Early P2Y12 Inhibitors Escalation in Primary PCI Patients: Insights from the RENOVAMI Registry

Abstract Background Early escalation from clopidogrel to new generation P2Y12 inhibitors is common practice in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Real-world data about this strategy, however, are limited. Methods From 2012 to 2015, 1,057 consecutive STEMI patients treated with pPCI in an Italian hub-and-spoke network were prospectively included in an observational registry (RENOVAMI, ClinicalTrials.gov Identifier: NCT01760382). We compared the prevalence, predictive factors and in-hospital outcomes of patients escalated to a new generation P2Y12 inhibitor within the first 24 hours from pPCI with those continuing on admission antiplatelet therapy. Results In the first 24 hours after pPCI, 165 patients (15.6%) were escalated from clopidogrel to a new generation P2Y12 inhibitor, while de-escalation to clopidogrel was occasional (19 patients, 1.8%) and switch between new generation P2Y12 inhibitors was rare (8 patients, 0.8%, all from ticagrelor to prasugrel). Drug eluting stent use (adjusted odds ratio [OR], 2.19, 95% confidence interval [CI], 1.55–3.08, p = 0.0002) and impaired renal function (adjusted OR, 0.19, 95% CI, 0.05–0.77, p = 0.02) were the only independent predictive factors for the decision to escalate. After adjustment for potential confounders, escalation did not predict in-hospital outcomes, whereas the overall use of new generation P2Y12 inhibitors was correlated with a better in-hospital survival (adjusted hazard ratio, 0.47, 95% CI, 0.25–0.91, p = 0.03). Moreover, escalation did not influence bleeding rates. Conclusions In this prospective registry of STEMI patients treated with pPCI and contemporary antiplatelet therapy, early escalation to a new generation P2Y12 inhibitor appeared safe and did not significantly affect in-hospital bleeding rates.


Introduction
Dual antiplatelet therapy (APT), combining aspirin with a P2Y12 inhibitor, is a cornerstone of primary percutaneous coronary interventions (pPCI). After over a decade of clopidogrel monopoly, more potent new generation agents like prasugrel 1 and ticagrelor 2 have been introduced into clinical practice, with strong levels of evidence in the latest European and American guidelines. 3,4 The simultaneous availability of these drugs, however, may lead to potentially hazardous combinations in daily practice. 5 In particular, the difficulty to harmonize protocols between hub and spoke hospitals and the uncertainties regarding antiplatelet drug pre-treatment, reflected in the latest European guidelines, 6 has led to the common practice of escalation from clopidogrel to a new generation P2Y12 inhibitor during, or just after, pPCI. 7 The pros and cons of this strategy, however, still represent a matter of discussion. Indeed, the PLATO trial allowed for open-label clopidogrel administration before randomization, 2 whereas the TRITON-TIMI 38 study excluded clopidogrel pre-treated patients. 8 Pharmacodynamics 9 and post-marketing registry [10][11][12][13][14][15][16][17][18][19] data support the feasibility of APT escalation, although at the cost of increased bleeding risk. 20 Of note, these data mainly refer to non-ST-elevation myocardial infarction (NSTEMI) patients escalated to prasugrel, whereas very limited data exist regarding ST-elevation myocardial infarction (STEMI) patients escalated to ticagrelor.
On this background, the aim of our study was to quantify the phenomenon of early (within 24 hours from pPCI) escalation from clopidogrel to a new generation P2Y12 inhibitor in a prospective, observational registry and to investigate the in-hospital outcomes associated with this therapeutic strategy.

