In-hospital outcomes of anemic patients with acute coronary syndrome receiving ticagrelor versus clopidogrel: Results of the Chinese Cardiovascular Care Improvement (CCC)-Acute Coronary Syndrome Project

To the Editor: Dual antiplatelet therapy (DAPT), which comprises aspirin plus a P2Y12 receptor inhibitor, is the standard approach for reducing cardiac and systemic ischemic events in individuals with coronary artery disease.[1] Although DAPT reduces ischemic episodes, it also increases the risk of bleeding. In individuals with acute coronary syndrome (ACS), bleeding incidents during hospitalization not only greatly increase the risk of in-hospital death but also increase the risk of long-term mortality and major adverse cardiovascular events.[2] Therefore, the management of DAPT must consider both bleeding and ischemic risks. Anemia is a frequently observed complication in individuals diagnosed with ACS.[3] Anemic patients have increased susceptibility to ischemia and bleeding events after percutaneous coronary intervention (PCI), especially in the case of ACS.[4] There are presently no particular guidelines for early antiplatelet treatment in anemic individuals with ACS receiving PCI. Therefore, the aim of our study was to assess the in-hospital effectiveness and safety of ticagrelor and clopidogrel in anemic ACS patients undergoing PCI. To enhance the standard of treatment for individuals with ACS, the American Heart Association (AHA) and the Chinese Society of Cardiology (CSC) collaborated on the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS) project. The project was launched in November 2014 and involves 240 hospitals located across various geographical and economic regions of China. Further details have been previously documented.[5] This study is registered at http://www.clinicaltrials.gov/ (NCT02306616). The study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (No.2014018) with a wavier of patient consent. From November 1, 2014 to December 30, 2019, the data of 113,650 ACS patients across 240 hospitals were recorded in the database. Among these patients, 69,608 underwent PCI and received DAPT (aspirin plus clopidogrel or ticagrelor). Of these patients, 7477 individuals diagnosed with anemia were categorized based on the specific P2Y12 receptor inhibitor utilized within the initial 24-hour period following their first medical contact. The patients were split into two groups: the ticagrelor group (aspirin plus ticagrelor group) and the clopidogrel group (aspirin plus clopidogrel group) [Supplementary Figure 1, https://links.lww.com/CM9/C128]. Hemoglobin (Hb) levels below 120 g/L for males and 110 g/L for females were considered to indicate anemia. Mild anemia was defined as follows: 90 g/L ≤Hb level <110 g/L for women, 90 g/L ≤Hb level <120 g/L for men; an Hb level <90 g/L indicated moderate to severe anemia. The initial dose of the P2Y12 receptor inhibitor was specified as being equal to or greater than 300 mg for clopidogrel and equal to or greater than 180 mg for ticagrelor. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). The primary efficacy endpoint focused on major adverse cardiovascular and cerebrovascular events (MACCEs) occurring during hospitalization. MACCEs were defined as a composite of cardiac death, non-fatal myocardial infarction (MI), stent thrombosis, and ischemic stroke observed within the inpatient setting. The primary safety endpoint was major bleeding, defined as a decrease in the Hb level of 5 g/dL, cardiac tamponade, surgical intervention for bleeding, the use of intravenous vasoactive agents for bleeding control, intracranial hemorrhage or fatal bleeding. These events were classified according to Bleeding Academic Research Consortium (BARC) types 3b-3c and 5. Patients with bleeding associated with coronary artery bypass grafting (CABG) (BARC type 4) were excluded. Continuous variables are reported using either mean ± standard deviation (SD) or median (interquartile range), and categorical variables are presented as proportions (n %). The standardized mean difference (SMD) was used to assess the baseline characteristics between the two groups, and an SMD value less than 0.1 was deemed to indicate statistical non-significance. A logistic regression model with multiple variables was utilized to calculate the propensity score (PS), where ticagrelor served as the outcome variable, and all variables listed in Supplementary Table 1, https://links.lww.com/CM9/C128 (excluding left ventricular ejection fraction (LVEF) and body mass index (BMI), which were unavailable for 20.4% and 38.7% of patients respectively) were considered independent variables. In the inverse probability treatment weighting (IPTW) analysis, the weight of each patient who received ticagrelor was determined by dividing the proportion of patients who received ticagrelor by their respective PS, while the weight of each patient who did not receive ticagrelor was calculated by dividing the proportion of patients who did not receive ticagrelor by one minus their PS. The sensitivity analysis employed multivariable logistic regression and added PS as a covariate to adjust for potential confounding factors. The statistical analyses were conducted using SPSS 22.0 (IBM Corp., Armonk, NY, USA) and R (version 4.4.2, R Foundation for Statistical Computing, Vienna, Austria). We performed statistical tests with a two-tailed approach and regarded a P-value <0.05 as suggestive of statistically significant findings. A total of 7477 patients (10.7%) met the criteria for anemia. Most of the 7477 anemic ACS patients were treated with clopidogrel (n = 5411, 72.4%). The baseline characteristics of the patients are summarized in Supplementary Table 1, https://links.lww.com/CM9/C128. Following the implementation of IPTW, the baseline characteristics of the two groups were well balanced (all SMD <0.10) [Supplementary Table 1, https://links.lww.com/CM9/C128]. In-hospital outcomes according to P2Y12status. No substantial differences in all-cause mortality, cardiac mortality, non-fatal MI, stent thrombosis, ischemic stroke, or MACCEs were detected between the two groups prior to IPTW. There was no significant difference in the occurrence of gastrointestinal bleeding between the two groups. Nonetheless, the ticagrelor group exhibited a greater