The RENAMI (REgistry of New Antiplatelet therapy in patients with Myocardial Infarction) is a retrospective, observational, multicenter, and international registry involving the voluntary participation of 11 centers from 6 European countries (Spain, Italy, Switzerland, Greece, Serbia, and the United Kingdom). The objective of this unfunded registry is to improve our understanding of ischemic and hemorrhagic complications in patients with ACS treated with DAPT with prasugrel or ticagrelor. All participating centers are third-level university hospitals with a 24-hour catheterization laboratory and internal medical records on ACS. From January 2012 to January 2016, each participating center consecutively enrolled patients with ACS and coronary stenosis ≥ 50% in the left main coronary artery and ≥ 70% in the rest of the coronary tree who underwent percutaneous coronary intervention (PCI). Additionally, these patients were discharged with DAPT comprising aspirin (100mg/24h) plus prasugrel (10mg/24h) or aspirin (100mg/24h) plus ticagrelor (90mg/12h). The design of the RENAMI registry and the inclusion and exclusion criteria are described in detail in the supplementary material. The variables included in the RENAMI registry are listed in Table 1 of the supplementary material and the participating centers in Table 2 of the supplementary material. The ACS was defined as ST-segment elevation myocardial infarction (STEMI), non-STEMI, and unstable angina according to the definitions accepted in clinical practice guidelines.8–10 Acute myocardial infarction (AMI) was diagnosed according to the universal definition of AMI.11 Unstable angina was diagnosed through the presence of its classic symptoms or objective evidence of myocardial ischemia in a stress test, together with detection of a culprit lesion on coronary angiography.

For the purpose of RENAMI, a database was designed to retrospectively include information on clinical, analytical, and angiographic variables, as well as data related to mortality and ischemic and hemorrhagic events. RENAMI registry analyses were carried out by 2 researchers from the coordination center (E. Abu-Assi and S. Raposeiras-Roubín). All procedures were performed according to the provisions of the Declaration of Helsinki and with the approval of the local ethics committees.

Of the 4424 patients in the RENAMI registry, the present study excluded those with no information on the type of stent implanted (n=297) and those with a first-generation drug-eluting stent (DES) (n=4). Thus, the final study cohort comprised 4123 patients.

The study endpoint was ST in patients receiving DAPT with ticagrelor or prasugrel, considering only thrombosis confirmed according to the definition of the Academic Research Consortium (angiographic or pathologic confirmation).12 STs were classified as early (occurring in the first month after PCI) or late (occurring between 1 and 12 months after PCI). In addition, early STs were subdivided into acute (first 24hours) and subacute (between 1 and 30 days). Stent thromboses occurring in the acute phase before the administration of prasugrel or ticagrelor (in the case of patients initially treated with DAPT with clopidogrel) were excluded from the event file because the objective was to study the ST rates of patients on DAPT with ticagrelor or prasugrel. Follow-up was censored at ST occurrence (n=41), death (n=72), DAPT suspension/withdrawal within 1 year after the PCI (n=382), or at 12 months of follow-up.

Analysis of the composite endpoint of death and/or ST is shown in Table 3 of the supplementary material. This secondary analysis was performed due to the small number of ST events.

Data on vital status (alive or dead) and event (ST) were obtained from hospital clinical data records and administrative records (vital statistics records, hospital discharge data, and emergency department data). When information was missing, patients or their relatives or primary care physicians were contacted by telephone.

According to a report of the European Society of Cardiology and the European Association of PCI,13 all stents succeeding the first-generation stents were considered new-generation DESs; the first-generation stents were the sirolimus-eluting CYPHER, paclitaxel-eluting TAXUS, and zotarolimus-eluting Endeavor. Thus, “new-generation DESs” refer to the everolimus-eluting XIENCE V (Abbott Vascular, Illinois, United States) and Promus (Boston-Scientific, Massachusetts, United States), zotarolimus-eluting Resolute (Medtronic; Minnesota, United States), sirolimus-eluting Yukon DES (Translumina GmbH; Hechingen, Germany), and biolimus-eluting Nobori (Terumo, Japan) and Biomatrix (Biosensors, Singapore). Bioabsorbable stents were also considered new-generation DESs.

Continuous variables are presented as mean±standard deviation. Discrete variables are expressed as percentages. Continuous variables were compared with the Student t test and discrete variables with the chi-square test or Fisher exact test, as necessary.

To study ST predictors, a competing risk analysis was performed with a Fine and Gray regression model,14 with death considered the competing event. All variables associated (P <.10) with ST in univariable analysis were included in a multivariable model. There was no evidence of noncompliance with the proportional hazards assumption, verified by studying the interaction of covariables in the models with time: in the absence of statistical significance (P> .05), it can be deduced that the proportional hazards assumption has not been violated. To account for the potential heterogeneity arising from the inclusion of centers from different European countries, an interaction term was included in the final model through a nonhierarchical grouping analysis by group (country). The predictive accuracy of the final model was calculated via the C-statistic, using the c-index function of the “pec” extension for R. Results are expressed as the subhazard ratio (sHR) with its corresponding 95% confidence interval (95%CI).

