Association between P2Y12 inhibitor reloading and In-hospital Outcomes for patients with Non-ST-segment Elevation Acute Coronary Syndrome already on Chronic P2Y12 receptor inhibitors therapy in China: Findings From the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project

Association between P2Y12 inhibitor reloading and In-hospital Outcomes for patients with Non-ST-segment Elevation Acute Coronary Syndrome already on Chronic P2Y12 receptor inhibitors therapy in China: Findings From the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association between P2Y12 inhibitor reloading and In-hospital Outcomes for patients with Non-ST-segment Elevation Acute Coronary Syndrome already on Chronic P2Y12 receptor inhibitors therapy in China: Findings From the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project Yintang Wang, Yu Geng, Ou Zhang, Qin Xu, Yajun Xue, Boda Zhou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2290839/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The association between P2Y12 receptor inhibitors reloading and in-hospital outcomes in non-ST-segment elevation acute coronary syndrome (NSTEACS) patients who were on chronic P2Y12 receptor inhibitors therapy remained underdetermined. Methods The Improving Care for Cardiovascular Disease in China–Acute Coronary Syndrome (CCC-ACS project) is a national registry active from November 2014 to December 2019. 4790 NSTEACS patients on chronic P2Y12 receptor inhibitors therapy were included. Cox proportional hazard models, Kaplan–Meier curves, and subgroup analyses were conducted. Results The NSTEACS patients who received reloading of P2Y12 receptor inhibitors were younger and had fewer comorbid conditions. The reloading group had a lower risk of major adverse cardiac events (MACE) (0.51% vs. 1.42%, P = 0.007), and all-cause death (0.36% vs. 0.99%, P = 0.028), the risks of myocardial infarction and major bleeding were not significantly different between patients with and without reloading. In survival analysis, a lower cumulative risk of MACE could be identified (Log-rank test, P = 0.007) in reloading group. In the unadjusted Cox model, reloading P2Y12 receptor inhibitors was associated with a decreased risk of MACE (HR, 0.35; 95% CI, 0.16-0.78; [ P = 0.010]) and all-cause death (HR, 0.37; 95% CI, 0.14-0.94; [ P = 0.036]). Reloading of P2Y12 receptor inhibitors was associated with a decreased risk of MACE in most of the subgroups. Conclusions In NSTEACS patients already taking P2Y12 receptor inhibitors, we observed a decreased risk of in-hospital MACEs and all-cause mortality and did not observe an increased risk of major bleeding, with reloading. The differential profile in the two groups might influence this association and further studies are warranted. Clinical trial registration : https://www.clinicaltrials.gov (Unique identifier: NCT02306616, date of first registration: 03/12/2014). P2Y12 receptor inhibitors non-ST-segment elevation acute coronary syndrome loading dose outcome therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Coronary heart disease remains a serious public health concern, emerging as the leading cause of mortality and morbidity from cardiovascular disease[ 1 ]. Approximately half of the reduction in mortality can be attributed to optimal management of the acute phase of acute coronary syndrome (ACS), improved revascularization, and prevention strategies [ 2 ]. According to current guidelines, dual antiplatelet therapy using aspirin and P2Y12 receptor inhibitors is the standard of care treatment in the management of patients with ACS. In ACS patients undergoing percutaneous coronary intervention (PCI), it is strongly recommended to receive a loading dose of dual antiplatelet therapy as early as possible[ 3 – 6 ]. In real-life clinic scenarios, physicians’ compliance with guideline recommendations remains suboptimal and challenging[ 7 ]. In addition, some patients may already be on long-term therapy with P2Y12 receptor inhibitors. Whether it is necessary to reload P2Y12 receptor inhibitors for these patients or not remained underdetermined. Patients on chronic clopidogrel therapy or treated with the daily clopidogrel dose were commonly excluded by most previous large randomized trials evaluating P2Y12 inhibitors for the treatment of ACS [ 8 – 12 ]. Thus, few studies have explored this issue to date. For STEMI (ST-segment elevation myocardial infarction) patients on long-term treatment with clopidogrel, clopidogrel reloading was associated with a decreased risk of in-hospital death and did not increase the risk of major bleeding[ 13 ]. However, previous reports about the effects of reloading P2Y12 inhibitors in non-ST-segment elevation acute coronary syndrome (NSTEACS) are conflicting. Compared with a maintenance dose of clopidogrel, a benefit of clopidogrel reloading was found in 242 NSTEACS patients planned for PCI[ 14 ]. However, the beneficial effect of clopidogrel reloading was not observed in the Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG) study[ 13 ]. In addition, with the application of more powerful antiplatelets such as ticagrelor, it may be warranted to evaluate the effects of reloading P2Y12 inhibitors in NSTEACS patients further. Therefore, this study was designed to examine the association between reloading with P2Y12 receptor inhibitors and the occurrence of in-hospital major adverse cardiac events or major bleeding in NSTEACS patients, with data from CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project. Methods The CCC-ACS project was a nationwide registry and quality improvement study focusing on quality of ACS care, which was launched in 2014 as a collaborative initiative of the American Heart Association and the Chinese Society of Cardiology. As a retrospectively observational study, each participating hospital recruited the first consecutive 20 to 30 ACS inpatient cases each month to the study, identified through principal discharge diagnosis based on review of the inpatient list. Details of the design and method of the CCC-ACS project have been published[ 15 ]. This project was registered at: https://www.clinicaltrials.gov (Unique identifier: NCT02306616, date of first registration: 03/12/2014). Basing on the principal discharge diagnosis, 113,650 ACS patients were enrolled from November 2014 to December 2019. Of these, 18,401 patients were identified as receiving long-term P2Y12 receptor inhibitors treatment (95,249 patients who did not take clopidogrel or ticagrelor within two weeks before admission were excluded). Reloading of P2Y12 inhibitors was regarded as occurring if patients received clopidogrel ≥ 300mg or ticagrelor ≥ 180mg within 24h of the first medical contact (10,397 patients without clopidogrel or ticagrelor prescription were excluded). 7,521 ACS patients with P2Y12 reloading were examined after eliminating those with missing data or obvious data error ( N = 483). 2,731 STEMI patients were also excluded. Finally, 4,790 NSTEACS patients represented the subject group, including 2,323 non–ST-segment elevation myocardial infarction (NSTEMI) patients and 2,467 unstable angina pectoris (UAP) patients (Fig. 1 ). The study was conducted in accordance with the Declaration of Helsinki. The CCC-ACS project was approved by the institutional review board of Beijing Anzhen Hospital. The institutional review board of Beijing Anzhen Hospital waived the need for informed consent as retrospective nature of the study. The definition of reloading of P2Y12 inhibitors is described above. A non-loading dose of P2Y12 inhibitors was defined as clopidogrel < 300mg or the ticagrelor < 180mg. Effectiveness outcomes were major adverse cardiovascular event (MACE), a composite of all-cause death, myocardial infarction (MI), stent thrombosis, and ischemic stroke during hospitalization. Safety outcomes were in-hospital major bleeding, including intracranial bleeding, retroperitoneal bleeding, a decline in hemoglobin levels ≥ 20g/L during hospitalization, and transfusion with overt bleeding. All of these outcomes were recorded by clinicians during patients’ hospitalization and recorded in the medical records. All the patients were categorized as either reloading of P2Y12 receptor inhibitors group and the non-reloading P2Y12 receptor inhibitors group. The demographic, clinical, and in-hospital treatment information of these two groups were compared. Continuous variables were presented as mean ± SD or median (interquartile range) according to different distributions. Categorical variables were shown as a number (percentage). Differences in various characteristics between the reloading group and the non-reloading group were compared using t- test, Wilcoxon test and chi-square test where applicable. Univariable and multivariable Cox proportional hazard models were performed to examine the association between reloading of P2Y12 receptor inhibitors and in-hospital outcomes. In multivariable analysis, different Cox regression models adjusting various variables were derived. Candidate adjustment variables were examined with forward stepwise selection setting entry and exit criteria at the P = 0.05 and 0.1 levels, respectively. Hazard ratios (HRs) for different variables and corresponding 95% confidence intervals (CIs) were shown. Survival curves of MACE and major bleeding were illustrated using Kaplan–Meier curves and compared by employing log-rank tests. Because most of the patients discharged within two weeks, this study only took events that occurred within fourteen days after admission into account. Thus, the Kaplan–Meier curves were based on an observation duration of fourteen days. In the subgroup analysis, clinically important variables were considered, including age (older than 75 years or not), Hemoglobin (> 110 g/L or not), previous bleeding history (yes or no), aspirin loading (yes or no) and left ventricular ejection fraction (LVEF) (< 30% or no). Overall, a two-sided P < 0.05 was considered statistically significant. All analyses were performed with SAS software version 9.4 (SAS Institute Inc, Cary, NC). Results In the present study, 48032 NSTEACS patients were analyzed, of whom 4790 (9.97%) were on long-term P2Y12 receptor inhibitors therapy, including 1,371 in the reloading of the P2Y12 receptor inhibitors group and 3,419 in the non-reloading group. For patients in the reloading group, 835 (60.9%) patients were clopidogrel reloaded and 536 (39.1%) patients were ticagrelor reloaded. 