P2Y12 receptor inhibitors in patients with non-ST-elevation acute coronary syndrome in the real world: use, patient selection, and outcomes from contemporary European registries

Abstract

Background

Antiplatelet therapy is recommended in all patients with acute coronary syndrome (ACS) regardless of their revasculari­zation strategy. The current guidelines of the European Society of Cardiology (ESC) on the management of patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) recommend aspirin for all patients without contraindications at an initial oral loading dose of 150–300 mg, and at a daily oral maintenance dose of 75–100 mg, long-term, regardless of treatment strategy.¹ Further, as part of dual antiplatelet therapy (DAPT), a P2Y12 receptor inhibitor should be added to aspirin and maintained over 12 months, unless there are contraindications such as excessive risk of bleeding (Class I level A recommendation). A 60 mg loading dose of prasugrel, followed by 10 mg/day maintenance doses, is recommended in patients who are proceeding to percutaneous coronary intervention (PCI) if there is no contraindication (Class I level B), but not in patients in whom coronary artery anatomy is not known (Class III level B). A 180 mg loading dose of ticagrelor, followed by 90 mg twice daily, is recommended in the absence of contraindi­cations for all patients at moderate-to-high risk of ischaemic events, regardless of initial treatment strategy and including those pre-treated with clopidogrel (Class I level B). Finally, a 300–600 mg loading dose of clopidogrel, followed by 75 mg daily maintenance doses, is recommended for patients who cannot receive ticagrelor or prasugrel or who require oral anticoagulation (Class I level B).¹ Because prasugrel and ticagrelor have higher antithrombotic potency and proven superiority in outcome trials [(as in ST-segment elevation myocardial infarction (STEMI)], these drugs are preferred over clopidogrel for patients presenting with NSTE-ACS.²

Registries and other observational studies are an important source of information on the efficacy and safety of medication under clinical practice conditions. The ‘Platelet Inhibition Registry in ACS EvalUation Study’ (PIRAEUS) group is composed of owners or principal investigators of national or multinational European ACS registries.³ The initiative aims to integrate the wide array of data generated by individual European ACS registries to gain a comprehensive overview on the efficacy and safety of the P2Y12 receptor inhibitors used for the treatment of this condition. We have described the participating registries in detail, in narrative and tabular form, in an earlier review,³ and also provided an overview on the outcomes of STEMI patients.⁴

This report presents data regarding NSTE-ACS patients in various European registries, with focus on the use of P2Y12 receptor inhibitor-based DAPT, patient selection, and outcomes.

Methods

In order to obtain a comprehensive contemporary overview of appropriate registries, the following selection criteria were applied: European multicentre or single-centre observational studies on real-life experience in the management of ACS within the last 5 years; large unselected patient cohorts; availability of data on PCI; availability of data on management during initial hospitalization for ACS; availability of follow-up data on outcomes (death, cardiac events, bleedings); previous publication of data in peer-reviewed journals and/or reporting of unpublished data, with information on outcomes of drug treatment of patients with P2Y12 receptor inhibitors at least until discharge from the hospital; and willingness of registry owners to take part in PIRAEUS and share data. Indeed, some of the registries started earlier than 5 years ago, but still provided data on clopidogrel-based DAPT therapy.

Of the registries fulfilling the above criteria and whose owners were contacted, a total of 17 registries were analysed. They are described in detail in a recent review paper including setting, aims and scope, and selected baseline characteristics of the included patients.³ Data on the completeness of values (i.e. considering rates of missing data) could not be obtained from the various registries.

Registry owners were asked to provide detailed current data on (i) the full ACS cohort, as well as for the STEMI and NSTE-ACS groups separately (irrespective of treatment) and (ii) subgroups of patients treated with the P2Y12 receptor inhibitors prasugrel, ticagrelor, or clopidogrel. Only aggregate data in tabular format were received, as the pooling of individual patient data was not covered by patients' informed consent and/or was not possible due to ownership of data issues. The data collection sheet specified time points at discharge from hospital, at 30 days, at 180 days, and at 1 year. Endpoints of interest were all-cause death, cardiovascular death, stroke, recurrent myocardial infarction (MI), and repeat PCI (for efficacy), as well as life-threatening/major and minor bleeding events (for safety). For bleeding events, the definition used by each registry was requested from the registry owners, but was not always available or sometimes had changed during the time of the registry data collection.

Registry owners were asked to provide percentages for the various events together with event number and patient number at the various time points. Data were not adjusted or weighted.

