Safety of Percutaneous Coronary Intervention Without P2Y12 Inhibitor Pretreatment From a Cohort of Unselected Patients

Abstract: Objectives. Recent studies have challenged systematic pretreatment with a P2Y₁₂ inhibitor before percutaneous coronary intervention (PCI) in elective and non-ST segment elevation myocardial infarction (NSTEMI) patients. The aim of this study was to assess outcomes after performing PCI immediately after coronary angiography with an exclusive “on-the-table” P2Y₁₂ inhibitor loading dose, by evaluating ischemic and bleeding complications in unselected patients. Methods. Consecutive patients admitted for elective PCI or NSTEMI were included in this two-center, prospective, observational study, and received a P2Y₁₂ inhibitor after coronary angiography when PCI was decided. The primary composite endpoint was first occurrence of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or use of bail-out glycoprotein IIb/IIIa inhibitors at 30 days after PCI. Stent thrombosis and bleeding criteria (Bleeding Academic Research Consortium [BARC]) were evaluated. Results. Among 299 included patients, a total of 188 were admitted for elective PCI and 111 for NSTEMI. The incidence of the primary endpoint was 8.5% (95% confidence interval [CI], 5.7-12.4). No definite stent thrombosis occurred. Three independent predictive factors were associated with the primary endpoint: NSTEMI setting (odds ratio [OR], 5.61; 95% CI, 1.75-17.98), thrombotic coronary lesion (OR, 4.26; 95% CI, 1.45-12.54), and longer procedure duration (OR, 1.06; 95% CI, 1.03-1.09). Clinically relevant bleedings (BARC 2, 3, or 5) occurred in 5.4% of patients. Conclusions. In an unselected population admitted for elective PCI or NSTEMI in real-world clinical practice, administration of a P2Y₁₂ inhibitor only after coronary angiography is associated with a low rate of ischemic and bleeding events at 30 days. 

J INVASIVE CARDIOL 2018;30(9):348-354. Epub 2018 July 15.

Key words: acute coronary syndromes, clopidogrel, coronary artery disease, P2Y₁₂ inhibitor, percutaneous coronary intervention, pretreatment

More than 15 years after the introduction of P2Y12 receptor inhibitors in percutaneous coronary intervention (PCI), the optimal timing of their administration remains controversial. Clopidogrel is a prodrug and needs a relatively complex hepatic biotransformation to become an active metabolite. Thus, the biological effect of clopidogrel is delayed, and this treatment has been given before the coronary angiogram in most European countries, as in the design of the CURE trial.¹ Recent studies and a meta-analysis have challenged the benefit of pretreatment in elective PCI,^2-4 suggesting that this therapeutic strategy might expose patients to more bleeding complications without the benefit of a reduction in ischemic events. In elective PCI, administration of a P2Y12 receptor inhibitor loading dose before PCI is a class IA recommendation once coronary anatomy is known,^5,6 whereas a class IIb, level of evidence C recommendation is proposed in patients with a high probability of coronary artery disease.

On the other hand, in patients admitted for a non-ST segment elevation myocardial infarction (NSTEMI), the ACCOAST trial,⁷ published in 2013, showed that pretreatment with prasugrel before the angiogram did not reduce the rate of major ischemic events at 30 days, but increased the rate of major bleeding complications compared with administration in the cath lab after visualization of the anatomy. Thus, prasugrel has been downgraded to a class III, level of evidence B recommendation.⁸ No study has investigated the value of pretreatment with clopidogrel or ticagrelor in patients with NSTEMI. The ideal timing of the loading dose remains under debate, and current guidelines have not made specific recommendations for or against pretreatment using clopidogrel or ticagrelor.⁸

Despite these recent findings, many hospitals in France still give systematic loading doses of a P2Y12 receptor inhibitor before coronary angiography, particularly in the NSTEMI setting. Given the lack of observational data from real-world clinical practices, the aim of our study was to assess the efficacy and safety of performing PCI with administration of a P2Y12 receptor inhibitor in the cath lab − during the procedure − once the coronary anatomy is known and the PCI is decided, by evaluating ischemic and bleeding complications in consecutive and unselected elective PCI and acute coronary syndrome (ACS) patients.