Population and Endpoints
The RENOVAMI ("REgister of Myocardial Infarction Patients Treated by the NOVAra STE-MI Network," ClinicalTrials.gov Identifier: NCT01760382) is a prospective, observational, registry enrolling STEMI patients in the hub-and-spoke pPCI network of the Oriental Piedmont (Italy). This network is made by three spoke hospitals (Borgomanero, Verbania, Domodossola) which transfer STEMI patients to the hub hospital of Novara. Moreover, the Territorial Emergency System triages patients from the territory and transports STEMI patients directly to the hub. The network collects patients from most of the population of the Oriental Piedmont region. RENOVAMI is endorsed by the Piedmont section of the Italian Council of Cardiology Practice (CFC Piedmont).
From the RENOVAMI population, we evaluated a cohort of consecutive STEMI patients undergoing pPCI between January 2012 (date since ticagrelor was first available in the network) and December 2015. STEMI was diagnosed according to standard criteria. 4 Patients were treated according to usual practice and pPCI performed using standard techniques. 6 The only exclusion criterion was the admission to the hub more than 12 hours after symptoms onset. A team of research nurses collected and entered clinical data in a dedicated database, with a particular attention to the detailed recording of the antiplatelet and antithrombotic treatments. The antithrombotic strategy and the initial P2Y12 inhibitor choice, along with the subsequent confirmation or change of hospital and pre-discharge APT, were at discretion of the treating physicians. We prospectively registered in-hospital adverse events, such as death, nonfatal myocardial infarction (MI), definite or probable stent thrombosis, urgent revascularization, stroke and bleeding events according to the Bleeding Academic Research Consortium (BARC) criteria. 21 A local Adjudicating Committee, formed by the Heads of the Cardiology Department, Coronary Care Unit and Catheterization Laboratory of the hub hospital, reviewed the medical records to adjudicate outcomes, resolving divergences by consensus.

Statistical Analysis
The primary focus of our analysis was the comparison of patients escalated from clopidogrel to a new generation P2Y12 inhibitor within the first 24 hours from pPCI (early escalation APT [EE-APT] group) with those continuing on the admission APT during the first 24 hours after pPCI (continuing admission APT [CA-APT] group). Categorical data are presented as counts and percentages, continuous data with normal and skewed distribution as means AE standard deviation (SD) and medians with interquartile range, respectively.
The Kolmogorov-Smirnov test was used to assess normality, and Student's or Mann-Whitney U tests were applied to unpaired comparisons. The chi-square and Fisher's test were applied to categorical variables. We employed logistic regression to identify the predictors of an early ATP escalation. We entered covariates significantly associated with the ATP escalation at a significance level of p-value of < 0.1 en bloc into a model. We tested potential interactions between covariates excluding those affected by multicollinearity. overall use of new generation P2Y12 inhibitors was correlated with a better in-hospital survival (adjusted hazard ratio, 0.47, 95% CI, 0.25-0.91, p ¼ 0.03). Moreover, escalation did not influence bleeding rates. Conclusions In this prospective registry of STEMI patients treated with pPCI and contemporary antiplatelet therapy, early escalation to a new generation P2Y12 inhibitor appeared safe and did not significantly affect in-hospital bleeding rates. Results were reported as odds ratios (ORs) with 95% confidence intervals (CIs) and the final model was tested with the Hosmer-Lemeshow goodness-of-fit test.
We tabulated Kaplan-Meier survival curves for in-hospital adverse events (death, non-fatal MI, stent thrombosis, BARC 2-3 bleeding) comparing survival with the log-rank test. Subsequently, we built proportional hazards Cox models for each in-hospital event (death, re-infarction, stent thrombosis and bleeding), with assignment to each group (EE-APT and CA-APT) as a stratum. We entered covariates with p < 0.1 at univariate comparison into the models en bloc, testing potential interactions between covariates and excluding those affected by multicollinearity. Results were reported as hazard ratios (HR) with 95% CI.
As a further confirmation of our results, we compared the EE-APT group with a 1:1 propensity score-matched population of patients selected from the CA-APT group. In total, we selected 18 clinical and angiographic variables potentially conditioning APT escalation to calculate propensity scores (age, male sex, body mass index, admission from a spoke hospital, symptoms to reperfusion time, hypertension or hypotensive therapy, type 2 diabetes or anti-diabetic therapy, dyslipidaemia or lipid-lowering therapy, tobacco use, peripheral vascular disease, glomerular filtration rate 30 mL/min, anterior STEMI, baseline left ventricular ejection fraction, previous MI, PCI or coronary artery bypass graft, clopidogrel pre-procedural load, multi-vessel and/or left main disease and drug-eluting stent [DES] deployment). A greedy, Mahalanobis distance 1:10 within-propensity score calipers (width of 0.20 of the standard deviation of the logit of the propensity score) matching was used. We considered standardized differences of the mean < 10% as indicators of good balance in the matched samples.
All tests were two-tailed. We considered statistical significance for p-values of < 0.05. Statistical analyses were performed using SPSS for Windows (version 16.0; SPSS Inc., Chicago, Illinois, United States) and NCSS 8 (NCSS, Kaysville, Utah, United States). The study was designed and conducted in accordance with the principles of the Declaration of Helsinki and was conducted according to the guidelines of the local institutional review board regarding non-interventional registries. All patients gave a written informed consent before enrolment.