62.1% patients received chronic P2Y12 receptor inhibitors in the reloading group, while 37.9% in the non-reloading group. As shown in Table 1 , there was a lower prevalence of previous myocardial infarction, PCI, atrial fibrillation, chronic heart failure, hypertension, diabetes mellitus, smoking, bleeding history, stroke/transient ischemic attacks (TIA), renal dysfunction and acute heart failure in the reloading group. Patients in the reloading group were more likely to receive proton pump inhibitors, a loading dose of aspirin, GP IIb/IIIa and percutaneous coronary intervention. Comparisons of baseline characteristics between reloading and the non-reloading groups in NSTEMI & UAP are shown in Supplement Table S2 . Table 1 Baseline characteristics of NSTEACS patients in reloading P2Y12 receptor inhibitors and non-reloading P2Y12 inhibitors group Reloading group ( N = 1371) Non-reloading group ( N = 3419) P value Demographics Age, (years) 64.33 ± 11.35 66.18 ± 11.48 < 0.001 Male, n(%) 946 (69.00) 2290 (66.98) 0.177 BMI, (kg/m 2 ) 24.49 ± 3.36 24.7 ± 3.53 0.101 Clinical history Previous MI 336 (24.51) 1125 (32.90) < 0.001 Previous PCI 389 (28.37) 1310 (38.32) < 0.001 Previous CABG 19 (1.39) 56 (1.64) 0.525 Atrial fibrillation 35 (2.55) 146 (4.27) 0.005 Chronic heart failure 53 (3.87) 282 (8.25) < 0.001 Hypertension 790 (57.62) 2179 (63.73) < 0.001 Diabetes mellitus 361 (26.33) 1066 (31.18) < 0.001 Hyperlipemia 224 (16.34) 592 (17.32) 0.416 Smoking 364 (26.55) 778 (22.76) 0.005 Bleeding history 14 (1.02) 68 (2.06) 0.014 Stroke/TIA 114 (8.32) 355 (10.38) 0.030 Peripheral vascular disease 28 (2.04) 94 (2.75) 0.160 COPD 28 (2.04) 71 (2.08) 0.9398 Renal dysfunction 26 (1.90) 162 (4.74) < 0.001 Presentation Cardiac shock 3 (0.22) 14 (0.41) 0.316 Acute heart failure 25 (1.82) 107 (3.13) 0.013 Cardiac arrest 1 (0.07) 7 (0.20) 0.313 GRACE score 126.98 ± 40.73 125.67 ± 40.96 < 0.001 Killip classification < 0.001 I 872(63.60%) 1763(51.56%) II 312(22.76%) 1024(29.95%) III 139(10.14%) 467(13.66%) IV 48(3.50%) 165(4.83%) Laboratory examinations Platelet, (*10 9 ) 203.6 ± 67.04 206.8 ± 64.85 0.131 Creatinine, (umol/l) 98.6 ± 86.8 93.35 ± 80.89 0.060 Hemoglobin, (g/l) 122.5 ± 11.08 123.5 ± 12.38 0.016 NT-proBNP, (pg/ml) 1786.12 ± 4006.99 2158.66 ± 4933.15 0.072 Medications Previous aspirin use 1094 (79.80) 2892 (84.59) < 0.001 Reloading aspirin 898 (65.50) 104 (3.04) < 0.001 Proton pump inhibitor 764 (55.73) 1640 (49.68) < 0.001 GP IIb/IIIa 170 (12.40) 310 (9.07) < 0.001 Operative treatment Thrombolysis 1 (1.92) 2 (2.13) 0.9335 Coronary artery angiography 1013 (73.89) 2088 (63.25) < 0.001 Three-vessel disease 352(25.67%) 634(18.54%) < 0.001 Left main disease 97(7.08%) 241(7.05) 0.974 PCI 829 (60.47) 1669 (48.82) < 0.001 CABG 9 (0.66) 9 (0.66) 0.773 Any Coagulant 845 (61.63) 1627 (47.59) < 0.001 Warfarin 9 (0.66) 27 (0.79) 0.629 Heparin 45 (5.33) 68 (4.18) 0.196 LMWH 787 (93.14) 1458 (89.61) 0.004 Bivalirudin 4 (0.29) 16 (0.47) 0.393 Fondaparinux 11 (1.30) 46 (2.83) 0.017 LVEF 58.46 ± 9.97 57.92 ± 10.09 0.141 Compared with the non-reloading group, the incidence of in-hospital effectiveness outcomes was much lower in the reloading group. Reloading P2Y12 receptor inhibitors had a lower incidence of MACE [7(0.51%) vs. 49 (1.42%), P = 0.007], predominantly driven by all-cause death [5 (0.36%) vs. 34 (0.99%), P = 0.028]. For the endpoint of myocardial infarction, there was no significant difference between the reloading group and the non-reloading group. For major bleeding, there was no obvious difference between these two groups (Fig. 2 ). A lower incidence of MACE was observed in the ticagrelor group, compared with non-reloading group (0.37% vs. 1.43%, P = 0.043). A similar tendency was also observed in the comparison of MACE between the clopidogrel group and the non-reloading group (0.60% vs. 1.43%, P = 0.054). No significant difference was found for major bleeding ( Supplement Table S5 ). As shown in Kaplan–Meier curves, the cumulative incidence of MACE was lower in the reloading P2Y12 receptor inhibitors group (Log-rank test, P = 0.007). We did not observe a difference in cumulative incidence of major bleeding between two groups (Fig. 3 ). In the unadjusted Cox regression model, reloading P2Y12 receptor inhibitors was associated with a decreased risk of MACE (HR, 0.35; 95% CI, 0.16–0.78; [ P = 0.010]) and all-cause death (HR, 0.37; 95% CI, 0.14–0.94; [ P = 0.036]) (Table 2 ). Among NSTEMI patients, the reloading P2Y12 receptor inhibitors group had a lower risk of MACE, all-cause death and myocardial infarction. However, this relationship could not be observed in the UAP patients. Table 2 Univariable Cox proportional hazard models for NSTEACS patients HR (95% CI) P value MACE 0.35 (0.16–0.78) 0.010 All-cause death 0.37 (0.14–0.94) 0.036 Myocardial infarction 0.29 (0.07–1.27) 0.100 Stent thrombosis NA NA Ischemic stroke NA NA Major bleeding : 0.41 (0.09–1.85) 0.248 Obvious bleeding 0.62 (0.13–2.93) 0.548 Transfusion bleeding 0.50 (0.06–4.26) 0.524 Intracranial bleeding 0.00 (0.00-∞) 0.995 Retroperitoneal bleeding NA NA In the multivariable Cox regression analysis (Table 3 ), reloading P2Y12 receptor inhibitors was independently associated with MACE after adjusting age and sex (HR, 0.39; 95% CI, 0.18–0.87; [ P = 0.021]). This relationship remained after adjusting age, sex and percutaneous coronary intervention (HR, 0.43; 95% CI, 0.19–0.96; [ P = 0.039]). (HRs in the adjusting models are shown in Supplement Table S3 ). However, when more variables were included in the multivariable Cox regression model, this association was undermined, with only a tendency for beneficial effects of reloading P2Y12 receptor inhibitors observed (the results for stepwise analysis are shown in Supplement Table S4 ). The variables that were significantly different between reloading and non-reloading groups, such as GRACE score and Killip classification, when adjusted in the multivariable Cox regression model, resulted in the loss of the beneficial effects of reloading P2Y12 receptor inhibitors for MACE (data not shown). Table 3 Multivariable Cox proportional hazard models for NSTEACS patients with MACE HR (95% CI) P value Model* 0.39(0.18–0.87) 0.021 Model † 0.43(0.19–0.96) 0.039 Model ‡ 0.49(0.22–1.10) 0.086 Model § 0.56(0.25–1.25) 0.156 *, adjusting age and sex; †, adjusting age, sex and percutaneous coronary intervention; ‡, adjusting age, sex and coronary artery angiography; §, stepwise regression model adjusting age, sex, previous myocardial infarction, previous heart failure, glycoprotein IIb/IIIa inhibitors and coronary artery angiography. Abbreviations: ACS, acute coronary syndrome; NSTEACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; UAP, unstable angina pectoris. Abbreviations: LVEF, Left ventricular ejection fraction; PCI, Percutaneous Coronary Intervention. Subgroup analyses were performed according to important baseline characteristics among NSTEACS patients, taking MACE into account. Reloading of P2Y12 receptor inhibitors was associated with a decreased risk of MACE in most subgroups (Fig. 4 ). Because no events occurred in some subgroups (such as the reloading group in patients with hemoglobin < 110g/L), comparisons were not applied. No interactions were found in different subgroups. Notably, P2Y12 inhibitors reloading was beneficial in those patients undergoing PCI (HR, 0.28; 95% CI, 0.11–0.71; [ P = 0.007]). Discussion In the present study, we evaluated the effect of reloading of P2Y12 inhibitors on in-hospital outcomes in ACS patients who were already on chronic treatment with P2Y12 inhibitors. The results showed that treating with a reloading dose of P2Y12 inhibitors within 24 hours of first medical contact was associated with decreased risk of major adverse cardiac events, and did not increase the risk of major bleeding. Previous studies had generally demonstrated that receiving treatment with adequate and timely platelet inhibition could decrease rates of ischemic events. Thus, antithrombotic treatment is fundamental in ACS patients. Some patients may be already taking P2Y12 receptor inhibitors for secondary prevention of myocardial infarction or stroke; or after the coronary or peripheral vascular intervention or primary intervention of atherosclerotic vascular diseases. Among NSTEACS patients, 9.97% (4790/48032) were on long-term P2Y12 receptor inhibitors therapy. Jacob A. Doll et.al reported that pre-admission P2Y12 receptor inhibitor use was 9.3% among STEMI patients and 18.9% among NSTEMI patients[ 13 ]. In a real-world clinical setting, the proportion of patients with AMI receiving loading doses of aspirin and P2Y12 inhibitors during hospitalization was relatively low[ 16 ]. For those patients on chronic treatment with P2Y12 inhibitors, the proportion of patients receiving loading doses of P2Y12 inhibitors was extremely low (28.6% in our present study). Thus, adherence to the use of enough antiplatelet therapy remained challenging. For the loading of antiplatelet therapy, many factors might influence the clinical decision. Elderly patients, concomitant comorbidities and those receiving conservative treatment were less likely to receive oral antiplatelet therapy. The effects of pretreatment with P2Y12 receptor inhibitors in patients with NSTEACS is controversial. Notably, the mortality risk and outcome of NSTEACS patients were influenced by both ischemic and bleeding complications[ 17 ]. Therefore, the optimal antiplatelet strategy should equally balance the ischemic and bleeding risk of the patient. Available evidence suggests that a “one-size-fits-all” strategy (i.e., routine use of pre-treatment or absolute avoidance of it) is unsuitable[ 18 ]. According to the current guidelines, whether to administer routine pre-treatment with a P2Y12 receptor inhibitor in NSTEACS patients or not is undetermined[ 3 , 5 ]. As for those already on chronic therapy with P2Y12 inhibitors, whether it is necessary to reload again is controversial. The Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty [ARMYDA-8 RELOAD-ACS] trial demonstrated the protective effect of clopidogrel reloading compared with a maintenance dose[ 14 ]. Similar to this result, our present study demonstrated that for patients presenting with NSTEACS particularly NSTEMI already taking long-term P2Y12 inhibitors, reloading of P2Y12 inhibitors was associated with a decreased risk of in-hospital major adverse cardiac events and did not increase the risk of major bleeding. Physiologically, loading antiplatelet therapy should be associated with an increased risk of bleeding. However, we found that loading P2Y12 inhibitors did not increase the risk of major bleeding. Similar results are found elsewhere[ 13 , 14 ]. In our cohort this might be due to a higher proportion of those receiving proton pump inhibitor treatment in the reloading group (55.73% vs. 49.68%, P < 0.001, Table 1 ), since gastrointestinal bleeding dominated the major bleeding in our present study. To date, the optimal reloading strategy for NSTEACS patients remains controversial. However, this beneficial effect of clopidogrel reloading was not observed in Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG)[ 13 ]. Among 39 158 patients with NSTEMI, no significant mortality difference was found (OR 1.13, 95% CI 0.93–1.37). Our present study found that reloading the P2Y12 inhibitor was related to decreased risk of in-hospital major adverse cardiac events, all-cause death and did not increase the risk of major bleeding for NSTEACS patients, particularly for NSTEMI patients. There were several potential explanations for the beneficial effect of reloading P2Y12 inhibitor. Firstly, patients