This was a real-world, single-center cohort study that retrospectively analyzed 1,816 high-risk ACS patients who underwent PCI and compared the impact of different DAPT regimens on patient prognosis. Research has revealed that in the real clinical world, double high-risk ACS patients account for a relatively high proportion of the total ACS population. For these patients, a dual DAPT regimen of conventional aspirin combined with clopidogrel is recommended, as it not only reduces the incidence of ischemic events but also does not increase bleeding events. An intensive DAPT regimen combining aspirin and ticagrelor can also be chosen, but caution should be exercised due to the potential for minor bleeding events. For such patients, a de-escalation treatment regimen of DAPT is not recommended.
The drug types and duration of DAPT for ACS patients have always been a controversial topic in the cardiovascular field. Current research has shown that the risk of ischemia and bleeding in patients can be evaluated using ischemia and bleeding scores, which can then guide the extension or shortening of the duration of DAPT. [11–14] Regarding the research population, most studies have focused on individuals at high risk for ischemia, and none of these studies have mentioned antiplatelet treatment regimens for ACS patients at high risk for both ischemia and bleeding. Our study adjusted for the types of antiplatelet drugs and maintained a DAPT duration of at least 12 months, and the dual high risk was based on the standards set by the BIRISK study. Currently, few related research reports are available. We divided patients into three groups according to the antiplatelet regimen consisting of combinations of different P2Y12 receptor inhibitors with aspirin. At 3 months post-PCI, patients in the de-escalation group were converted from 90 mg of ticagrelor to 60 mg of ticagrelor or 75 mg of clopidogrel. The idea of de-escalation is based on clinical observations showing that some patients who take 90 mg of ticagrelor experience irritating bleeding events, such as skin and limb mucosal congestion, gingival bleeding, and nasal bleeding, which are considered to be active de-escalation events. The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial revealed that both 90 mg and 60 mg of ticagrelor reduced the incidence of MACCEs compared to that of clopidogrel (90 mg group vs. placebo, HR 0.85, P = 0.008; 60 mg of ticagrelor vs. placebo, HR 0.84, P = 0.004) and suggested that 60 mg of ticagrelor may provide a more desirable cost-effectiveness ratio than 90 mg of this drug [15] and be a safer antiplatelet option for the East Asian population. [16] However, the study enrolled stable coronary heart disease patients. Our study revealed that de-escalation treatment did not reduce the incidence of bleeding events. Although this treatment could reduce minor bleeding events, it increased the incidence of MACCEs. Moreover, no significant difference in the incidence of minor bleeding events was observed among the three groups within 3 months after PCI.
In the early stage of ACS (within 1 month), ticagrelor still has a significant advantage in preventing ischemic events. [17] Within 6 months after drug-eluting stent (DES) implantation, the risk of thrombosis in the stent continues to increase, especially within 4 − 6 weeks after PCI. However, in patients who had implantation of a new-generation DES, no significant difference in the incidence of stent thrombosis was observed between patients on DAPT for 3 months and those on DAPT for 6 months. [18] The conversion of P2Y12 receptor inhibitors requires clinical physicians to evaluate the potential ischemic risk due to de-escalation. If de-escalation is needed, it should be performed no less than 1 month after PCI, preferably 3 months post-PCI. The reason is that the ischemic risk of ACS is related to time. [19] Therefore, we chose to reduce the dose of ticagrelor or change to clopidogrel at 3 months after PCI to reduce ischemic events, including thrombosis in the stent. However, the results of this study showed that for ACS patients at dual high risk, de-escalation treatment at 3 months after PCI actually increased the incidence of MACCEs and did not reduce the risk of bleeding. Therefore, for ACS patients at dual high risk, this study does not recommend using a de-escalation treatment plan at 3 months after PCI.