incidence of major bleeding than did the clopidogrel group (2.2% [n = 45] vs. 1.3% [n = 68], P = 0.003) [Supplementary Table 2, https://links.lww.com/CM9/C128]. After IPTW, no significant differences were observed in terms of all-cause mortality, cardiac mortality, non-fatal MI, stent thrombosis, ischemic stroke, or MACCEs. The incidence of gastrointestinal bleeding did not significantly differ between the two groups. The frequency of major bleeding events in the ticagrelor group was significantly greater than that in the clopidogrel group (2.3% [n = 48] vs. 1.3% [n = 69], P = 0.002) [Supplementary Table 2, https://links.lww.com/CM9/C128]. Sensitivity analysis. Compared with the use of clopidogrel, the use of ticagrelor was found to significantly increase the likelihood of major bleeding according to both univariate logistic regression (odds ratios [OR] [95% confidence interval [CI]: 1.750 [1.196, 2.559], P = 0.004) and IPTW models (OR [95% CI]: 1.836 [1.264, 2.668], P = 0.001). However, no significant differences were observed between the group receiving clopidogrel and the group receiving ticagrelor in terms of all-cause mortality, cardiac mortality, non-fatal MI, stent thrombosis, ischemic stroke, or MACCEs. After multivariable adjustment with the PS, compared with the use of clopidogrel, the use of ticagrelor significantly increased the likelihood of major bleeding (OR [95% CI]: 1.658 [1.112, 2.472], P = 0.013). There was no significant difference in the risk of all-cause mortality, cardiac mortality, non-fatal MI, stent thrombosis, ischemic stroke, or MACCEs between the group receiving clopidogrel and the group receiving ticagrelor [Supplementary Table 3, https://links.lww.com/CM9/C128]. The outcomes of the sensitivity assessment exhibited congruity with those obtained from the primary analysis. Subgroup analysis. No significant differences in MACCEs were observed among the subgroups [Supplementary Figure 2, https://links.lww.com/CM9/C128]. Ticagrelor exhibited a stronger association with major bleeding risk in females than in males (P for interaction = 0.034) [Supplementary Figure 3, https://links.lww.com/CM9/C128]. The effect of mild and moderate to severe anemia on the outcomes of patients receiving different antiplatelet therapies is shown in Supplementary Figure 4, https://links.lww.com/CM9/C128. Ticagrelor is a powerful P2Y12 receptor inhibitor with direct and reversible actions. Compared with clopidogrel, ticagrelor inhibits platelets more effectively and rapidly.[6] According to the findings of the Platelet Inhibition and Patient Outcomes (PLATO) study, compared with clopidogrel treatment, ticagrelor treatment significantly decreased the risk of MI, stroke, and vascular death without increasing the total rate of major bleeding.[7] The PLATO study included only a few Asian patients, and it has been reported that various racial groups may experience variable risks of ischemia and bleeding episodes. East Asian patients typically exhibit decreased susceptibility to ischemic events but increased vulnerability to bleeding.[8] Several studies conducted in East Asian populations with ACS have shown no clear benefit of ticagrelor over clopidogrel. In a large retrospective study of 62,580 American and Korean patients, the risk of ischemia events and mortality were not significantly different between the ticagrelor and clopidogrel groups. However, it was shown that ticagrelor was linked to a greater incidence of gastrointestinal bleeding or hemorrhagic stroke and dyspnea.[9] Another possible explanation for the reduced benefit of ticagrelor is the use and development of drug-eluting stents. Drug-eluting stents can deliver anti-intimal hyperplasia drugs to the vessel wall to prevent restenosis while retaining the support of bare metal stents. An abundance of clinical studies has demonstrated that the likelihood of in-stent restenosis can be greatly reduced by comparing drug-eluting stents to conventional bare-metal stents. Newer iterations of drug-eluting stents further improve the prognosis of individuals with ACS. In the PLATO study, more than 60% of the study participants were given bare-metal stents, and the majority of the remaining participants received first-generation drug-eluting stents. In contrast, contemporary patients use more drug-eluting stents. In our study, drug-eluting stents were administered to 84.9% of anemic patients, which may have somewhat decreased the need for stronger P2Y12 inhibitors. Additionally, anemic ACS patients tend to be of advanced age and present with other concomitant bleeding risk factors. Several studies have shown that ticagrelor has no significant benefit over clopidogrel in the elderly population, even in non-East Asian regions. Sex disparities in the risk profiles of ACS patients receiving PCI have been noted. Some studies have shown that females exhibit a greater tendency to experience elevated bleeding risk than males.[10] In the present investigation, we observed no statistically significant differences between the sexes in the use of ticagrelor and clopidogrel. Compared to their male counterparts, women were found to exhibit a greater likelihood of experiencing major bleeding when administered ticagrelor as opposed to clopidogrel (P for interaction = 0.034). Our study suggested that ticagrelor should be used more cautiously in anemic women with ACS. In conclusion, in anemic ACS patients receiving PCI, patients who received ticagrelor had a comparable risk of MACCEs to those who received clopidogrel but a noticeably increased risk of major bleeding during hospitalization. Randomized controlled trials with a large number of participants are necessary to explore the optimal antiplatelet therapy for anemic ACS patients. Funding This study was supported by the China National Key R&D Project (contract No. 2022YFC2503500); The CCC-ACS project is a program of the AHA and the CSC. The AHA received funding from Pfizer through an independent grant for learning and change and AstraZeneca as a quality improvement initiative. Acknowledgement The authors would like to express their sincere gratitude for the invaluable technical support provided by Dr. Jun Liu and her team. We thank the hospitals that took part for their contributions to the CCC-ACS Project. Conflicts of interest None.