on pre-admission clopidogrel may be at higher risk of adverse outcomes. In the TRILOGY trial[ 11 ], the incidence of the ischemic event at thirty months after NSTEACS was higher compared to those without chronic clopidogrel therapy. It was necessary to reinforce antithrombotic therapy in these patients who were already taking clopidogrel. Laboratory examinations of platelet function in 166 patients already on clopidogrel therapy suggested inhibition of platelet aggregation 4 hours after reloading-dose clopidogrel occurred in a dose-dependent manner[ 19 , 20 ]. An additional antiplatelet effect obtained with a reloading dose of clopidogrel on the basis of the maintenance dose of clopidogrel might potentially improve clinical outcomes. Secondly, reloading clopidogrel patients were younger and more likely to be with fewer comorbid conditions[ 13 ]. As shown in Table 1 , reloading P2Y12 patients had a lower incidence of comorbidity and were more likely to receive invasive intervention, resulting in improvement of in-hospital outcomes. After adjusting age, sex and coronary artery angiography, reloading P2Y12 inhibitors remained independently associated with MACE ( Supplement Table S3 ). Thirdly, more powerful inhibition of platelet activation and the coagulation cascade in the initial phase and evolution of NSTEACS might play an important role. Based on different pharmacokinetic and pharmacodynamic characteristics between clopidogrel and ticagrelor, ticagrelor might provide more rapid and potent platelet inhibition. In the study of Jacob A. Doll et.al , no beneficial effect of reloading P2Y12 inhibitors for NSTEMI patients was observed[ 13 ]. In their study, only clopidogrel reloading was examined. As demonstrated in the PLATO trial[ 10 ], clopidogrel was proved to be inferior to ticagrelor in ACS patients. In our study, not only clopidogrel but also ticagrelor were included. The P2Y12 reloading group included 835(60.9%) clopidogrel reloading and 536 (39.1%) ticagrelor reloading. For the endpoint of major adverse cardiac events, reloading of ticagrelor tended to be superior to clopidogrel compared with non-reloading group (HR = 0.26 [95% CI, 0.06–1.07), P = 0.061 and HR = 0.42 [95% CI, 0.17–1.04], P = 0.062, respectively). In the management of NSTEACS, some baseline characteristics of patients should be considered when deciding on antithrombotic strategies. These characteristics are described in the subgroup analyses. For NSTEACS, age was a predictor of in-hospital and 6-month mortality[ 21 , 22 ]. In addition, elderly patients were vulnerable to major bleeding, which was associated with prolonged hospitalization and increased mortality[ 23 ]. In our present study, whether in subgroups under or over 75 years of age, reloading P2Y12 inhibitors tended to be associated with a lower risk of MACE and not associate with a risk of major bleeding, suggesting reloading might be efficient and safe for elder patients. Because of lack of end-point events in the remainder of the subgroups, we could not evaluate the effects of association between the reloading P2Y12 inhibitors and in-hospital outcomes. Antithrombotic strategies should be considered depending on the balance between ischemic risk and bleeding risk in actual clinical setting[ 5 , 24 ]. In a real-world clinical scenario, younger patients without fewer comorbidities undergoing intervention tend to be treated with a loading dose of P2Y12 inhibitor. In clinical practice, P2Y12 inhibitors and aspirin were always simultaneously administered if loading dose was considered. Reloading of P2Y12 receptor inhibitors tended to decrease the risk of MACE both in the subgroup with and without aspirin loading. We attempted to adjust the potential factors that might affect the clinical decision on reloading P2Y12 inhibitors. Multivariable Cox proportional models were derived to minimize the effects of confounding factors. There are several limitations in this study. This is a real-world observational study, and thus cannot determine causality. As a post hoc analysis from the CCC program, the present study should be considered as hypothesis-generating. We attempted to adjust the potential confounders with the multivariable Cox regression model, to explore the association between reloading P2Y12 inhibitors and in-hospital outcomes improvement in NSTEACS patients. Given the relatively few composite endpoint events that occurred in the present study and events per variable (EPV) ratio no less than 10, we attempted to limit the number of variables included in the multivariable Cox models to avoid the problem of overfitting[ 25 ]. Thus, with more adjusting variables included in the multivariable Cox regression model, the beneficial effect of reloading P2Y12 inhibitors seemed to be weakened. Therefore, no amount of statistical adjusting can completely remove confounding factors. Significant differences in baseline characteristics might significantly affect the outcomes, as well as the interpretation of the final results. We conducted propensity score (PS) match analysis. After PS matching of a total of 668 cases, 334 in reloading and non-loading groups, there were no significant differences of baseline characteristics. Limited by the relatively small sample size and number of events, no difference of risk of MACE and major bleeding between the two groups was found (data was not shown). A larger scale study is warranted to verify the association between P2Y12 receptor inhibitors and the outcomes. Additionally, only in-hospital outcomes could be obtained and analyzed limited by the design of the CCC program. A previous study indicated that different effects of initial antiplatelet drugs occurred within ten days in accordance with different types and dosages of antiplatelet agents[ 26 ] and the majority of events occurred in the first week after discontinuation of P2Y12 inhibitors[ 27 ]. Thus, the major effects of reloading P2Y12 inhibitors could be observed during hospitalization. The association between reloading P2Y12 inhibitors within 24 hours after first medical contact and long-term outcomes could be further explored in the future. Lastly, all results of this study were derived from Chinese patients. Whether this result could be extrapolated to all ethnic groups of NSTEACS patients is unclear. Conclusion In patients presenting with NSTEACS particularly NSTEMI already taking P2Y12 receptor inhibitor, we observed a decreased risk of in-hospital major adverse cardiac events and all-cause mortality, and did not observe an increase the risk of major bleeding, with reloading of P2Y12 receptor inhibitors within 24 hours after first medical contact. The differential profile and the global management of the patients might influence the interpretation of results, and more studies are warranted to verify the association between reloading of P2Y12 receptor inhibitors and outcomes. Abbreviations ACS, acute coronary syndrome; BMI, Body Mass Index; CABG, Coronary Artery Bypass Grafting; CI, Confidence Intervals; COPD, Chronic Obstructive Pulmonary Disease; HR, Hazard Ratios; LVEF, Left ventricular ejection fraction; NSTEACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, Percutaneous Coronary Intervention; STEMI, ST-segment elevation myocardial infarction; TIA, Transient Ischemic Attacks; UAP, unstable angina pectoris. Declarations Acknowledgments We acknowledge the contribution of all investigators in the participating hospitals in the project. A complete list of CCC-ACS Investigators was given in Supplement Table S1 . We also thank Professor Daniel Porter for his help in polishing the manuscript. Author Contributions: All authors contributed to the writing and editing of the manuscript. Ping Zhang, Yintang Wang, Yu Geng and Ou Zhang conceived and designed the project; The statistician Qin Xu contributed to design and analyze data. Yajun Xue, Yingtang Wang and Yu Geng conducted data collection. Funding The CCC-ACS project is a collaborative study of the American Heart Association (AHA) and the Chinese Society of Cardiology. The American Heart Association received funding from Pfizer through an independent grant for learning and change and AstraZeneca as a quality improvement initiative. The work was also supported by the Beijing Municipal Administration of Hospitals’ Ascent Plan (Code: DFL20190902), Tsinghua University Spring Breeze Fund, and the Beijing Tsinghua Changgung Hospital Fund (Grant No. 12019C1009). Availability of data and materials The data presented in this study are available on request to the corresponding author ( [email protected] or [email protected] ) for purposes of reproducing the results or replicating the procedure. The data are not publicly available due to privacy restrictions. Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki. The CCC-ACS project was approved by the institutional review board of Beijing Anzhen Hospital. The institutional review board of Beijing Anzhen Hospital waived the need for informed consent as retrospective nature of the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Author details 1 Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China. 2 China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. 3 Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. 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Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–77. Collet JP, Thiele H, Barbato E, Barthelemy O, Bauersachs J, Bhatt DL, Dendale P, Dorobantu M, Edvardsen T, Folliguet T, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42(14):1289–367. Capodanno D, Alfonso F, Levine GN, Valgimigli M, Angiolillo DJ. ACC/AHA Versus ESC Guidelines on Dual Antiplatelet Therapy: JACC Guideline Comparison. J Am Coll Cardiol. 2018;72(23 Pt A):2915–31. Singh M, Bhatt DL, Stone GW, Rihal CS, Gersh BJ, Lennon RJ, Narula J, Fuster V. Antithrombotic Approaches in Acute Coronary Syndromes: Optimizing Benefit vs Bleeding Risks. Mayo Clin Proc. 2016;91(10):1413–47. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial I: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494–502. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):1179–89. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297–309. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15. Doll JA, Li S, Chiswell K, Roe MT, Kosiborod M, Scirica BM, Wang TY. Clopidogrel reloading for patients with acute myocardial infarction already on clopidogrel therapy. Eur Heart J. 2018;39(3):193–200. Patti G, Pasceri V, Mangiacapra F, Colonna G, Vizzi V, Ricottini E, Montinaro A, D'Ambrosio A, Wijns W, Barbato E, et al. Efficacy of clopidogrel reloading in patients with acute coronary syndrome undergoing percutaneous coronary intervention during chronic clopidogrel therapy (from the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty [ARMYDA-8 RELOAD-ACS] trial). Am J Cardiol. 