Patient Population
We describe the study population enrolment with drug treatment patterns in ►Fig. 1 and demographic characteristics in ►Table 1. We enrolled 1,057 consecutive STEMI patients treated with pPCI. The large majority received aspirin at the first medical contact (922 patients, 87.2%), while 107 patients (10.1%) were on chronic aspirin treatment. The initial P2Y12 inhibitor was clopidogrel in 543 patients (51.4%), ticagrelor in 485 patients (45.9%) and prasugrel in 29 patients (2.7%). In 676 patients (64.0%), a P2Y12 inhibitor was given prior to cath laboratory admission and coronary angiography (in 370 patients, 35.0%, clopidogrel and in the remaining 306, 28.9%, a new generation P2Y12 inhibitor). In 381 patients (36.0%), the P2Y12 inhibitor was added after coronary angiography (in 153 patients clopidogrel and in 228 patients a new generation P2Y12 inhibitor).

Other Clinical and Angiographic Characteristics of the Study Population
We summarized clinical and angiographic characteristics of the study population in ►Table 1. In comparison with the CA-APT group, EE-APT patients were younger and more frequently males. In the EE-APT group, we also observed a lower prevalence of hypertension and impaired renal function. A significantly lower mean thrombolysis in myocardial infarction (TIMI) risk score compounded the globally more favourable thrombotic risk profile of the EE-APT patients. These differences disappeared in the propensity score-matched population (►Table 1). On the other hand, the EE-APT group showed a more favourable haemorrhagic risk profile, with more frequent use of radial access and of bivalirudin as procedural anticoagulant, and lower rates of glycoprotein IIb/IIIa inhibitors use (►Table 1). A lower CRUSADE mean score in the EE-APT patients highlighted this trend.
Patients of the EE-APT group were treated more often with a DES (►Table 1). The clinical decision to escalate APT was influenced by DES implantation, which was an independent predictive factor for escalation from clopidogrel to a new generation P2Y12 inhibitor in the logistic regression analysis (adjusted OR, 2.19, 95% CI, 1.55-3.08, p < 0.0001, ►Table 2). The presence of an impaired renal function, conversely, was an independent predictor of continuing on the admission APT (adjusted OR, 0.19, 95% CI, 0.05-0.77, p ¼ 0.02, ►Table 2).

Procedural, Laboratory and Clinical Outcomes
EE-APT patients showed angiographic outcomes similar to the CA-APT group. In particular, post-procedural TIMI flow and troponin levels were similar (►Table 3). Haemoglobin  BARC type 2 to 3 bleeding rates were similar in both groups (►Table 3, ►Fig. 2A). Intracranial bleeding was rare, with only two cases, all in the CA-APT group (►Table 3). In-hospital death was more frequent in the CA-APT group (65, 7.3% vs. 1, 0.6%, p < 0.002, ►Table 3, ►Fig. 2B). Finally, in-hospital nonfatal MI or acute/sub-acute stent thrombosis rates were similar in the two groups (►Table 3, ►Fig. 2C and D). Similar results were obtained comparing EE-APT patients with propensity score-matched patients from the CA-APT cohort (►Table 3). Kaplan-Meier curves confirmed these results, with a lower inhospital mortality for the EE-APT patients (log-rank test p ¼ 0.016, ►Fig. 2B) and absence of significant differences in BARC 2 to 3 bleedings (►Fig. 2A), in-hospital non-fatal MI (►Fig. 2C) and in-hospital stent thrombosis (►Fig. 2D). However, the Cox proportional hazard model, adjusting for covariates, did not confirm the better in-hospital survival of the EE-APT group (►Table 4). Among the model covariates, baseline left ventricular ejection fraction showed an independent positive correlation with in-hospital survival, whereas age, diabetes and impaired renal function negatively affected this endpoint. Of note, in this multivariate analysis, the overall administration of a new generation P2Y12 inhibitor emerged as being independently associated with a better in-hospital survival (HR, 0.47, 95% CI, 0.25-0.91, p ¼ 0.03, ►Table 4).

