Jing-jing Xu, Si-da Jia, Lin Jiang, Ying Song, Pei Zhu, De-shan Yuan, Yi Yao, Xue-yan Zhao, Jian-xin Li, Yue-jin Yang, Shu-bin Qiao, Bo Xu, Run-lin Gao, Jin-qing Yuan
Department of Cardiology, Fuwai Hospital and Cardiovascular Institute, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
KEYWORDS: Dual antiplatelet therapy; Acute coronary syndrome; Drug-eluting stent implantation
Acute coronary syndrome (ACS) is a critical manifestation of coronary artery disease with high mortality and disability.[1,2]Antiplatelet therapy is the most important measure to reduce ischemic events, especially for patients with ACS.[3]Dual antiplatelet therapy (DAPT) with aspirin and one P2Y12 receptor inhibitor is the standard therapy for patients with ACS undergoing drugeluting stent (DES) implantation, but the optimal duration of DAPT is debated.[4,5]Prolonging DAPT has been shown to reduce the incidence of ischemic events,[6]but the benefit is offset by a potential increase in bleeding risk. For Asian patients, especially Chinese patients, who are considered to have a higher bleeding risk,[7]conservative decisions regarding DAPT duration must be made to balance the risk for ischemic and bleeding events.
A previous study from our center reported that compared with a standard DAPT duration (1 year), prolonging DAPT to more than 1 year reduced the incidence of all-cause death, cardiac death, and stent thrombosis at the 2-year followup in patients with ACS who underwent DES implantation without increasing the bleeding risk.[8]However, it was unclear whether prolonging DAPT would continue to be beneficial beyond 2 years and which DAPT duration was more appropriate. Therefore, we investigated 5-year clinical outcomes to evaluate the impact of different DAPT durations on long-term prognosis.
Study population
This is a prospective, observational study. In total, 10,724 patients underwent percutaneous coronary intervention (PCI) at Fuwai Hospital, National Center for Cardiovascular Diseases (Beijing, China) from January to December 2013. Patients with ACS (including unstable angina pectoris, non-ST segment elevation myocardial infarction [MI], and ST segment elevation MI) were selected for the present study. The following patients were excluded: patients who received only bare metal stents (n=64); patients who were treated with balloon angioplasty alone (n=237); patients who had adverse cardiovascular, cerebrovascular, or bleeding events within 1 year after PCI (n=612); patients who had a DAPT duration ＜1 year (n=157); and patients who had single antiplatelet therapy (n=120). Finally, 5,187 patients with ACS who underwent DES implantation and received DAPT were enrolled (supplementary Figure 1). The study protocol was approved by our Institutional Review Board, and written informed consent was obtained from all patients before the intervention.
Procedures and medications
The PCI strategy and stent type were at the treating physician’s discretion. Before the procedure, if patients were not receiving long-term aspirin and clopidogrel, those scheduled for PCI received 300 mg aspirin and a loading dose of clopidogrel (300 mg or 600 mg) orally as soon as possible. During the procedure, unfractionated heparin (100 U/kg) was administered to all patients, with glycoprotein IIb/IIIa inhibitors based on the operator’s judgment. In 2013, other P2Y12 inhibitors (e.g., prasugrel and ticagrelor) were not routinely used in our center; only 16 patients (0.16%) received ticagrelor (loading dose, 180 mg) during that time.
Patient follow-up
All patients were evaluated by clinic visits or by a phone call at 1, 3, and 6 months and 1, 2, and 5 years after their procedure. Patients were advised to return for coronary angiography if clinically indicated by symptoms or if they showed signs of myocardial ischemia.
Definitions
The duration of DAPT was defined as the length of time between the date of PCI procedure and DAPT cessation. Patients were divided into four groups based on DAPT duration: standard DAPT group (11-13 months,n=1,568) and prolonged DAPT groups (13-18 months [n=308], 18-24 months [n=2,125], and ＞24 months [n=1,186]) (supplementary Figure 1). New-generation DESs were defined as second-generation and biodegradable polymer DESs. MI was defined using the third universal definition of MI.[9]Target vessel revascularization (TVR) was defined as repeated revascularization by PCI or surgery on the target vessel. Bleeding was defined using the definition of the Bleeding Academic Research Consortium (BARC).[10]
Endpoints
The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs) (composing all-cause death, cardiac death, MI, TVR, and stroke) at the 5-year follow-up. The secondary endpoints were individual MACCE components and bleeding. All endpoint events were adjudicated by two independent cardiologists, with any disagreement resolved by consensus.