Methods

Study design. We conducted a prospective, observational study in two high-volume centers (Nîmes and Montpellier University Hospitals in France) between November 1, 2015 and August 31, 2016. Patients were followed for 1 month after hospital discharge by a trained research assistant supervised by the study investigator, and a dedicated telephone questionnaire focusing on all ischemic and bleeding complications and compliance with dual-antiplatelet therapy was completed for each patient. In case of bleeding or ischemic adverse events noted by the patients, the relevant information was checked in their medical files. All data were collected using a standardized form, and were entered into an electronic database. All patients were given full study information. The protocol was approved by the local review board and the institutional regulatory authorities, and was conducted according to the principles of the Declaration of Helsinki. The clinical research department of Nîmes University Hospital analyzed the data according to the protocol. 

Study population. All patients who underwent coronary angiography with scheduled PCI were screened. The  inclusion criterion was receipt of a P2Y12 receptor inhibitor loading dose only after coronary anatomy was known and PCI was decided. NSTEMI was defined as the detection of an increase and/or decrease in high-sensitivity cardiac troponin with or without ST-segment or T-wave changes on the admission electrocardiogram. Patients admitted for unstable angina, without an increase in high-sensitivity troponin, were considered to be elective patients.⁸

Exclusion criteria included admission for ST-segment elevation myocardial infarction (STEMI), cardiogenic shock status, or cardiac arrest, as well as long-term P2Y12 receptor inhibitor treatment or those admitted for NSTEMI and who received a P2Y12 receptor inhibitor before the coronary anatomy was known.

Study procedures. All procedures were performed through radial or femoral access, and the decision regarding revascularization was made in accordance with current guidelines.⁵ 

The decision about the type (clopidogrel, prasugrel, ticagrelor) and dose of P2Y12 receptor inhibitor was left at the discretion of the interventional cardiologist, and was made in accordance with guidelines and the usual precautions for use.⁵ All drugs were administered at the moment of PCI, either as whole tablets or crushed to achieve faster and greater bioavailability.^9-11 All patients received long-term low-dose aspirin, and aspirin-naive patients received an intravenous loading dose of 250-500 mg before PCI. All patients also received an intravenous bolus of anticoagulant (unfractionated heparin or enoxaparin) during the procedure. Glycoprotein IIb/IIIa inhibitors (GPIs) were only used in bail-out situations to treat an angiographically identified thrombus before PCI or thrombotic complications during PCI in accordance to guidelines.⁵ After discharge, all patients received dual-antiplatelet therapy for 1 month after bare-metal stent implantation, for 6 months after drug-eluting stent implantation in elective patients, and for 12 months in patients admitted for an ACS in the absence of bleeding complications and in accordance with current guidelines.⁵ In patients requiring long-term anticoagulation, triple-antithrombotic therapy was proposed for the first month; beyond that, an antithrombotic regimen as well as continuation of dual-antiplatelet therapy were discussed individually, in accordance with local practice. Procedure duration was defined as the time between the first and last acquisitions of x-ray fluoroscopy.

Study endpoints. The primary composite endpoint was defined as the first occurrence of death from cardiovascular causes, myocardial infarction (MI), stroke, urgent revascularization, or the need for bail-out GPI rescue therapy in the 30 ± 7 days after PCI. Periprocedural MI was defined in accordance with the third universal definition, requiring evidence of prolonged ischemia or angiographic flow-limiting complication or imaging of new loss of viable myocardium or new regional wall-motion abnormality, in addition to troponin increase.¹² The key secondary efficacy endpoints included a composite of major adverse cardiac or cerebrovascular events, consisting of death from cardiovascular causes, MI, or stroke death from any cause, as well as stent thrombosis, which was classified as definite, probable, or possible according to the Academic Research Consortium definition.¹³Safety endpoints of major and minor bleeding according to the Bleeding Academic Research Consortium (BARC)¹⁴ criteria were evaluated for all bleeding episodes, and according to whether the bleeding was related or not related to coronary artery bypass graft (CABG) surgery.