Statistical analysis

For the current paper, patients with NSTE-ACS diagnosis at admission were selected for analysis. Patients from 10 registries were included for statistical analysis. The data at the study level (not individual patient level) were used by a statistician to calculate event rates for the total cohort and by DAPT regimen specifically for each registry separately, with two-sided 95% confidence intervals (CI) using the Clopper–Pearson interval. Cohorts comprising fewer than 100 patients were excluded from analyses because of the small number of events. Event rates were defined as cumulative incidence rates. Event rates and 95% CI for each cohort were shown using forest plots. Bubble plots were used to confirm the relationships between age and event rates whereby the size of the bubble depended on the number of patients in the respective subgroup. These analyses were sent to the individual registry holders for them to confirm the data, enter corrections, and, if indicated, provide additional data.

A description of the registries that provided NSTE-ACS data is given in the Supplementary material online.

Results

In total, 10 registries provided specific information about NSTE-ACS patients (Table 1). Of these, six provided specific data on P2Y12 DAPT (AAPCI/ADAPT, AMIS Plus, ATACS, DIOCLES, SCAAR, and SPUM). All reported data on clopidogrel, five reported data on prasugrel (all with the exception of DIOCLES), and three reported data on ticagrelor (AAPCI/ADAPT, AMIS Plus, and SCAAR). The remaining four registries (BLITZ-4, CZECH-2, FAST-MI, and Newcastle) had only data on NSTE-ACS patients overall, but no data on P2Y12 treatment groups.

Characterization of the non-ST-elevation acute coronary syndrome cohorts

Total patient numbers in the different registries ranged between 586 (CZECH-2) and 52 319 (SCAAR). Mean patient age in the registries varied between 65 (AAPCI, SPUM, Newcastle) and 70 years (CZECH-2), with the other registries in between. Males were more frequent than females in all registries. Diabetes mellitus was frequently noted as a co-morbidity, in the range of 18.9 (Newcastle 2010) to 40.5% (CZECH-2). The prevalence of previously diagnosed coronary artery disease (CAD) varied substantially from 28.6 (SCAAR) to 100% [ATACS, with this rate due to the fact that CAD was an inclusion criterion] and prior MI rates ranged from 17 (AAPCI) to 30.2% (Newcastle 2012). Prior stroke ranged from 2.7 (SPUM) to 9.4% (SCAAR).

Chronic aspirin treatment rates at the time of the NSTE-ACS index event refer to a mixed population of individuals who had a first NSTE-ACS event and those who were previously known to have CAD. Only the latter group had an indication for chronic antiplatelet treatment. Unsurprisingly, given the substantial variations in patient characteristics, rates of chronic aspirin treatment as long-term treatment for CAD (unrelated to the index ACS event) varied between 30 (FAST-MI) and 52.8% (ATACS). Chronic treatment with P2Y12 inhibitors was reported in seven registries, with the highest rate seen in ATACS (24.9%).

Pre-hospital use of P2Y12 inhibitors (pre-treatment) was reported in CZECH-2 (14.7% of patients received clopidogrel), FAST-MI 2010 (20% clopidogrel, 1% prasugrel), SCAAR (48.9% clopidogrel, 0.6% prasugrel, 16.8% ticagrelor), and SPUM (14.5% clopidogrel, 0.5% prasugrel, 0.4% ticagrelor).

In hospital, almost all patients received loading doses of P2Y12 inhibitors for the treatment of the index NSTE-ACS event. Switching between drugs, most frequently from clopidogrel to prasugrel, was not widespread (0% in AAPCI to 11% in FAST-MI, for switching from clopidogrel to prasugrel). After the NSTE-ACS event, almost all patients in the registries received aspirin plus a P2Y12 receptor inhibitor (DAPT).

Time from first medical contact to PCI was reported in five registries, ranging from 4.6 (AAPCI/ADAPT) to 27.4 h (FAST-MI 2010). The great majority of patients received coronary angiography (66% in CZECH-2, 79.6% in DIOCLES, and 100% in AAPCI and ATACS, the latter being related to the inclusion criteria), and a substantial proportion received PCI (47% in CZECH-2 to 98.4% in SPUM, the latter being again rather high, mostly related to inclusion criteria). Where reported, radial access for PCI varied between 26.5 (ATACS) to 81–83% (Newcastle).

Outcomes

For various ischaemic and bleeding outcomes, event rates are presented descriptively for the NSTE-ACS cohort in total (Table 2) and by P2Y12 inhibitor (Table 3). Further, they are plotted against mean age of the patients in the various registries (Figure 2 and bubble plots in the Supplementary material online).