Statistical analysis
Continuous variables are presented as the mean±standard deviation, and categorical variables are presented as numbers and percentages. Continuous variables were compared by one-way analysis of variance as appropriate. Categorical variables were compared using aZ-test with Bonferroni correction between columns, and the overallP-value was calculated with Pearson Chi-square test. Survival curves were calculated using Kaplan-Meier estimates, and endpoints were compared with a log-rank test. We used the standard DAPT as a reference and justified the variables of age, sex, body mass index, hypertension, diabetes mellitus, hyperlipidemia, previous PCI, and Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score before PCI for multivariable Cox regression models. The results of the Cox regression analysis were expressed as hazard ratios (HR) and 95% confidence intervals (CI). Subgroup analyses were performed using factors associated with high bleeding risk (age, sex, presence of diabetes, left ventricular ejection fraction [LVEF], weight, and renal function) to analyze interactions between DAPT duration and the selected outcome factors. Two-tailedP-values ＜0.05 were considered statistically significant. All analyses were conducted with SPSS version 19.0 (IBM, USA).
Baseline characteristics
The response rate of the 5-year follow-up was 91.5%. Patients’ basic characteristics by standard and prolonged DAPT are shown in supplementary Table 1. Basic characteristics were similar across the four DAPT duration groups, except for older age, higher incidence of previous PCI, and previous stroke history in the group with DAPT ＞24 months.
Five-year outcomes
During the 5-year follow-up, the incidences of MACCEs, all-cause death, cardiac death, and MI were significantly lower in the DAPT group at 18-24 months than in the other groups (11-13 months vs. 13-18 months vs. 18-24 months vs. ＞24 months: MACCEs 14.1% vs. 11.7% vs. 9.6% vs. 24.2%,P＜0.001; all-cause death 4.8% vs. 3.9% vs. 2.1% vs. 2.6%,P＜0.001; cardiac death 3.1% vs. 2.6% vs. 1.4% vs. 1.9%,P=0.004; MI 3.8% vs. 4.2% vs. 2.5% vs. 5.8%,P＜0.001, respectively). The incidence of stroke and bleeding was not different among the four groups. As shown in Table 1, the Kaplan-Meier estimates showed the same trend (Figure 1).
Figure 1. The Kaplan-Meier estimate curve of different dual antiplatelet therapy durations.
Multivariable analysis
Cox multivariable regression analysis showed that compared with standard DAPT duration, prolonged DAPT (18-24 months) was a protective factor for MACCEs (HR0.802, 95%CI0.729-0.882,P＜0.001), all-cause death (HR0.660, 95%CI0.547-0.795,P＜0.001), cardiac death (HR0.663, 95%CI0.526-0.835,P＜0.001), MI (HR0.796, 95%CI0.662-0.957,P=0.015), and TVR (HR0.867, 95%CI0.755-0.996,P=0.044). A DAPT duration of more than 24 months was positively correlated with MI (HR1.139, 95%CI1.014-1.280,P=0.028) and TVR (HR1.472, 95%CI1.358-1.596,P＜0.001) (Table 2).
Subgroup analysis
We performed subgroup analysis for all-cause death and MACCEs between standard and prolonged (18-24 months) DAPT to evaluate patients with a high risk for bleeding. DAPT of 18-24 months reduced the risk for all-cause death and MACCEs in those aged ≤75 years, females, patients with diabetes mellitus, patients with LVEF ≥40%, patients who weighed ≤60 kg, and patients without renal dysfunction (supplementary Table 2).
Table 1. The 5-year long-term outcomes in patients with different DAPT durations
Table 2. Adjusted hazard ratios for clinical outcomes in patients with prolonged DAPT
The major findings of this study were as follows. (1) Compared with the standard DAPT duration, a prolonged DAPT duration in patients with ACS is common in China. (2) Prolonged DAPT duration was related to reducedadverse cardiovascular events, including all-cause death and cardiac death, without increasing the risk for bleeding. (3) Prolonged DAPT duration of 18-24 months may be the most appropriate DAPT strategy for patients with ACS, even for those with a high risk for bleeding.
Selection of DAPT duration and guideline recommendations
The American and European guidelines recommended a DAPT duration of 1 year for patients with ACS, with appropriate adjustment of DAPT duration based on the risk for ischemic events and bleeding.[11]The Chinese guideline also recommended at least 1 year of DAPT for patients with ACS after DES implantation and suggested individualized DAPT duration based on balancing bleeding and ischemic risks.[12,13]In our cohort of patients with ACS undergoing DES in the largest cardiovascular center in China, we found that prolonged DAPT was more common than the standard DAPT duration as required by the guidelines. The high proportion of patients with prolonged DAPT duration refl ected the situation of the widespread application of DAPT in real-world clinical practice and the concerns of doctors and patients about recurrent ischemic events after ACS.
