticagrelor or prasugrel [7]. Hence, we support the routine use of prasugrel or ticagrelor and recommend clopidogrel in patients > 70 years of age. Factors to be taken into account in choosing either P2Y₁₂ receptor inhibitor include logistical and patient- and drug-related considerations (one P2Y₁₂ receptor inhibitor for all indications, dosing frequency, side effects, prasugrel contraindicated in stroke patients and no net benefit in elderly).

The working groups recognise the recent data on pretreatment and the choice of P2Y₁₂ receptor inhibitors. Despite the noted limitations of the ISAR-REACT 5 trial and the recent SCAAR database analysis, we do not recommend routine P2Y₁₂ receptor inhibition pretreatment in NSTE-ACS (in line with the 2020 ESC Guidelines) when invasive coronary angiography (ICA) is expected the same day (Fig. 1). However, for patients with established NSTE-ACS who are not scheduled for ICA on the same day but later during the index hospitalisation, the working groups recommend to consider pretreatment with ticagrelor, or clopidogrel in patients > 70 years of age or in patients with a high bleeding risk (Academic Research Consortium for High Bleeding Risk ≥ 1 major or ≥ 2 minor criteria (Tab. 7 of the 2020 ESC Guidelines on NSTE-ACS), or Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score ≥ 25).

We endorse the recommendations in the 2020 ESC Guidelines that immediate (analogous to STEMI management) invasive strategy is necessary in very high-risk patients, given the poor prognosis if left untreated. The presence of ≥ 1 very high-risk criterion justifies immediate ICA or transfer to a PCI centre (Fig. 1).

The 2020 ESC Guidelines give a Class I, LoE A recommendation for ICA within 24 h in the presence of an established NSTE-ACS diagnosis or > 1 high-risk criterion (Fig. 1) and same-day transfer to a PCI centre for such patients. In previous reports, we have communicated our appraisal of and thoughts on the early invasive strategy and same-day transfer recommendations in the 2015 NSTE-ACS Guidelines [15, 16]. Since the publication of these guidelines, three new RCTs have been published focusing on the timing of angiography within the routine invasive strategy.

For daily clinical practice, it is noteworthy to realise that the interpretation of trial data is limited by several factors. The first limitation is how the time to ICA is measured. In most trials, this is based on the time from randomisation and not the time from symptom onset or hospital admission. Second, treatment strategy trials comparing an early with a delayed treatment strategy use different timing definitions.

The EARLY trial was an open-label RCT that compared immediate (median time between randomisation and angiography 0 h) versus early angiography (median time 18 h) in 741 NSTE-ACS patients (median Global Registry of Acute Coronary Events (GRACE) risk score 121 vs 123). The primary endpoint rate (composite of cardiovascular death and recurrent ischaemic events at 1 month) was significantly lower in the immediate group (4.4% vs 21.3%, HR 0.20, p < 0.001). However, this difference was driven by a reduction in the number of symptoms of ischaemia with dynamic electrocardiogram changes (2.9% vs 19.8%, p < 0.001). No difference was observed in rate of cardiovascular death or MI.

Although smaller in size but quite similar in timing strategy, the OPTIMA‑2 trial did not show any benefit at 1 year follow-up of an immediate (< 3 h) ICA strategy compared with an early one (< 24 h). The trial was terminated early for futility after 249 NSTE-ACS patients were randomised [17].

The RIDDLE-NSTEMI study, a small RCT with 323 NSTEMI patients, compared an immediate (median 1.4 h) with a delayed ICA strategy (median 61.0 h). The rate of death, new MI or recurrent ischaemia was lower in the immediate-intervention group at both 30 days (6.8% vs 26.7%, p < 0.001) and 1 year (15.4% vs 33.1%, p < 0.001). This difference was mainly driven by a reduction in MI rate [18, 19].

In the VERDICT trial, 2147 patients with a clinical suspicion of NSTE-ACS were included [20]. The primary endpoint of all-cause death, non-fatal recurrent MI, hospital admission for refractory ischaemia or hospital admission for heart failure did not differ between the early invasive group (median 4.7 h) and the delayed invasive group (median 61.6 h). However, among patients with a GRACE risk score > 140, a reduction in the primary endpoint was observed (HR 0.81, 95% CI 0.67–1.01, p-value for interaction = 0.023); however, which separate endpoints drove this outcome difference were not reported.

The 2020 ESC Guidelines recommend to perform ICA < 24 h in patients presenting after resuscitation for cardiac arrest without ST-segment elevation or cardiogenic shock. However, this strategy is mainly derived from observational studies. On the other hand, in the recently published COACT trial, patients who had been successfully resuscitated after out-of-hospital cardiac arrest and had no signs of STEMI, a strategy of immediate angiography was not found to be better than a strategy of delayed angiography with respect to overall survival at 90 days [22]. Median time from randomisation to coronary angiography in the delayed angiography group was 119 h in this study. For this reason, the Dutch ACS working group does not recommend ICA < 24 h in the context of resuscitation after cardiac arrest and NSTE-ACS. It is justifiable to await neurological recovery before performing ICA.