Statistical analysis. The primary efficacy analysis was done by a calculation of rates, which are expressed with their 95% confidence intervals (CIs). A multivariate analysis was performed using a logistic regression model to adjust the occurrence of ischemic complications for covariate effects. After the univariate analysis, variables with a P-value <.10 were used to integrate the multivariate model. The link between covariates was tested and highly related covariates were not entered simultaneously in the multivariate model. The following factors and covariates were candidates for entering the multivariate model: age, diabetes mellitus, chronic renal failure, NSTEMI, presence of thrombus, bifurcation lesions, number of stents, B2/C type lesion, clopidogrel use, and procedure duration. Interactions between factors and covariates were tested. Statistical analysis was performed using R software, version 3.0.2 (R Development Core Team 2009, R Foundation for Statistical Computing). We calculated that 236 patients were necessary to estimate incidence of the primary composite endpoint, expected at 11%,⁷ with a precision of ±4%.

Results

Study population. During the inclusion period, a total of 2203 PCIs were performed and 617 patients were admitted for STEMI. Elective PCI was performed in 1116 patients and 470 patients were admitted for NSTEMI. A total of 299 patients (18.9%) satisfied the inclusion criteria and were included in the analysis, with 188 (16.8%) in the elective PCI subgroup and 111 (23.6%) in the NSTEMI subgroup (Figure 1). The baseline characteristics are represented in Table 1. Procedural details are listed in Table 2. Four patients (1.3%) were lost to follow-up by day 30. 

Ischemic endpoints. Twenty-five patients (8.5%) met the primary endpoint in the 30 days after PCI (Table 3). In the total population, the mean delay between coronary angiography and occurrence of the primary endpoint was 5.44 days. The composite endpoint (cardiovascular death, MI, or stroke) occurred in 9 patients (3.1%). No definite stent thrombosis occurred during our follow-up period, although 2 out of the 3 cardiovascular deaths could be considered as due to probable stent thrombosis (0.7%); the third death was caused by terminal cardiac failure. Two patients died from a non-cardiovascular cause (1 anaphylactic shock and 1 septic shock after a perforated gastric ulcer). 

By evaluating clinical endpoints for the two clinical settings of admission, the primary composite endpoint occurred in 6/188 patients (3.2%) admitted for elective PCI vs 19/111 (17.1%) admitted for NSTEMI (Table 3). Considering the different components of the primary endpoint, events were mainly driven by use of bail-out GPI, which was more frequently used in NSTEMI patients (13 patients) than in elective patients (2 patients). One cardiovascular death occurred in the elective PCI group and 2 cardiovascular deaths occurred in the NSTEMI group. No definite stent thrombosis occurred, and probable stent thrombosis was found once in each group. These results are also illustrated in Table 3. 

Univariate and multivariate analyses were performed to assess predictive factors associated with the occurrence of the primary endpoint (Table 4). Among the different clinical and procedural variables tested and after removal of variables with significant interaction, three independent predictive factors were identified in multivariate analysis: NSTEMI setting, presence of thrombus, and longer procedure duration (Table 4).

Safety evaluation. Bleeding, regardless of severity (BARC types 1 to 5), occurred in 50 patients (16.9%) at 30 days. Clinically relevant bleedings (BARC types 2, 3, or 5) occurred in 16 patients (5.4%), with BARC type 3 occurring in only 4 patients (1.3%). No fatal bleedings occurred in our study, and only 1 patient had a BARC type 3b complication, consisting of gastrointestinal bleeding that required invasive treatment of a gastric ulcer. The Thrombolysis in Myocardial Infarction (TIMI) system classified 45 patients (15.2%) with minimal bleeding, 5 patients (1.7%) with minor bleeding, and no patient with major bleeding. 

Discussion

This study provides new data on outcomes after PCI without systematic P2Y12 inhibitor pretreatment before coronary angiography in real-world clinical practice. There are three main findings. First, in a high-risk population admitted for elective PCI or NSTEMI, one-third of whom were elderly, this therapeutic strategy appears to be safe, with an incidence of the main composite endpoint of only 8.5% at 30 days, mainly driven by bail-out GPI administration. The incidence of major adverse cardiac or cerebrovascular events was relatively low, occurring in only 3.1% of patients, with no case of definite stent thrombosis. Second, three independent predictive factors of the primary efficacy endpoint were identified: admission for NSTEMI, thrombotic coronary lesions, and longer duration of coronary angiography procedure. Third, the combination of a radial approach for most patients and loading of P2Y12 inhibitor after angiography was associated with a low rate of clinically relevant bleeding (BARC 2, 3, or 5 in 5.4% of patients), and only 4 bleedings (1.3%) of BARC type 3 or higher.

