Effects of dual antiplatelet therapy de-escalation on the prognosis of acute coronary syndrome patients at high risk of ischemia who underwent percutaneous coronary intervention

To the Editor: Current guidelines recommend that for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT), preferably involving powerful P2Y12 receptor inhibitors, including ticagrelor or prasugrel, should be used for at least 12 months.[1–3] However, there is a lack of relevant evidence regarding the feasibility of de-escalation treatment and specific DAPT treatment regimens for ACS patient populations with high ischemic risk. From March 2017 to September 2021, 1335 ACS patients with Optimal Antiplatelet Therapy for Chinese Patients with Coronary Artery Disease (OPT-CAD) ischemia scores of at least 91 points and with a ≥12-month history of oral DAPT were identified at Langfang People’s Hospital to explore the impact of a de-escalation treatment regimen, namely, replacing ticagrelor with clopidogrel or reducing the dosage of ticagrelor, on the prognosis of ACS patients at high risk of ischemia undergoing PCI. The study involving human participants were reviewed and approved by the Ethics Committee of Clinical Investigation, Langfang People’s Hospital (No. 2023-YXLW-014). The exemption of informed consent has been approved by the medical ethics committee. According to the type and dosage of antiplatelet drugs, the study included 679 patients in the clopidogrel group, 469 patients in the ticagrelor group, 76 patients in de-escalation group 1, and 111 patients in de-escalation group 2. The patients in de-escalation group 1 were administered DAPT after PCI (aspirin 100 mg one time a day (qd) + ticagrelor 90 mg twice a day (bid)); dosage of ticagrelor was reduced to 60 mg bid at 3 months after PCI, and DAPT was continued for 9 more months. Ticagrelor was replaced with clopidogrel 75 mg qd at 3 months after PCI, and DAPT was continued for 9 more months for patients of de-escalation group 2. The patients in the clopidogrel group were administered DAPT after PCI (aspirin 100 mg qd + clopidogrel 75 mg qd) for 12 months. The patients in the ticagrelor group were administered DAPT after PCI (aspirin 100 mg qd + ticagrelor 90 mg bid) for 12 months. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCEs) during follow-up, including cardiac death, myocardial infarction, ischemia-driven revascularization, and stroke. The primary safety end point was bleeding events, including major bleeding and minor bleeding defined by thrombolysis in myocardial infarction (TIMI).[4] The follow-up period was 12 months after PCI (the median follow-up duration was 38.32 months [17.72, 71.73]). The OPT-CAD scoring system was used in this study [Supplementary Table 1, https://links.lww.com/CM9/B891].[5] SPSS 26.0 software (IBM, Armonk, New York, USA) was used for statistical analysis. Measurement data with normal distribution are expressed as the mean ± standard deviation, and comparisons among the groups were analyzed by one-factor analysis of variance (ANOVA). Measurement data with non-normal distribution are expressed as median and interquartile interval, and comparisons among the groups were analyzed by the rank-sum test. Count data are expressed as frequencies and percentages, and the chi-squared test was used for analysis among the groups. Cox multivariate regression analysis was used to adjust the baseline data. Kaplan–Meier analysis was used to analyze the survival rate of the four groups of patients. Based on bilateral tests, P ≤0.008 indicated a statistically significant difference among the four groups. According to the baseline data, the age of the clopidogrel group (64.16 ± 8.54 years) was larger than that of the ticagrelor group (60.94 ± 9.30 years) (P <0.001) and de-escalation group 2 (61.05 ± 8.82 years) (P = 0.001) [Supplementary Table 2, https://links.lww.com/CM9/B891]. The proportion of unstable angina in the ticagrelor group (97/469 [20.7%]) was significantly smaller than that in the clopidogrel group (269/679 [39.6%]) and de-escalation group 2 (39/111 [35.1%]) (P <0.001, P = 0.001, respectively). The proportion of ST-segment elevation myocardial infarction (STEMI) patients in the ticagrelor group (341/469 [72.7%]) was significantly larger than that in the clopidogrel group (362/679 [53.3%]) and de-escalation group 2 (66/111 [59.5%]) (P <0.001, P = 0.006, respectively). The proportion of emergency PCI patients in the ticagrelor group (314/469 [67.0%]) was larger than that in de-escalation groups 1 (39/76 [51.3%]) and 2 (50/111 [45.0%]) and the clopidogrel group (306/679 [45.1%]) (P = 0.008, P <0.001, P <0.001, respectively). The proportion of high-risk patients with the Academic Research Consortium for High Bleeding Risk (ARC-HBR) scores in the clopidogrel group (198/679 [29.2%]) was statistically significantly larger than that in the ticagrelor group (81/469 [17.3%]) and de-escalation group 2 (17/111 [15.3%]) (P <0.001; P = 0.002). According to the laboratory test results, the N-terminal proBNP level in de-escalation group 1 (393.00 [107.00, 450.00] ng/L) was lower than that in the clopidogrel group (465.00 [153.25, 1105.00] ng/L) and the ticagrelor group (569.00 [233.75, 1337.75] ng/L) (P = 0.005, P <0.001, respectively) [Supplementary Table 3, https://links.lww.com/CM9/B891]. The proportion of patients with ostial lesions in de-escalation group 2 (13/111 [11.7%]) was lower than that in