2013;112(2):162–8. Hao Y, Liu J, Liu J, Smith SC Jr, Huo Y, Fonarow GC, Ma C, Ge J, Taubert KA, Morgan L, et al. Rationale and design of the Improving Care for Cardiovascular Disease in China (CCC) project: A national effort to prompt quality enhancement for acute coronary syndrome. Am Heart J. 2016;179:107–15. Tang X, Liu L, Yang J, Gao Z, Zhao X, Qiao S, Gao R, Wang Z, Yuan J, Yang Y. Evidence-based oral antiplatelet therapy among hospitalized Chinese patients with acute myocardial infarction: results from the Chinese acute myocardial infarction registry. BMC Cardiovasc Disord. 2021;21(1):299. Ndrepepa G, Berger PB, Mehilli J, Seyfarth M, Neumann FJ, Schomig A, Kastrati A. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol. 2008;51(7):690–7. Ferreiro JL. Pre-Treatment With Oral P2Y12 Inhibitors in Non-ST-Segment Elevation Acute Coronary Syndromes: Does One Size Fit All? JACC Cardiovasc Interv. 2020;13(8):918–20. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schomig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation. 2004;110(14):1916–9. Collet JP, Silvain J, Landivier A, Tanguy ML, Cayla G, Bellemain A, Vignolles N, Gallier S, Beygui F, Pena A, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the Reload with Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy (RELOAD) study. Circulation. 2008;118(12):1225–33. Fox KA, Eagle KA, Gore JM, Steg PG, Anderson FA, Grace, Investigators G. The Global Registry of Acute Coronary Events, 1999 to 2009–GRACE. Heart. 2010;96(14):1095–101. Rosengren A, Wallentin L, Simoons M, Gitt AK, Behar S, Battler A, Hasdai D. Age, clinical presentation, and outcome of acute coronary syndromes in the Euroheart acute coronary syndrome survey. Eur Heart J. 2006;27(7):789–95. Andreotti F, Rocca B, Husted S, Ajjan RA, ten Berg J, Cattaneo M, Collet JP, De Caterina R, Fox KA, Halvorsen S, et al. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2015;36(46):3238–49. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213–60. Concato J, Peduzzi P, Holford TR, Feinstein AR. Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy. J Clin Epidemiol. 1995;48(12):1495–501. Cadroy Y, Bossavy JP, Thalamas C, Sagnard L, Sakariassen K, Boneu B. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation. 2000;101(24):2823–8. Franchi F, Rollini F. Patterns and Outcomes of Dual Antiplatelet Therapy Discontinuation After Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2022;15(8):807–09. Additional Declarations No competing interests reported. Supplementary Files SupplementTable.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2290839","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":160267641,"identity":"8803d85b-8b38-4c71-bc82-47a6ac01c60e","order_by":0,"name":"Yintang Wang","email":"","orcid":"","institution":"Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Yintang","middleName":"","lastName":"Wang","suffix":""},{"id":160267642,"identity":"da8e086f-d5a0-43be-a5eb-74afe3547d7c","order_by":1,"name":"Yu Geng","email":"","orcid":"","institution":"Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Geng","suffix":""},{"id":160267644,"identity":"064e23c6-41bc-420f-9d38-428849987372","order_by":2,"name":"Ou Zhang","email":"","orcid":"","institution":"Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Ou","middleName":"","lastName":"Zhang","suffix":""},{"id":160267645,"identity":"a96c139a-f842-48cc-abb6-a35753e3b9c0","order_by":3,"name":"Qin Xu","email":"","orcid":"","institution":"China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Xu","suffix":""},{"id":160267647,"identity":"9594d073-7870-4ca8-91c6-d14614f7cb1a","order_by":4,"name":"Yajun Xue","email":"","orcid":"","institution":"Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Yajun","middleName":"","lastName":"Xue","suffix":""},{"id":160267650,"identity":"1ab0ec10-a9ad-406e-a0a6-344656e9a6dc","order_by":5,"name":"Boda Zhou","email":"","orcid":"","institution":"Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Boda","middleName":"","lastName":"Zhou","suffix":""},{"id":160267652,"identity":"b654324c-a9e2-4921-8533-2cac7f6cffdf","order_by":6,"name":"Ping Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApklEQVRIiWNgGAWjYDACCTCy4eFnbyBNS5qMZM8B0rQctjG44UCkDvnZvQdvfKg5z8Nwg4Hxw8ccIrQwzjmXbDnj2G0extkNzJIztxGhhVkix0yat+E2D7PMATZmXmK0sEG0nONhk0ggUgsPRMsBHh6itUhI5IH8kswjwXOwmTi/yM/IBYWYnb398eaDHz4SowXoNBiDsYEo9chaRsEoGAWjYBTgAACxXS/BEPxqdAAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University","correspondingAuthor":true,"prefix":"","firstName":"Ping","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2022-11-19 09:44:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2290839/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2290839/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":30522444,"identity":"68865c4f-7af8-4c9a-b46f-ae9356efdd2a","added_by":"auto","created_at":"2022-12-19 15:33:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":86786,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram of the study selection process.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: ACS, acute coronary syndrome; NSTEACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; UAP, unstable angina pectoris.\u003c/p\u003e","description":"","filename":"Figure1flowchart.png","url":"https://assets-eu.researchsquare.com/files/rs-2290839/v1/49c1c80a8aa01012bd640727.png"},{"id":30521617,"identity":"194acebc-3ddd-495b-82d0-604df841f37b","added_by":"auto","created_at":"2022-12-19 15:25:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":327817,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIn-hospital outcomes within 15 days after hospitalization.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence of in-hospital primary effectiveness outcomes (major adverse cardiovascular event [MACE]) (A) and all cause death (B) were higher in the non-reloading group compared with reloading group in NSTEACS study population. The incidence of both MI (C) and major bleeding (D) were no statistically significant difference compared with the non-reloading group in both the whole study population.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2290839/v1/1b8887adf035ffe846783107.jpg"},{"id":30521613,"identity":"feae5aa4-5bb7-46e8-b7d0-f0c54f66b7fe","added_by":"auto","created_at":"2022-12-19 15:25:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":624034,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative Kaplan–Meier curve estimates of effectiveness outcomes during the 15-day in hospital period.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurvival curves of MACE and major bleeding were illustrated using Kaplan–Meier curves and compared employing log-rank tests. A and B, Data for the primary effectiveness outcomes of amajor adverse cardiovascular event (MACE) and the primary safety outcomes in the NSTEACS patients.\u003c/p\u003e","description":"","filename":"Figure3KMcurve.png","url":"https://assets-eu.researchsquare.com/files/rs-2290839/v1/486d081209716e1459daec80.png"},{"id":30521614,"identity":"eed6010f-d4e7-45fa-8357-62c2135206f2","added_by":"auto","created_at":"2022-12-19 15:25:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":155956,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe subgroup analysis was performed according to important baseline characteristics in the whole NSTEACS patients, taking into account of MACE.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eValues are given as number of patients (%).\u003c/p\u003e\n\u003cp\u003eAbbreviations: LVEF, Left ventricular ejection fraction; PCI, Percutaneous Coronary Intervention.\u003c/p\u003e","description":"","filename":"Figure4SubgroupMACEforest.png","url":"https://assets-eu.researchsquare.com/files/rs-2290839/v1/a7edf50d1a4d1f67700df2e0.png"},{"id":31515122,"identity":"33ac1b45-b20f-440d-836a-7c220b586b9e","added_by":"auto","created_at":"2023-01-13 05:29:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":969267,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2290839/v1/f9047933-52a5-40a1-8e0e-3d4f93eee36f.pdf"},{"id":30521616,"identity":"05cefb2f-317a-433e-a042-6ce3fd2adff1","added_by":"auto","created_at":"2022-12-19 15:25:37","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":79798,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-2290839/v1/4f12c7ba0b069dabc96877ed.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between P2Y12 inhibitor reloading and In-hospital Outcomes for patients with Non-ST-segment Elevation Acute Coronary Syndrome already on Chronic P2Y12 receptor inhibitors therapy in China: Findings From the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCoronary heart disease remains a serious public health concern, emerging as the leading cause of mortality and morbidity from cardiovascular disease[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately half of the reduction in mortality can be attributed to optimal management of the acute phase of acute coronary syndrome (ACS), improved revascularization, and prevention strategies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to current guidelines, dual antiplatelet therapy using aspirin and P2Y12 receptor inhibitors is the standard of care treatment in the management of patients with ACS. In ACS patients undergoing percutaneous coronary intervention (PCI), it is strongly recommended to receive a loading dose of dual antiplatelet therapy as early as possible[\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In real-life clinic scenarios, physicians\u0026rsquo; compliance with guideline recommendations remains suboptimal and challenging[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In addition, some patients may already be on long-term therapy with P2Y12 receptor inhibitors. Whether it is necessary to reload P2Y12 receptor inhibitors for these patients or not remained underdetermined.\u003c/p\u003e \u003cp\u003ePatients on chronic clopidogrel therapy or treated with the daily clopidogrel dose were commonly excluded by most previous large randomized trials evaluating P2Y12 inhibitors for the treatment of ACS [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Thus, few studies have explored this issue to date. For STEMI (ST-segment elevation myocardial infarction) patients on long-term treatment with clopidogrel, clopidogrel reloading was associated with a decreased risk of in-hospital death and did not increase the risk of major bleeding[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, previous reports about the effects of reloading P2Y12 inhibitors in non-ST-segment elevation acute coronary syndrome (NSTEACS) are conflicting. Compared with a maintenance dose of clopidogrel, a benefit of clopidogrel reloading was found in 242 NSTEACS patients planned for PCI[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the beneficial effect of clopidogrel reloading was not observed in the Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG) study[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition, with the application of more powerful antiplatelets such as ticagrelor, it may be warranted to evaluate the effects of reloading P2Y12 inhibitors in NSTEACS patients further.