Our study population, which consists of consecutive, unselected patients undergoing PCI, is a true reflection of real-life patients, meaning that the population is more complex than those usually studied in randomized controlled trials with several exclusion criteria.^3,4,7 Indeed, we included high-risk and elderly patients, with 35.5% aged >75 years and 18.1% treated with a long-term anticoagulant. Likewise, coronary lesions were not selected, and complex lesions, such as American College of Cardiology/American Heart Association type B2 or C lesions, bifurcation lesions, left main artery, or unstable thrombotic lesions, are represented. 

The mortality rate was relatively low, and MI, stroke, urgent revascularization, and stent thrombosis were rare complications, mostly affecting the NSTEMI group, as demonstrated in the ACCOAST trial.⁷ However, it is difficult to compare the incidence of our primary composite endpoint across the different published randomized controlled trials, as the endpoints were often slightly different, especially in terms of the use of GPI bail-out therapy as an endpoint, as well as the definition of periprocedural MI. Indeed, our study used the last definition of MI, which explains partly why the rate of MI is lower than in previous studies.^3,4,15 

When focusing on stent thrombosis – probably the most feared complication in terms of our strategy – the low incidence of definite or probable stent thrombosis in our study was similar to the rate found in the ACCOAST trial.⁷ Moreover, administration of a P2Y12 receptor inhibitor loading dose was feasible for all the patients in our study, and these encouraging results are probably partly explained by the frequent use of high clopidogrel loading doses (ie, 600 or 900 mg) or new P2Y12 receptor inhibitors in the NSTEMI setting, which have been proven to reduce stent thrombosis.^16-18 

In elective PCI, although recent data from the United States show a limited use of pretreatment,¹⁹ many hospitals in France continue to use loading doses of a P2Y12 receptor inhibitor before coronary angiography, despite current guidelines.⁵ Many recent trials have been published in this field,^3,4,15 and our findings of a very low 1.1% rate of major adverse cardiac or cerebrovascular events in elective PCI and rare major bleeding complications are consistent with a recent meta-analysis of more than 37,000 patients showing no benefit and a trend toward more bleeding events with clopidogrel pretreatment in patients undergoing elective PCI.² Moreover, no randomized controlled trial has evaluated the feasibility of immediate PCI following diagnostic coronary angiography. 

The PCI-CURE study, which was published in 2001, set the precedent for clopidogrel pretreatment before catheterization in NSTEMI patients.²⁰ Thereafter, several trials tested different clopidogrel loading doses to achieve faster platelet inhibition,^21,22 and more potent and rapid-onset P2Y12 receptor inhibitors (prasugrel, ticagrelor, cangrelor) in ACS or elective PCI,^23-25 but none of the trials addressed the specific question of pretreatment. The ACCOAST trial⁷ was the first to evaluate pretreatment with prasugrel in NSTEMI. Pretreatment with 30 mg of prasugrel was not associated with a reduction in ischemic events, but with an increase in bleeding complications. Likewise, a recent meta-analysis, including data from ACCOAST, highlighted no benefit of pretreatment.²⁶ A more recent meta-analysis²⁷ suggests a better outcome with clopidogrel pretreatment, with fewer major adverse cardiac events and a better all-cause mortality in the pretreatment group, but percentages of events in the pretreatment group of this meta-analysis are similar in our study. The debate over the benefit/risk balance of pretreatment continues because of the heterogeneity and different risk profiles of patients admitted for NSTEMI.²⁸ Our findings are consistent with those of the ACCOAST trial,⁷ with a low incidence of major adverse cardiac or cerebrovascular events despite an unselected population including high-risk patients. This result supports the possibility and safety of a P2Y12 inhibitor loading dose only after coronary anatomy is known. 