Finally, the Cox proportional hazard model confirmed the safety of EE-APT strategy in terms of haemorrhagic complications, showing no increase in BARC 2 to 3 bleedings (►Table 4).
On the other hand, female sex, age, impaired renal function, peri-procedural use of glycoprotein IIb/IIIa inhibitors, femoral access and intra-aortic balloon pump resulted as independent predictors of in-hospital BARC 2 to 3 bleeding, whereas left ventricular ejection fraction and a body mass index of > 30 kg/ m 2 resulted as independent protective factors (►Table 4).

Discussion
Our registry demonstrates that an early escalation (within 24 hours) from clopidogrel to a more potent APT (mostly ticagrelor) is a frequent and common practice in a real-world, "hub-and-spoke" STEMI network. This practice appears safe, as does not seem to be associated with an increased haemorrhagic or ischemic risk.
We also observed that DES use (as opposed to pPCI with bare metal stents [BMS]) had a significant influence on physicians' decision to escalate APT, overshadowing the ischemic and bleeding risk assessment. Finally, overall treatment with a new generation P2Y12 inhibitor (as opposed to clopidogrel) was associated with an independent mortality benefit after multivariate adjustment, replicating in a registry the findings of PLATO and TRITON-TIMI 38 randomized studies. 22 P2Y12 inhibition is a therapeutic cornerstone in STEMI treatment, as platelet activation plays a key role in the pathogenesis of this condition. 23 Before the availability of new generation P2Y12 inhibitors, no study had convincingly demonstrated a significant effect of the timing of clopidogrel treatment on in-hospital outcomes. 24,25 When prasugrel and ticagrelor were introduced in clinical practice, pharmacodynamic studies suggested a potential advantage in escalating from maintenance clopidogrel therapy. [26][27][28] However, more recently, a randomized comparison of ticagrelor given as ambulance pre-treatment or at the time of PCI has substantially failed to clarify the picture. 29 Thus, in clinical practice, the contemporary availability of clopidogrel, prasugrel and ticagrelor has led to conflicting therapeutic combinations 7,15,30 and the harmonization of therapeutic antiplatelet protocols has proven an elusive goal, especially in complex clinical settings such as hub-and-spoke STEMI networks.
Under these circumstances, an early escalation from clopidogrel to a more potent APT (before coronary angiography, or immediately after PCI) has become common practice, 7,15,30 possibly due to the high chances of encountering clopidogrel resistance, 24,31,32 and the low probability of emergency surgical revascularization in these patients. Pharmacodynamic studies have shown that this practice results in rapid enhancement of platelet inhibition, using either ticagrelor or prasugrel. 7,[26][27][28] It should also be noted that the practice of an early (within 24 hours from admission) escalation to a novel APT can be considered relatively different from a later (> 24 hours) escalation. Indeed, whereas a delay in escalating the APT might favour a better patient's clinical evaluation, the same practice may also keep the patient undertreated during the most highrisk period for stent thrombosis and, in general, for ischemic complications.

Comparison with Previous Studies: Incidence and Predictors of P2Y12 Inhibitor Escalation
Whereas several previous studies have described in-hospital P2Y12 inhibitor escalation in unselected acute coronary syndrome (ACS) populations, no specific data focused on STsegment elevation (STE)-ACS and on early APT escalation have been published so far. In general, a change of P2Y12 inhibitor has been reported in around 5 to 50% of ACS patients, and factors commonly associated with change included highrisk angiographic characteristics (thrombotic, long and bifurcating lesions), STE-ACS presentation, in-hospital events, young age, high body mass, male gender 7,20,30 and, in American registries, also being employed and having private health insurance coverage. 11 Similar to the previously cited studies, we observed that P2Y12 inhibitor escalation is not rare, with a 15.6% rate in our sample. Our cohort of escalated patients showed, in comparison with those continuing on clopidogrel, lower TIMI and CRUSADE scores, and a higher rate of radial access and of DES implantation. After multivariate analysis, only the use of DES resulted to be independently associated with P2Y12 inhibitor escalation, confirming data from other recent Italian and American registries. 5,33 Conversely, an interaction between early P2Y12 inhibitor escalation and the peri-procedural use of bivalirudin or glycoprotein IIb/IIIa inhibitors was not seen in our sample, while in the GRAPE study, bivalirudin use during pPCI was a strong predictor of subsequent transition from clopidogrel to prasugrel or ticagrelor. 10 Overall, our report that DES implantation predicts P2Y12 inhibitor escalation, whereas TIMI and CRUSADE risk scores do not, is probably explained by the timing of decision to escalate APT (before or just after pPCI), with the interventional cardiologist focused on the perceived risk of stent thrombosis. It should also be noted that several variables included in the CRUSADE score (e.g., haematocrit or glomerular filtration rate) might not have been available at the time of pPCI.