the clopidogrel group (175/679 [25.8%]) and the ticagrelor group (120/469 [25.6%]) (P = 0.001, P = 0.002, respectively) [Supplementary Table 4, https://links.lww.com/CM9/B891]. The proportion of patients with diffused lesions in the clopidogrel group (324/679 [47.7%]) was statistically significantly higher than that in de-escalation group 2 (33/111 [29.7%]) (P <0.001). The incidence of in-stent restenosis in de-escalation group 1 (5/76 [6.6%]) was higher than that in the clopidogrel group (8/679 [1.2%]) (P = 0.003). The cox regression showed an increased incidence of MACCEs in the de-escalation group 2 compared with the clopidogrel group (hazard ratio [HR] = 2.359, 95% confidence interval [CI]: 1.233–4.512, P = 0.009), and patients with complete revascularization have a lower incidence of MACCEs (HR = 0.507, 95% CI: 0.311–0.829, P = 0.007) [Supplementary Table 5, https://links.lww.com/CM9/B891]. The incidence of MACCEs was significantly lower in the ticagrelor group (13/469 [2.8%]) than that in de-escalation group 2 (10/111 [9.0%]) (P = 0.003) [Supplementary Table 6, https://links.lww.com/CM9/B891]. The Kaplan–Meier curve showed that the incidence of MACCEs in both de-escalation groups did not significantly increase within 3 months after PCI (P = 0.651); the incidence of MACCEs in the ticagrelor group was significantly lower than that in de-escalation group 2 (P = 0.001) from the 3rd to 12th month after PCI, and there was no significant difference in bleeding risk among the four groups [Figure 1].Figure 1: (A) MACCE cumulative incidence. Cut-off point: 3 months after PCI. (B) Bleeding event cumulative incidence. Cut-off point: 3 months after PCI. (C) Major bleeding event cumulative incidence. Cut-off point: 3 months after PCI. MACCEs: Major adverse cardiovascular and cerebrovascular events; PCI: Percutaneous coronary intervention.The results confirmed that for ACS patients with a moderate or high risk of ischemia (with OPT-CAD ischemic scores ≥91), de-escalation to aspirin and ticagrelor 60 mg after 3 months increased the risk of MACCEs. In the TALOS AMI study, de-escalation from a powerful P2Y12 receptor inhibitor to clopidogrel one month after PCI was performed, and the results confirmed that de-escalation can reduce the incidence of bleeding events within one year (3.0% vs. 5.6%, P = 0.001) and did not increase the incidence of ischemic events (2.1% vs. 3.1%, P = 0.148).[6] However, the patients selected for that study were all patients who had no adverse events within one month after PCI. Our study had a relatively clear definition of high ischemic risk and a relatively complete evaluation system. The Kaplan–Meier curve suggested that intensive treatment with ticagrelor 90 mg reduced the occurrence of MACCEs and improved the prognosis of patients within one year after PCI. From the Kaplan–Meier curve we can conclude that although not statistically significant, de-escalation from ticagrelor 90 mg to ticagrelor 60 mg and initial application of clopidogrel showed an increase tendency of MACCEs, which reflects the advantage of intensive antiplatelet therapy with ticagrelor 90 mg in improving the prognosis of patients at high ischemic risk. In our study, some patients, especially those at high risk according to the ARC-HBR score, were administered the DAPT regimen of aspirin combined with clopidogrel after PCI. Although drug adjustments are consistent with the status of real-world retrospective cohort studies, active drug adjustments for high bleeding risk patients can also have an impact on the research results. The de-escalation of antiplatelet therapy is an individualized and optimized treatment for patients with CHD. The essence of this is the individualized evaluation of CHD patients and the maximization of drug benefits. A review of 21 related randomized controlled trials (RCTs) suggests that complete revascularization can reduce the incidence of MACCEs in patients with acute myocardial infarction,[7] which was similar to our outcome of the cox regression. It is suggested that for patients at high risk of ischemia with multiple vessel lesions, complete revascularization should be performed while fully evaluating the characteristics of the lesions. The limitations of this study were as follows: First, it was a retrospective study with a small sample size and short follow-up time, resulting in a low incidence of primary endpoint events, which affects the overall testing efficiency of this study. Second, for the standard group of patients who started using clopidogrel, the proportion of HBR-ARC high-risk patients was the highest, with statistical significance between groups. Active de-escalation based on high bleeding risk also affects the outcome of the final bleeding event. In conclusion, for ACS patients with high ischemic risk undergoing PCI, a de-escalation treatment regimen of clopidogrel at 3 months increased the incidence of ischemic events compared with an intensive treatment regimen of ticagrelor 90 mg, while there was no significant difference in the incidence of bleeding events. For such patients, 12 months of ticagrelor 90 mg intensive antiplatelet therapy could be considered. Funding This study was supported by the Self-financing Project of Lang Fang Science and Technology Research and Development Plan (Nos. 2022013038 and 2020013106), and Guiding Project of Hebei Medical Science Research Program (No. 20232053). Conflicts of interest None.