Regarding the study population, ACS patients enrolled in the TOPIC study and AMI patients with high ischemic risk in the TALOS study underwent de-escalation one month after PCI. In the de-escalation group, the DAPT regimen was changed from aspirin combined with a new P2Y12 receptor inhibitor (prasugrel or ticagrelor) to aspirin combined with clopidogrel one month after PCI. The maintenance group was treated with aspirin combined with a new P2Y12 receptor inhibitor (prasugrel or ticagrelor) after PCI. The study revealed that the DAPT de-escalation scheme (converting from ticagrelor to clopidogrel) was superior to the maintenance DAPT scheme based on ticagrelor, with a significant reduction in bleeding risk and no increase in ischemic risk. [20–21] The subgroup analysis of high bleeding risk in the TWILIGHT study confirmed that for patients with high bleeding defined by the ARC-HBR criteria, converting a combination of ticagrelor and aspirin to ticagrelor monotherapy at 3 months after treatment reduced the bleeding risk compared to 12 months of treatment with ticagrelor (P = 0.008). [8] The MASTER-DAPT study showed that for high bleeding risk (HBR) patients who had implantation of DESs, MACCEs were not inferior in patients who received a shorter DAPT duration one month after PCI than in those who received the standard DAPT regimen (95% CI: -1.80 to 33, pnoninferiority < 0.001), and the MACCEs reduced the incidence of bleeding events (6.5% vs. 9.11%, 95% CI: -4.40 to 1.24, pnoninferiority < 0.001). [7] Therefore, in HBR patients after PCI, a shorter duration of DAPT (1 − 3 months) is also a potential option. However, none of the abovementioned patients were double high-risk patients. Currently, only the OPT-BIRISK study has focused on antiplatelet strategies in ACS patients with high risk for both ischemia and bleeding after PCI, but it investigated the selection of antiplatelet drugs 9 − 12 months after PCI. Additionally, we studied the impact of selecting the type of P2Y12 receptor inhibitor on prognosis during the 12-month follow-up period after PCI, covering the combination of aspirin and different P2Y12 receptor inhibitors that are commonly used in real clinical work.
Cox regression analysis revealed that intensive DAPT can reduce the incidence of ischemic events, and compared to routine DAPT, intensive DAPT did not increase the incidence of major bleeding events, which is consistent with the results of the PLATO study. [4] Although intensive treatment with ticagrelor can reduce ischemic events compared with that of de-escalation treatment, no difference in ischemic events was observed when compared with routine treatment with clopidogrel combined with aspirin; however, ticagrelor increases the risk of bleeding, especially minor bleeding, compared with that of routine treatment. If the risk of minor bleeding is ignored, intensive antithrombotic therapy can be an alternative option for the dual high-risk population. However, the OPT-BIRISK study defines the "dual high-risk population" as individuals who are elderly (over 75 years of age), between ages 65 and 75 years and meet one of the criteria to be considered at high risk of ischemia or bleeding, or aged < 65 years and meet the criteria for high risk of both ischemia and bleeding. However, relatively few variables are related to a high bleeding risk, such as whether oral anticoagulants are taken simultaneously; the presence of liver dysfunction; past history of bleeding, surgery, and tumor; and other bleeding-related factors. The lack of relevant bleeding variables may lead to bias in the selected population, in that the selected patients may be more inclined toward a high risk of ischemia, resulting in research results recommending the use of intensive antiplatelet therapy. In addition, the BIRISK study defined high-risk ACS populations based on age which included not only individuals who met criteria for both ischemia and bleeding risks but also individuals with an relationship between ischemia and bleeding risks. Whether this definition should be used to explain "dual high risks" remains to be debated.
In this study, a history of cerebrovascular disease and atrial fibrillation were found to be independent risk factors for NACEs and MACCEs, indicating an increased risk of ischemia in patients with cerebrovascular disease. However, in patients with atrial fibrillation, oral anticoagulants may reduce the use of antiplatelet drugs, thereby increasing the incidence of ischemic events.
In summary, for ACS patients with a high risk for both ischemia and bleeding, conventional aspirin combined with clopidogrel treatment is the preferred antiplatelet regimen. This combination does not increase bleeding events as does ticagrelor, nor does it avoid the increase in ischemic events caused by de-escalation.