Cumulative incidence function curves were plotted for ticagrelor and prasugrel after estimation of the cumulative incidence function curve using a flexible parametric model for competing risks,15 adjusted for the variables associated (P <.10) in the univariable analysis with a higher incidence of ST (Table 1): age, previous myocardial infarction, STEMI presentation, left ventricular ejection fraction <40%, and serum creatinine.

The composite analysis of death and ST (Figure of the supplementary material) was performed using a Cox model; ticagrelor and prasugrel curves were compared by a log-rank test and the restricted mean survival time method.16

Statistical analyses were performed with Stata 13.1 and R version 3.3.1. P <.05 was considered statistically significant.

The clinical characteristics of the study population are shown in Table 1 according to use of ticagrelor and prasugrel. The 2 drugs clearly display different prescription patterns.

Regarding DAPT, 63.2% of patients (n=2604) received ticagrelor and 36.8% (n=1519) received prasugrel. The mean follow-up time was 10.9±2.9 months; 82.9% of patients completed 12 months of follow-up with DAPT (94.4%> 6 months, 88.4%> 9 months).

Bare-metal stents were used in 29.2% of the patients (n=1205) and new-generation DESs in the remaining 70.8% (n=2918). Only 4.0% of patients treated with DESs received bioabsorbable stents (n=117): 24.8% received zotarolimus-eluting stents; 24.4%, everolimus-eluting; 12.8%, biolimus-eluting; and 3.1%, sirolimus-eluting. The remaining 30.9% received new-generation DESs (nonbioabsorbable) but the type was not specified.

Of the 4123 patients with ACS treated with DAPT with ticagrelor and/or prasugrel, 41 experienced ST in the first year (1.10/100 person-years, 95%CI, 0.81-1.49) (Figure 1); 58.6% of the STs were early, occurring in the first month (36.6% in the first 24h and 22.0% between the first day and the first month), whereas 41.5% were late, occurring between the first month and the first year.

Figure 1.

Cumulative incidence of ST in the first year in patients with acute coronary syndrome on DAPT with aspirin plus prasugrel or ticagrelor. 95%CI, 95% confidence interval; DAPT, dual antiplatelet therapy; ST, stent thrombosis.

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Regarding stent type, there were no significant differences in the cumulative incidences of ST between bare-metal stents (0.83%; 95%CI, 0.43-1.60) and new-generation DESs (1.20%; 95%CI, 0.85-1.70). Bioabsorbable stents were implanted in 127 patients; of these, only 1 experienced a ST in the first year.

The association between the clinical variables analyzed and a higher incidence of ST in the first year in the univariable analysis is shown in Table 2. Multivariable analysis identified the following independent predictors of ST in the first year: age, STEMI presentation, previous AMI, and serum creatinine (Table 3). The discriminative ability of the final model was good, with a C-statistic of 0.70. The same variables were significant in the univariable analysis if it was limited to ST in the first month (Table 2). However, after multivariable adjustment, the only independent predictors of early ST were age, STEMI presentation, and serum creatinine (Table 3).

The cumulative incidence of ST occurring in the first year was 1.21% (95%CI, 0.53-1.56) with ticagrelor and 0.90% (95%CI, 0.84-1.76) with prasugrel. There were no significant differences between the 2 drugs regarding the risk of ST in the first year (ticagrelor vs prasugrel, sHR=1.29; 95%CI, 0.67-2.45; P=.445). The adjusted curves of the cumulative incidence of ST estimated with ticagrelor and prasugrel in the first year are shown in Figure 2. There were also no significant differences between ticagrelor and prasugrel in terms of ST in the first month (0.7% vs 0.4%; P=.144).

Figure 2.

Cumulative incidence of ST estimated according to the type of antiplatelet agent, after adjustment for age, previous myocardial infarction, presentation as ST-segment elevation acute myocardial infarction, left ventricular ejection fraction <40%, and serum creatinine. 95%CI, 95% confidence interval; CIF, cumulative incidence function curve; DAPT, dual antiplatelet therapy; ST, stent thrombosis.

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No associations were found for ST risk with ticagrelor vs prasugrel, bare-metal stents (ticagrelor vs prasugrel, sHR=1.40; 95%CI, 0.35-5.56; P=.635), or new-generation DESs (sHR=1.23; 95%CI, 0.58-2.58; P=.587).

The 2 main limitations of this study lie in its retrospective design and in the sample size. The study suffers from the same limitations as other retrospective studies. Specifically, because it is not randomized and ticagrelor and prasugrel use are at the discretion of the treating physician, comparisons between these drugs or between bare-metal stents and DESs should be interpreted with caution due to the possible interaction of unmeasured confounding variables. For example, RENAMI does not provide information on angiographic characteristics possibly critically involved, particularly in early ST, such as TIMI (Thrombolysis In Myocardial Infarction) flow after PCI, stent diameter/length, residual untreated coronary dissection, and high residual thrombotic load. There is also no information on how many patients underwent intracoronary imaging after PCI to verify proper stent expansion. In addition, the sample size of the study, with 4123 patients, is insufficient to reach robust conclusions due to the low frequency of the study event (ie, ST), as already mentioned. However, given the high lethality posed by ST and the limited scientific evidence available on this event in patients on DAPT with ticagrelor or prasugrel, the present study—even with a more descriptive than analytical approach—has scientific value in hypothesis generation for subsequent scientific studies (clinical trials or meta-analyses).