\u003c/p\u003e \u003cp\u003eTherefore, this study was designed to examine the association between reloading with P2Y12 receptor inhibitors and the occurrence of in-hospital major adverse cardiac events or major bleeding in NSTEACS patients, with data from CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e The CCC-ACS project was a nationwide registry and quality improvement study focusing on quality of ACS care, which was launched in 2014 as a collaborative initiative of the American Heart Association and the Chinese Society of Cardiology. As a retrospectively observational study, each participating hospital recruited the first consecutive 20 to 30 ACS inpatient cases each month to the study, identified through principal discharge diagnosis based on review of the inpatient list. Details of the design and method of the CCC-ACS project have been published[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This project was registered at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.clinicaltrials.gov\u003c/span\u003e\u003cspan address=\"https://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Unique identifier: NCT02306616, date of first registration: 03/12/2014).\u003c/p\u003e \u003cp\u003eBasing on the principal discharge diagnosis, 113,650 ACS patients were enrolled from November 2014 to December 2019. Of these, 18,401 patients were identified as receiving long-term P2Y12 receptor inhibitors treatment (95,249 patients who did not take clopidogrel or ticagrelor within two weeks before admission were excluded). Reloading of P2Y12 inhibitors was regarded as occurring if patients received clopidogrel\u0026thinsp;\u0026ge;\u0026thinsp;300mg or ticagrelor\u0026thinsp;\u0026ge;\u0026thinsp;180mg within 24h of the first medical contact (10,397 patients without clopidogrel or ticagrelor prescription were excluded). 7,521 ACS patients with P2Y12 reloading were examined after eliminating those with missing data or obvious data error (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;483). 2,731 STEMI patients were also excluded. Finally, 4,790 NSTEACS patients represented the subject group, including 2,323 non\u0026ndash;ST-segment elevation myocardial infarction (NSTEMI) patients and 2,467 unstable angina pectoris (UAP) patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The study was conducted in accordance with the Declaration of Helsinki. The CCC-ACS project was approved by the institutional review board of Beijing Anzhen Hospital. The institutional review board of Beijing Anzhen Hospital waived the need for informed consent as retrospective nature of the study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe definition of reloading of P2Y12 inhibitors is described above. A non-loading dose of P2Y12 inhibitors was defined as clopidogrel\u0026thinsp;\u0026lt;\u0026thinsp;300mg or the ticagrelor\u0026thinsp;\u0026lt;\u0026thinsp;180mg. Effectiveness outcomes were major adverse cardiovascular event (MACE), a composite of all-cause death, myocardial infarction (MI), stent thrombosis, and ischemic stroke during hospitalization. Safety outcomes were in-hospital major bleeding, including intracranial bleeding, retroperitoneal bleeding, a decline in hemoglobin levels\u0026thinsp;\u0026ge;\u0026thinsp;20g/L during hospitalization, and transfusion with overt bleeding. All of these outcomes were recorded by clinicians during patients\u0026rsquo; hospitalization and recorded in the medical records.\u003c/p\u003e \u003cp\u003eAll the patients were categorized as either reloading of P2Y12 receptor inhibitors group and the non-reloading P2Y12 receptor inhibitors group. The demographic, clinical, and in-hospital treatment information of these two groups were compared. Continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (interquartile range) according to different distributions. Categorical variables were shown as a number (percentage).\u003c/p\u003e \u003cp\u003eDifferences in various characteristics between the reloading group and the non-reloading group were compared using \u003cem\u003et-\u003c/em\u003etest, Wilcoxon test and chi-square test where applicable.\u003c/p\u003e \u003cp\u003eUnivariable and multivariable Cox proportional hazard models were performed to examine the association between reloading of P2Y12 receptor inhibitors and in-hospital outcomes. In multivariable analysis, different Cox regression models adjusting various variables were derived. Candidate adjustment variables were examined with forward stepwise selection setting entry and exit criteria at the \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05 and 0.1 levels, respectively. Hazard ratios (HRs) for different variables and corresponding 95% confidence intervals (CIs) were shown.\u003c/p\u003e \u003cp\u003eSurvival curves of MACE and major bleeding were illustrated using Kaplan\u0026ndash;Meier curves and compared by employing log-rank tests. Because most of the patients discharged within two weeks, this study only took events that occurred within fourteen days after admission into account. Thus, the Kaplan\u0026ndash;Meier curves were based on an observation duration of fourteen days.\u003c/p\u003e \u003cp\u003eIn the subgroup analysis, clinically important variables were considered, including age (older than 75 years or not), Hemoglobin (\u0026gt;\u0026thinsp;110 g/L or not), previous bleeding history (yes or no), aspirin loading (yes or no) and left ventricular ejection fraction (LVEF) (\u0026lt;\u0026thinsp;30% or no).\u003c/p\u003e \u003cp\u003eOverall, a two-sided P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All analyses were performed with SAS software version 9.4 (SAS Institute Inc, Cary, NC).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn the present study, 48032 NSTEACS patients were analyzed, of whom 4790 (9.97%) were on long-term P2Y12 receptor inhibitors therapy, including 1,371 in the reloading of the P2Y12 receptor inhibitors group and 3,419 in the non-reloading group. For patients in the reloading group, 835 (60.9%) patients were clopidogrel reloaded and 536 (39.1%) patients were ticagrelor reloaded. 62.1% patients received chronic P2Y12 receptor inhibitors in the reloading group, while 37.9% in the non-reloading group. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, there was a lower prevalence of previous myocardial infarction, PCI, atrial fibrillation, chronic heart failure, hypertension, diabetes mellitus, smoking, bleeding history, stroke/transient ischemic attacks (TIA), renal dysfunction and acute heart failure in the reloading group. Patients in the reloading group were more likely to receive proton pump inhibitors, a loading dose of aspirin, GP IIb/IIIa and percutaneous coronary intervention. Comparisons of baseline characteristics between reloading and the non-reloading groups in NSTEMI \u0026amp; UAP are shown in \u003cb\u003eSupplement Table S2\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of NSTEACS patients in reloading P2Y12 receptor inhibitors and non-reloading P2Y12 inhibitors group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReloading group\u003c/p\u003e \u003cp\u003e(\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1371)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-reloading group\u003c/p\u003e \u003cp\u003e(\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3419)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDemographics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.33\u0026thinsp;\u0026plusmn;\u0026thinsp;11.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.18\u0026thinsp;\u0026plusmn;\u0026thinsp;11.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e946 (69.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2290 (66.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.177\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.49\u0026thinsp;\u0026plusmn;\u0026thinsp;3.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious MI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e336 (24.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1125 (32.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious PCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e389 (28.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1310 (38.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious CABG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (1.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.525\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial fibrillation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (2.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e146 (4.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic heart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (3.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e282 (8.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e790 (57.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2179 (63.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e361 (26.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1066 (31.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperlipemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e224 (16.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e592 (17.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.416\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e364 (26.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e778 (22.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (2.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke/TIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114 (8.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e355 (10.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral vascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (2.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (2.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (2.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (2.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9398\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (1.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e162 (4.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresentation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (0.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (0.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute heart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (1.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107 (3.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac arrest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (0.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.313\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGRACE score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126.98\u0026thinsp;\u0026plusmn;\u0026thinsp;40.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125.67\u0026thinsp;\u0026plusmn;\u0026thinsp;40.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKillip classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e872(63.60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1763(51.56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e312(22.76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1024(29.95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139(10.14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e467(13.66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48(3.