Comparison with Previous Studies: Outcome of Escalated APT
Information about the safety of an escalation to a novel and more potent P2Y12 inhibitor was first available from the PLATO study, in which 44% of the overall ticagrelor cohort had received open-label clopidogrel before randomization. 2 The STEMI subgroup analysis of the PLATO, however, while reporting results consistent with the overall PLATO trial, did not evaluate in detail the effect of pre-randomization, open-label clopidogrel on both safety and efficacy endpoints. 22 In Italy, the EYESHOT registry reported a 9.6% rate of in-hospital escalation to prasugrel or ticagrelor in invasively treated ACS patients, but information regarding clinical outcomes were not reported. 5 In the FAST-MI French registry, Schiele et al reported that in-hospital escalation from clopidogrel to prasugrel (ticagrelor was not yet available) occurred in 16.5% of the 4,169 included patients (mostly > 48 hours after admission). In this study, the escalation was associated with more inhospital thrombotic events (cardiovascular [CV] death, reinfarction, stroke, stent thrombosis) in a propensity-paired matched analysis of 625 patients, as compared with patients who remained on clopidogrel (3.5% vs. 0.8%, p ¼ 0.0005). 19 In another report from the TRANSLATE-ACS study, Bagai et al reported $10% in-hospital escalation from clopidogrel to new generation P2Y12 inhibitor, with no significant increase of bleeding or other adverse effects, 33 although no separate results for STE-ACS and non-STE (NSTE)-ACS were provided. In the large MULTIPRAC registry, focused on STE-ACS, Clemmensen et al reported a rate of in-hospital escalation from clopidogrel to prasugrel comparable to our data. 12 Whereas APT escalation had neutral effect on major adverse CV events and death rate, the relative risk of bleeding of patients with APT escalation was increased, nearing significance. 12 The GRAPE registry, in a population of 1,794 ACS patients treated with PCI, demonstrated a 35.5% in-hospital APT change rate, in the majority consisting in escalation from clopidogrel to ticagrelor (50.3%) or prasugrel (40.1%). Of note, more BARC type 1, type 2 and any type events and fewer major adverse CV events were seen in the APT escalation group versus clopidogrel-only administration. 10 Finally, a recent meta-analysis, compounding these data with other small registries, 13,15,16,18 hypothesized that P2Y12 inhibitor escalation could be more effective than both strategies of continuing on clopidogrel or upfront initiation of a new generation P2Y12 inhibitor, even if at the price of greater haemorrhagic risks. 20 Our results also complement those of the recently published SWEDEHEART study, 34 in which the prescription at discharge of ticagrelor versus clopidogrel was compared in 45,073 patients with an ACS. In this nationwide registry, ticagrelor was associated with a significantly reduced rate of the primary composite endpoint of death from any cause, MI or stroke (24month adjusted HR, 0.85, 95% CI, 0.78-0.93) and a lower overall mortality was also seen in the ticagrelor group (adjusted HR, 0.83, 95% CI, 0.75-0.92). As pointed out in the accompanying editorial, 35 in-hospital mortality was not included in the main analysis, a limitation that might also have influenced the results, with the sickest patients dying and being excluded. The fact that in our cohort of higher risk patients sampled during the highest risk period (limited to STE-ACS in the acute phase, no excluded patients) use of new generation P2Y12 inhibitors (largely ticagrelor) independently predicted in-hospital survival with similar direction and magnitude as in the 24-month follow-up SWEDEHEART registry, provides further support regarding the consistency of this effect.
Finally, our data confirm the result of the recently published SCOPE study, an Italian multi-centre registry aimed to evaluate the incidence and 1-month outcome of P2Y12 receptor inhibitors escalation in ACS patients undergoing PCI. 36 Similar to our study, APT escalation in the SCOPE population (limited to 2-3% in a mixed ACS population) was not associated to an excess of ischemic or bleeding events.