Furthermore, time from diagnosis to PCI might be a confounding factor, explaining why the subject remains under debate. Indeed, performing coronary angiography in the 24 hours after the diagnosis is associated with a reduction in ischemic complications,²⁹ whereas faster intervention did not prove to be superior.³⁰ For patients undergoing catheterization during the first 24 hours, pretreatment can seriously be questioned, as 31% did not need pretreatment in the ACCOAST trial because they underwent CABG or received medical treatment with or without further P2Y12 inhibition. The remaining 69% did not have a better outcome in terms of ischemic events.⁷

The bleeding complication rate was remarkably low in our population, which included patients at high risk of bleeding, with one-third being elderly and one-fifth receiving long-term anticoagulation before PCI. No BARC type 5 or TIMI major bleeding occurred in our study. The P2Y12 receptor inhibitor loading dose remains safe, and the low incidence of bleeding events compared with larger studies might be explained, in particular, by the high use of the radial approach. Moreover, the absence of a systematic P2Y12 receptor inhibitor loading dose before the diagnostic coronary angiogram avoids unnecessarily exposing patients who do not require PCI to a bleeding complication.

In the multivariate analysis, three independent predictive factors were associated with occurrence of the primary endpoint at 30 days. Patients with NSTEMI are more prone to major adverse cardiac or cerebrovascular events than elective patients,⁸ which was perfectly reflected in our study. Indeed, the occurrence of the primary composite endpoint at 30 days was five-times more frequent in patients admitted for NSTEMI compared with elective patients, mainly because of the use of a GPI, which accounted for 60% of the primary endpoint in our entire study population. Thrombotic lesions were also strongly related to our primary endpoint, since the presence of thrombus in a P2Y12 receptor-inhibitor naive patient often calls for the use of a GPI due to its rapid onset of action. Complex procedures are not rare in an unselected population, but were not predictive of more ischemic complications in our study in the multivariate model. On the other hand, two-thirds of our population were elective patients, for whom only clopidogrel is recommended because of the lack of data to support the use of new P2Y12 inhibitors, and clopidogrel use appeared safe and was not a predictor of the primary endpoint, regardless of the loading dose proposed. 

Study limitations. The population of this two-center study was relatively small, with a potential lack of statistical power. In addition, leaving the choice of P2Y12 inhibitor and the decision to use GPIs to practitioners could be considered a limitation, but we felt that it would be interesting to evaluate antiplatelet strategy according to a real-world clinical practice in unselected patients. Otherwise, our study was limited by the low number of ischemic events, which was insufficient to allow multivariate analysis in each group of elective PCI and NSTEMI patients, as well as multivariate analysis of major adverse cardiac or cerebrovascular events (ie, without GPI use). Finally, follow-up was only limited to 1 month, but the involvement of pretreatment in the occurrence of ischemic events, and particularly stent thrombosis, appears limited beyond this first month.

Conclusion

In an unselected population admitted for elective PCI or NSTEMI, performing PCI with a P2Y12 receptor inhibitor loading dose only after coronary anatomy is known is associated with a low rate of ischemic and bleeding events at 30 days. These findings support the current guidelines, which recommend not delivering pretreatment for elective patients, but further studies with the new P2Y12 receptor inhibitors appear necessary, particularly in the context of NSTEMI. 

Acknowledgments. The authors acknowledge Amandine Minaud, Chrystel Leperchois, and Elodie Delelo for their support with inclusion and follow-up. Editorial assistance was provided by MedLink Healthcare Communications, and was funded by the authors.

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From the ¹Cardiology Department, Caremeau University Hospital, Nîmes, France; ²Department of Epidemiology, Medical Statistics and Public Health, Caremeau University Hospital, Nîmes, France; and ³Cardiology Department, Arnaud de Villeneuve University Hospital, Montpellier, France.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lattuca reports consulting income from AstraZeneca, Daiichi-Sankyo, and Eli Lilly; research grant support from the French Society of Cardiology, Biotronik, and Daiichi-Sankyo. Dr Cayla reports consulting/lecture income from AstraZeneca, Eli Lilly, Daiichi-Sankyo, Abbott Vascular, BMS, Bayer, Boehringer-Ingelheim, CLS Behring, Iroko Cardio, Pfizer, Novartis, and Boston Scientific. Dr Robert reports grant support from Edwards Lifesciences. Dr Roubille reports personal fees from Daiichi-Sankyo; personal fees/grant support from AstraZeneca. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 13, 2018, provisional acceptance given May 6, 2018, final version accepted May 17, 2018.

Address for correspondence: Guillaume Cayla, MD, PhD, Cardiology Department, Nîmes University Hospital, Place Pr Debré, 30029 Nîmes, Cedex, France. Email: cayla.guillaume@gmail.com