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e165(4.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory examinations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet, (*10\u003csup\u003e9\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e203.6\u0026thinsp;\u0026plusmn;\u0026thinsp;67.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e206.8\u0026thinsp;\u0026plusmn;\u0026thinsp;64.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine, (umol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98.6\u0026thinsp;\u0026plusmn;\u0026thinsp;86.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93.35\u0026thinsp;\u0026plusmn;\u0026thinsp;80.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin, (g/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123.5\u0026thinsp;\u0026plusmn;\u0026thinsp;12.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNT-proBNP, (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1786.12\u0026thinsp;\u0026plusmn;\u0026thinsp;4006.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2158.66\u0026thinsp;\u0026plusmn;\u0026thinsp;4933.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious aspirin use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1094 (79.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2892 (84.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReloading aspirin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e898 (65.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104 (3.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProton pump inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e764 (55.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1640 (49.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGP IIb/IIIa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170 (12.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e310 (9.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOperative treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombolysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9335\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoronary artery angiography\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1013 (73.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2088 (63.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree-vessel disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e352(25.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e634(18.54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft main disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97(7.08%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e241(7.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.974\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e829 (60.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1669 (48.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCABG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (0.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (0.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.773\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny Coagulant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e845 (61.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1627 (47.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWarfarin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (0.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (5.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (4.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLMWH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e787 (93.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1458 (89.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBivalirudin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (0.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (0.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.393\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFondaparinux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (1.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (2.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.46\u0026thinsp;\u0026plusmn;\u0026thinsp;9.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.92\u0026thinsp;\u0026plusmn;\u0026thinsp;10.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCompared with the non-reloading group, the incidence of in-hospital effectiveness outcomes was much lower in the reloading group. Reloading P2Y12 receptor inhibitors had a lower incidence of MACE [7(0.51%) vs. 49 (1.42%), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007], predominantly driven by all-cause death [5 (0.36%) vs. 34 (0.99%), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028]. For the endpoint of myocardial infarction, there was no significant difference between the reloading group and the non-reloading group. For major bleeding, there was no obvious difference between these two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A lower incidence of MACE was observed in the ticagrelor group, compared with non-reloading group (0.37% vs. 1.43%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043). A similar tendency was also observed in the comparison of MACE between the clopidogrel group and the non-reloading group (0.60% vs. 1.43%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.054). No significant difference was found for major bleeding (\u003cb\u003eSupplement Table S5\u003c/b\u003e). As shown in Kaplan\u0026ndash;Meier curves, the cumulative incidence of MACE was lower in the reloading P2Y12 receptor inhibitors group (Log-rank test, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007). We did not observe a difference in cumulative incidence of major bleeding between two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the unadjusted Cox regression model, reloading P2Y12 receptor inhibitors was associated with a decreased risk of MACE (HR, 0.35; 95% CI, 0.16\u0026ndash;0.78; [\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010]) and all-cause death (HR, 0.37; 95% CI, 0.14\u0026ndash;0.94; [\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036]) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among NSTEMI patients, the reloading P2Y12 receptor inhibitors group had a lower risk of MACE, all-cause death and myocardial infarction. However, this relationship could not be observed in the UAP patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariable Cox proportional hazard models for NSTEACS patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMACE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.35 (0.16\u0026ndash;0.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll-cause death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.37 (0.14\u0026ndash;0.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyocardial infarction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.29 (0.07\u0026ndash;1.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStent thrombosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIschemic stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMajor bleeding\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.41 (0.09\u0026ndash;1.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.248\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObvious bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62 (0.13\u0026ndash;2.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.548\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransfusion bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.50 (0.06\u0026ndash;4.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.524\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.00 (0.00-\u0026infin;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.995\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRetroperitoneal bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the multivariable Cox regression analysis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), reloading P2Y12 receptor inhibitors was independently associated with MACE after adjusting age and sex (HR, 0.39; 95% CI, 0.18\u0026ndash;0.87; [\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021]). This relationship remained after adjusting age, sex and percutaneous coronary intervention (HR, 0.43; 95% CI, 0.19\u0026ndash;0.96; [\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039]). (HRs in the adjusting models are shown in \u003cb\u003eSupplement Table S3\u003c/b\u003e). However, when more variables were included in the multivariable Cox regression model, this association was undermined, with only a tendency for beneficial effects of reloading P2Y12 receptor inhibitors observed (the results for stepwise analysis are shown in \u003cb\u003eSupplement Table S4\u003c/b\u003e). The variables that were significantly different between reloading and non-reloading groups, such as GRACE score and Killip classification, when adjusted in the multivariable Cox regression model, resulted in the loss of the beneficial effects of reloading P2Y12 receptor inhibitors for MACE (data not shown).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable Cox proportional hazard models for NSTEACS patients with MACE\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.39(0.18\u0026ndash;0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.43(0.19\u0026ndash;0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026Dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.49(0.22\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.086\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.56(0.25\u0026ndash;1.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*, adjusting age and sex; \u0026dagger;, adjusting age, sex and percutaneous coronary intervention; \u0026Dagger;, adjusting age, sex and coronary artery angiography; \u0026sect;, stepwise regression model adjusting age, sex, previous myocardial infarction, previous heart failure, glycoprotein IIb/IIIa inhibitors and coronary artery angiography.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: ACS, acute coronary syndrome; NSTEACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; UAP, unstable angina pectoris.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: LVEF, Left ventricular ejection fraction; PCI, Percutaneous Coronary Intervention.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSubgroup analyses were performed according to important baseline characteristics among NSTEACS patients, taking MACE into account. Reloading of P2Y12 receptor inhibitors was associated with a decreased risk of MACE in most subgroups (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Because no events occurred in some subgroups (such as the reloading group in patients with hemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;110g/L), comparisons were not applied. No interactions were found in different subgroups. Notably, P2Y12 inhibitors reloading was beneficial in those patients undergoing PCI (HR, 0.28; 95% CI, 0.11\u0026ndash;0.71; [\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007]).