Limitations of the Study
The observational design of our study suffers from the limitations typical for non-randomized studies. Difference in mortality, bleeding and other endpoints may be affected by selection bias, even after careful adjustment for demographic and clinical confounders. Thus, our registry results should be considered confirmatory and/or hypothesis generating. External validation in registries, however, is increasingly considered essential to generalize the results of randomized trials, potentially hampered by strict inclusion and exclusion criteria. 37 Second, our registry enrolled a single-centre, even if large, patient cohort and could be subjected to bias regarding ethnicity, environment and local clinical practices. In particular, our population shows a high rate of BMS implantation, which reflects a local precautionary practice of avoiding widespread use of DES in pPCI due to both lack of conclusive data about DES safety in STEMI patients and economic reasons. This practice was subsequently abandoned, as data concerning safety in STEMI interventions accumulated. Thus, caution should be taken before extrapolating the results of our study to the general population.
Third, most of the APT changes observed in the study population were escalations from clopidogrel to ticagrelor in the first 24 hours after PCI. Rates of de-escalation from a new generation APT to clopidogrel or change from a new generation APT to another were minimal (1.8 and 0.8%, respectively), and probably reflect a selection bias (patients treated with successful pPCI in the same hub centre with narrow window of observation). As the randomized TOPIC 38 and Thrombosis and Haemostasis Vol. 118 No. 5/2018 TROPICAL-ACS 39 trials have recently suggested a clinical advantage for APT de-escalation a few weeks after PCI for ACS, and data from the PRAGUE 18 study in STEMI patients support such clinical practice, 40 it would be desirable to gain more data about de-escalation, which may have important clinical and economic implications. 41,42 In our registry, the few cases of APT de-escalation or change were all driven by clinical reasons, and the outcome was excellent. Thus, we cannot draw any significant conclusion in support of APT deescalation or change.

Conclusion
In a large "all comers" population of pPCI patients, an early escalation to new generation P2Y12 inhibitors was a common practice. In this clinical setting, P2Y12 inhibitor escalation appeared safe, without evidence of increased bleeding or other adverse clinical events in the patient population examined. Moreover, data from the present registry confirm the association of new generation more potent antiplatelet therapies with lower in-hospital mortality rates.
What is known about this topic?
• Dual antiplatelet therapy, combining aspirin with a P2Y12 inhibitor, is a cornerstone of primary percutaneous coronary interventions but the availability of more potent antiplatelet agents like prasugrel and ticagrelor may lead to potentially hazardous combinations or changes in daily practice. • Pharmacodynamic studies and post-marketing registries support the feasibility of escalation from clopidogrel to ticagrelor, but these data mainly refer to non-ST-elevation myocardial infarction and to escalation from clopidogrel to prasugrel. • Very limited data exist regarding ST-elevation myocardial infarction patients escalated to ticagrelor, with the exception of a large subgroup of the PLATO study, which allowed for open-label clopidogrel administration before randomization.
What does this paper add?
• Data from the RENOVAMI registry demonstrate that the escalation from clopidogrel to a more potent antiplatelet drug within 24 hours following primary PCI is a frequent and common practice in a real-world, "hub-and-spoke" STEMI network. This practice did not seem to be associated with an increased haemorrhagic or ischemic risk. • In the setting of RENOVAMI, the decision to escalate was mainly influenced by the primary PCI features, overshadowing the clinical ischemic and bleeding risk assessment. • In the RENOVAMI population, the overall treatment with a new generation P2Y12 inhibitor (as opposed to clopidogrel) was associated with an independent mortality benefit, replicating the findings of PLATO and TRITON-TIMI 38 randomized studies.

Funding
None.