Benefits of prolonging DAPT duration
Whether prolonging DAPT duration benefits patients remains controversial. Of the 2,110 patients enrolled (n=1,679, ＞12 months from the index ACS) in the TIMI-38 Coronary Stent Registry,[14]DAPT was continued in 554 (26%) patients. After follow-up for 2.1 years, recurrent ischemic events were similar in patients who received continued and discontinued DAPT (P=0.74 for cardiovascular death/MI/stroke;P=0.72 for definite or probable stent thrombosis). However, the DAPT study[15]indicated that continued treatment with thienopyridine could reduce the rates of stent thrombosis (0.4% vs. 1.4%;HR0.29, 95%CI0.17-0.48;P＜0.001) and MACCEs (4.3% vs. 5.9%;HR0.71, 95%CI0.59-0.85;P＜0.001). However, DAPT beyond 1 year was associated with an increased risk for bleeding. In a previous study conducted at our center, prolonged DAPT for more than 1 year was associated with a reduction in all-cause death, cardiac death, and stent thrombosis (0.1% vs. 1.8%; 0.1% vs. 0.8%; 0.2% vs. 0.7%; allP＜0.01) and did not increase the incidence of bleeding events (all bleeding events: 2.6% vs. 3.0%,P=0.45; BARC ≥2: 1.3% vs. 1.7%,P=0.36).[6]
The purpose of prolonging DAPT is to further reduce the incidence of MI and other ischemic events that are not related to late (＞30 d) or very late (＞1 year) stent thrombosis[16]and enhance the secondary prevention of coronary atherosclerosis.[17]In the present study, prolonged DAPT for more than 1 year was associated with a decrease in adverse cardiovascular events. The group with a DAPT duration of 18-24 months had the lowest incidences of MACCEs, all-cause death, cardiac death, and MI. Cox multivariable regression also showed DAPT duration of 18-24 months was a protective factor for MACCEs, all-cause death, cardiac death, MI, and TVR. Appropriate prolonged DAPT duration was beneficial by reducing adverse cardiovascular ischemic events, and these benefits continued over the 5-year long-term follow-up. In addition, prolonging DAPT did not increase the risk for bleeding, which ensures the safety of DAPT. Therefore, it is essential to assess the benefits and risks of prolonging DAPT for patients with unstable coronary artery disease to guide decisionmaking regarding DAPT duration. A DAPT duration of 18-24 months may be suitable for patients with ACS who underwent DES.
Patients with high bleeding risk also benefited from prolonged DAPT
Subgroup analysis of those with a high risk for bleeding by all-cause death and MACCEs between standard and prolonged (18-24 months) DAPT duration showed that prolonged DAPT could reduce the risk for allcause death and MACCEs for several subgroups (females, patients with diabetes mellitus, patients who weighed ≤60 kg, patients with LVEF ≥40%, and patients without renal dysfunction). These results indicated that for ACS patients with high bleeding risk, appropriately prolonging DAPT may offer benefits in terms of reducing the risk for allcause death and MACCEs.
Potential clinical implications
Patients with ACS may be more likely to benefit from prolonged DAPT duration because of the higher risk of recurrent ischemic events compared with stable coronary artery disease.[18,19]Our study confirmed that prolonging DAPT duration could decrease the risk for ischemic events, including all-cause death, cardiac death, and MI, without increasing the risk for bleeding. This result indicated the safety and efficacy of prolonging DAPT. Appropriate prolongation of DAPT may be reasonable for patients with ACS after DES implantation, and the most beneficial DAPT duration may be 18-24 months.
Limitations
Several limitations of our study must be considered. First, this was an observational study. Patients’ medication situations could not be interfered with; therefore, the evaluation of drug therapy efficacy was limited. In addition, this observational study was nonrandomized with unmeasured confounders that may preclude definitive conclusions. Second, because of the drawbacks of an observational study, only patients who could tolerate prolonged DAPT were enrolled, which might have introduced bias into this analysis. In addition, the sample size of the group with 13＜DAPT≤18 months was significantly smaller than that of the other groups, which may have impacted the study results. Third, our data were obtained from a single clinical center, and the results cannot simply be extended to all Chinese population. Fourth, information on how DAPT was discontinued was not available (i.e., discontinuation, interruption, and disruption).
For patients with ACS after DES, an appropriately prolonged DAPT duration may be associated with a reduced risk of adverse ischemic events without increasing bleeding risk, and the most beneficial DAPT duration may be 18-24 months.
Funding:The present study was supported by the National High Level Hospital Clinical Research Funding (2022-GSPQN-1); the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences (NCRC2020013); the National Natural Science Foundation of China (81900323); China International Exchange and Promotion Association for Medical and Healthcare Investigator Sponsored Study (CN174125, DIREGL08735-DAPT).
Ethical approval:The study protocol was approved by our Institutional Review Board, and written informed consent was obtained from all patients before the intervention.
Confl icts of interest:There are no potential confl icts of interest to be disclosed for the authors of this manuscript.
Contributors:JJX contributed to the project design and writing the article; SDJ, LJ, YS, PZ, and DSY contributed to data collection and arrangement; XYZ contributed to the project design; YY and JXL contributed to data sorting, patient follow-up, and statistics; YJY, SBQ, and BX contributed to the project design and operation; RLG and JQY contributed to the project design and overall plan.
All the supplementary files in this paper are available at http://wjem.com.cn.
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