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we evaluated the effect of reloading of P2Y12 inhibitors on in-hospital outcomes in ACS patients who were already on chronic treatment with P2Y12 inhibitors. The results showed that treating with a reloading dose of P2Y12 inhibitors within 24 hours of first medical contact was associated with decreased risk of major adverse cardiac events, and did not increase the risk of major bleeding.\u003c/p\u003e \u003cp\u003ePrevious studies had generally demonstrated that receiving treatment with adequate and timely platelet inhibition could decrease rates of ischemic events. Thus, antithrombotic treatment is fundamental in ACS patients. Some patients may be already taking P2Y12 receptor inhibitors for secondary prevention of myocardial infarction or stroke; or after the coronary or peripheral vascular intervention or primary intervention of atherosclerotic vascular diseases. Among NSTEACS patients, 9.97% (4790/48032) were on long-term P2Y12 receptor inhibitors therapy. Jacob A. Doll \u003cem\u003eet.al\u003c/em\u003e reported that pre-admission P2Y12 receptor inhibitor use was 9.3% among STEMI patients and 18.9% among NSTEMI patients[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In a real-world clinical setting, the proportion of patients with AMI receiving loading doses of aspirin and P2Y12 inhibitors during hospitalization was relatively low[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. For those patients on chronic treatment with P2Y12 inhibitors, the proportion of patients receiving loading doses of P2Y12 inhibitors was extremely low (28.6% in our present study). Thus, adherence to the use of enough antiplatelet therapy remained challenging. For the loading of antiplatelet therapy, many factors might influence the clinical decision. Elderly patients, concomitant comorbidities and those receiving conservative treatment were less likely to receive oral antiplatelet therapy. The effects of pretreatment with P2Y12 receptor inhibitors in patients with NSTEACS is controversial. Notably, the mortality risk and outcome of NSTEACS patients were influenced by both ischemic and bleeding complications[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, the optimal antiplatelet strategy should equally balance the ischemic and bleeding risk of the patient. Available evidence suggests that a \u0026ldquo;one-size-fits-all\u0026rdquo; strategy (i.e., routine use of pre-treatment or absolute avoidance of it) is unsuitable[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. According to the current guidelines, whether to administer routine pre-treatment with a P2Y12 receptor inhibitor in NSTEACS patients or not is undetermined[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. As for those already on chronic therapy with P2Y12 inhibitors, whether it is necessary to reload again is controversial. The Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty [ARMYDA-8 RELOAD-ACS] trial demonstrated the protective effect of clopidogrel reloading compared with a maintenance dose[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Similar to this result, our present study demonstrated that for patients presenting with NSTEACS particularly NSTEMI already taking long-term P2Y12 inhibitors, reloading of P2Y12 inhibitors was associated with a decreased risk of in-hospital major adverse cardiac events and did not increase the risk of major bleeding. Physiologically, loading antiplatelet therapy should be associated with an increased risk of bleeding. However, we found that loading P2Y12 inhibitors did not increase the risk of major bleeding. Similar results are found elsewhere[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our cohort this might be due to a higher proportion of those receiving proton pump inhibitor treatment in the reloading group (55.73% vs. 49.68%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), since gastrointestinal bleeding dominated the major bleeding in our present study. To date, the optimal reloading strategy for NSTEACS patients remains controversial. However, this beneficial effect of clopidogrel reloading was not observed in Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Among 39 158 patients with NSTEMI, no significant mortality difference was found (OR 1.13, 95% CI 0.93\u0026ndash;1.37).\u003c/p\u003e \u003cp\u003eOur present study found that reloading the P2Y12 inhibitor was related to decreased risk of in-hospital major adverse cardiac events, all-cause death and did not increase the risk of major bleeding for NSTEACS patients, particularly for NSTEMI patients. There were several potential explanations for the beneficial effect of reloading P2Y12 inhibitor. Firstly, patients on pre-admission clopidogrel may be at higher risk of adverse outcomes. In the TRILOGY trial[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], the incidence of the ischemic event at thirty months after NSTEACS was higher compared to those without chronic clopidogrel therapy. It was necessary to reinforce antithrombotic therapy in these patients who were already taking clopidogrel. Laboratory examinations of platelet function in 166 patients already on clopidogrel therapy suggested inhibition of platelet aggregation 4 hours after reloading-dose clopidogrel occurred in a dose-dependent manner[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. An additional antiplatelet effect obtained with a reloading dose of clopidogrel on the basis of the maintenance dose of clopidogrel might potentially improve clinical outcomes. Secondly, reloading clopidogrel patients were younger and more likely to be with fewer comorbid conditions[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, reloading P2Y12 patients had a lower incidence of comorbidity and were more likely to receive invasive intervention, resulting in improvement of in-hospital outcomes. After adjusting age, sex and coronary artery angiography, reloading P2Y12 inhibitors remained independently associated with MACE (\u003cb\u003eSupplement Table S3\u003c/b\u003e). Thirdly, more powerful inhibition of platelet activation and the coagulation cascade in the initial phase and evolution of NSTEACS might play an important role. Based on different pharmacokinetic and pharmacodynamic characteristics between clopidogrel and ticagrelor, ticagrelor might provide more rapid and potent platelet inhibition. In the study of Jacob A. Doll \u003cem\u003eet.al\u003c/em\u003e, no beneficial effect of reloading P2Y12 inhibitors for NSTEMI patients was observed[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In their study, only clopidogrel reloading was examined. As demonstrated in the PLATO trial[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], clopidogrel was proved to be inferior to ticagrelor in ACS patients. In our study, not only clopidogrel but also ticagrelor were included. The P2Y12 reloading group included 835(60.9%) clopidogrel reloading and 536 (39.1%) ticagrelor reloading. For the endpoint of major adverse cardiac events, reloading of ticagrelor tended to be superior to clopidogrel compared with non-reloading group (HR\u0026thinsp;=\u0026thinsp;0.26 [95% CI, 0.06\u0026ndash;1.07), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.061 and HR\u0026thinsp;=\u0026thinsp;0.42 [95% CI, 0.17\u0026ndash;1.04], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.062, respectively).\u003c/p\u003e \u003cp\u003eIn the management of NSTEACS, some baseline characteristics of patients should be considered when deciding on antithrombotic strategies. These characteristics are described in the subgroup analyses. For NSTEACS, age was a predictor of in-hospital and 6-month mortality[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In addition, elderly patients were vulnerable to major bleeding, which was associated with prolonged hospitalization and increased mortality[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In our present study, whether in subgroups under or over 75 years of age, reloading P2Y12 inhibitors tended to be associated with a lower risk of MACE and not associate with a risk of major bleeding, suggesting reloading might be efficient and safe for elder patients. Because of lack of end-point events in the remainder of the subgroups, we could not evaluate the effects of association between the reloading P2Y12 inhibitors and in-hospital outcomes. Antithrombotic strategies should be considered depending on the balance between ischemic risk and bleeding risk in actual clinical setting[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In a real-world clinical scenario, younger patients without fewer comorbidities undergoing intervention tend to be treated with a loading dose of P2Y12 inhibitor. In clinical practice, P2Y12 inhibitors and aspirin were always simultaneously administered if loading dose was considered. Reloading of P2Y12 receptor inhibitors tended to decrease the risk of MACE both in the subgroup with and without aspirin loading. We attempted to adjust the potential factors that might affect the clinical decision on reloading P2Y12 inhibitors. Multivariable Cox proportional models were derived to minimize the effects of confounding factors.\u003c/p\u003e \u003cp\u003eThere are several limitations in this study. This is a real-world observational study, and thus cannot determine causality. As a post hoc analysis from the CCC program, the present study should be considered as hypothesis-generating. We attempted to adjust the potential confounders with the multivariable Cox regression model, to explore the association between reloading P2Y12 inhibitors and in-hospital outcomes improvement in NSTEACS patients. Given the relatively few composite endpoint events that occurred in the present study and events per variable (EPV) ratio no less than 10, we attempted to limit the number of variables included in the multivariable Cox models to avoid the problem of overfitting[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Thus, with more adjusting variables included in the multivariable Cox regression model, the beneficial effect of reloading P2Y12 inhibitors seemed to be weakened. Therefore, no amount of statistical adjusting can completely remove confounding factors. Significant differences in baseline characteristics might significantly affect the outcomes, as well as the interpretation of the final results. We conducted propensity score (PS) match analysis. After PS matching of a total of 668 cases, 334 in reloading and non-loading groups, there were no significant differences of baseline characteristics. Limited by the relatively small sample size and number of events, no difference of risk of MACE and major bleeding between the two groups was found (data was not shown). A larger scale study is warranted to verify the association between P2Y12 receptor inhibitors and the outcomes. Additionally, only in-hospital outcomes could be obtained and analyzed limited by the design of the CCC program. A previous study indicated that different effects of initial antiplatelet drugs occurred within ten days in accordance with different types and dosages of antiplatelet agents[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] and the majority of events occurred in the first week after discontinuation of P2Y12 inhibitors[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Thus, the major effects of reloading P2Y12 inhibitors could be observed during hospitalization. The association between reloading P2Y12 inhibitors within 24 hours after first medical contact and long-term outcomes could be further explored in the future. Lastly, all results of this study were derived from Chinese patients. Whether this result could be extrapolated to all ethnic groups of NSTEACS patients is unclear.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients presenting with NSTEACS particularly NSTEMI already taking P2Y12 receptor inhibitor, we observed a decreased risk of in-hospital major adverse cardiac events and all-cause mortality, and did not observe an increase the risk of major bleeding, with reloading of P2Y12 receptor inhibitors within 24 hours after first medical contact. The differential profile and the global management of the patients might influence the interpretation of results, and more studies are warranted to verify the association between reloading of P2Y12 receptor inhibitors and outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACS, acute coronary syndrome; BMI, Body Mass Index; CABG, Coronary Artery Bypass Grafting; CI, Confidence Intervals; COPD, Chronic Obstructive Pulmonary Disease; HR, Hazard Ratios; LVEF, Left ventricular ejection fraction; NSTEACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, Percutaneous Coronary Intervention; STEMI, ST-segment elevation myocardial infarction; TIA, Transient Ischemic Attacks; UAP, unstable angina pectoris.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the contribution\u0026nbsp;of all investigators in the participating hospitals in the project. A complete list of CCC-ACS Investigators was given in \u003cstrong\u003eSupplement Table S1\u003c/strong\u003e. We also thank Professor Daniel Porter for his help in polishing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the writing and editing of the manuscript. Ping Zhang, Yintang Wang, Yu Geng and Ou Zhang conceived and designed the project; The statistician Qin Xu contributed to design and analyze data. Yajun Xue, Yingtang Wang and Yu Geng conducted data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CCC-ACS project is a collaborative study of the American Heart Association (AHA) and the Chinese Society of Cardiology. The American Heart Association received funding from Pfizer through an independent grant for learning and change and AstraZeneca as a quality improvement initiative.\u0026nbsp;The work was also supported by the Beijing Municipal Administration of Hospitals\u0026rsquo; Ascent Plan (Code: DFL20190902), Tsinghua University Spring Breeze Fund, and the Beijing Tsinghua Changgung Hospital Fund (Grant No. 12019C1009).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data presented in this study are available on request to the corresponding author ([email protected] or [email protected]) for purposes of reproducing the results or replicating the procedure. The data are not publicly available due to privacy restrictions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki. The CCC-ACS project was approved by the institutional review board of Beijing Anzhen Hospital. The institutional review board of Beijing Anzhen Hospital waived the need for informed consent as retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eChina National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, Boehme AK, Buxton AE, Carson AP, Commodore-Mensah Y, et al. 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N Engl J Med. 2012;367(14):1297\u0026ndash;309.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoll JA, Li S, Chiswell K, Roe MT, Kosiborod M, Scirica BM, Wang TY. Clopidogrel reloading for patients with acute myocardial infarction already on clopidogrel therapy. Eur Heart J. 2018;39(3):193\u0026ndash;200.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatti G, Pasceri V, Mangiacapra F, Colonna G, Vizzi V, Ricottini E, Montinaro A, D'Ambrosio A, Wijns W, Barbato E, et al. Efficacy of clopidogrel reloading in patients with acute coronary syndrome undergoing percutaneous coronary intervention during chronic clopidogrel therapy (from the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty [ARMYDA-8 RELOAD-ACS] trial). Am J Cardiol. 2013;112(2):162\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHao Y, Liu J, Liu J, Smith SC Jr, Huo Y, Fonarow GC, Ma C, Ge J, Taubert KA, Morgan L, et al. Rationale and design of the Improving Care for Cardiovascular Disease in China (CCC) project: A national effort to prompt quality enhancement for acute coronary syndrome. Am Heart J. 2016;179:107\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang X, Liu L, Yang J, Gao Z, Zhao X, Qiao S, Gao R, Wang Z, Yuan J, Yang Y. Evidence-based oral antiplatelet therapy among hospitalized Chinese patients with acute myocardial infarction: results from the Chinese acute myocardial infarction registry. BMC Cardiovasc Disord. 2021;21(1):299.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNdrepepa G, Berger PB, Mehilli J, Seyfarth M, Neumann FJ, Schomig A, Kastrati A. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol. 2008;51(7):690\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreiro JL. Pre-Treatment With Oral P2Y12 Inhibitors in Non-ST-Segment Elevation Acute Coronary Syndromes: Does One Size Fit All? JACC Cardiovasc Interv. 2020;13(8):918\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schomig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation. 2004;110(14):1916\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCollet JP, Silvain J, Landivier A, Tanguy ML, Cayla G, Bellemain A, Vignolles N, Gallier S, Beygui F, Pena A, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the Reload with Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy (RELOAD) study. Circulation. 2008;118(12):1225\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFox KA, Eagle KA, Gore JM, Steg PG, Anderson FA, Grace, Investigators G. The Global Registry of Acute Coronary Events, 1999 to 2009\u0026ndash;GRACE. Heart. 2010;96(14):1095\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosengren A, Wallentin L, Simoons M, Gitt AK, Behar S, Battler A, Hasdai D. Age, clinical presentation, and outcome of acute coronary syndromes in the Euroheart acute coronary syndrome survey. Eur Heart J. 2006;27(7):789\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndreotti F, Rocca B, Husted S, Ajjan RA, ten Berg J, Cattaneo M, Collet JP, De Caterina R, Fox KA, Halvorsen S, et al. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2015;36(46):3238\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConcato J, Peduzzi P, Holford TR, Feinstein AR. Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy. J Clin Epidemiol. 1995;48(12):1495\u0026ndash;501.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCadroy Y, Bossavy JP, Thalamas C, Sagnard L, Sakariassen K, Boneu B. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation. 2000;101(24):2823\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranchi F, Rollini F. Patterns and Outcomes of Dual Antiplatelet Therapy Discontinuation After Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2022;15(8):807\u0026ndash;09.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"P2Y12 receptor inhibitors, non-ST-segment elevation acute coronary syndrome, loading dose, outcome, therapy","lastPublishedDoi":"10.21203/rs.3.rs-2290839/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2290839/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe association between P2Y12 receptor inhibitors reloading and in-hospital outcomes in non-ST-segment elevation acute coronary syndrome (NSTEACS) patients who were on chronic P2Y12 receptor inhibitors therapy remained underdetermined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Improving Care for Cardiovascular Disease in China–Acute Coronary Syndrome (CCC-ACS project) is a national registry active from November 2014 to December 2019. 4790 NSTEACS patients on chronic P2Y12 receptor inhibitors therapy were included. Cox proportional hazard models, Kaplan–Meier curves, and subgroup analyses were conducted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NSTEACS patients who received reloading of P2Y12 receptor inhibitors were younger and had fewer comorbid conditions. The reloading group had a lower risk of major adverse cardiac events (MACE) (0.51% vs. 1.42%, \u003cem\u003eP\u003c/em\u003e = 0.007), and all-cause death (0.36% vs. 0.99%, \u003cem\u003eP\u003c/em\u003e = 0.028), the risks of myocardial infarction and major bleeding were not significantly different between patients with and without reloading. In survival analysis, a lower cumulative risk of MACE could be identified (Log-rank test, \u003cem\u003eP\u003c/em\u003e = 0.007) in reloading group. In the unadjusted Cox model, reloading P2Y12 receptor inhibitors was associated with a decreased risk of MACE (HR, 0.35; 95% CI, 0.16-0.78; [\u003cem\u003eP\u003c/em\u003e = 0.010]) and all-cause death (HR, 0.37; 95% CI, 0.14-0.94; [\u003cem\u003eP\u003c/em\u003e = 0.036]). Reloading of P2Y12 receptor inhibitors was associated with a decreased risk of MACE in most of the subgroups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn NSTEACS patients already taking P2Y12 receptor inhibitors, we observed a decreased risk of in-hospital MACEs and all-cause mortality and did not observe an increased risk of major bleeding, with reloading. The differential profile in the two groups might influence this association and further studies are warranted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e: https://www.clinicaltrials.gov (Unique identifier: NCT02306616, date of first registration: 03/12/2014).\u003c/p\u003e","manuscriptTitle":"Association between P2Y12 inhibitor reloading and In-hospital Outcomes for patients with Non-ST-segment Elevation Acute Coronary Syndrome already on Chronic P2Y12 receptor inhibitors therapy in China: Findings From the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-19 15:25:32","doi":"10.21203/rs.3.rs-2290839/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"41b66f8a-1e3e-4091-8c8c-8a8f7e63c1ea","owner":[],"postedDate":"December 19th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-17T14:14:32+00:00","versionOfRecord":[],"versionCreatedAt":"2022-12-19 15:25:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2290839","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2290839","identity":"rs-2290839","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}