Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and the leading cause of cardioembolic stroke,1,2 with a prevalence ranging from 0.1% in patients below 55 years to over 9% in octogenarian patients, and fivefold elevation in the risk of ischemic stroke (IS) among individuals with AF.3 It has been well accepted that oral anticoagulants substantially reduce the risk for IS in patients with AF determined to be at intermediate to high risk for thromboembolism.4 The latest guidelines consider that antiplatelet therapy is not recommended for stroke prevention in AF patients.5,6 Despite that, aspirin (ASA), the mainstay antiplatelet treatment in patients with cardiovascular disease (CVD), has been received by a considerable number of AF patients.7 It has been reported that AF patients with concomitant stable coronary artery disease are also likely to receive combined antiplatelet and anticoagulant therapy.8–10 Therefore, this study sought the association between ASA monotherapy and the risk of major adverse cardiac and cerebrovascular events (MACCE) in patients with AF.

Methods Study Participants and Grouping

The Kailuan study is an ongoing prospective community-based cohort study to investigate the risk factors for cardiovascular and cerebrovascular diseases in the city of Tangshan, China. The study participants are the employees and retirees from the Kailuan Group. Participants were originally recruited for physical examination. The present study is based on the data of Kailuan study from the year of 2014 to 2016. Based on the recorded medical histories, patients with AF were selected for our present study as per the relevant diagnostic criteria.11

Clinical Endpoints and Follow-Up

The clinical endpoints are MACCE, including myocardial infarction (MI), IS, and hemorrhagic stroke (HS). Follow-up started from the first physical examination and ended on December 31, 2022.

Statistical Analysis

The measurement data of normal distribution was expressed as mean ± standard deviation. A power analysis was used to estimate the smallest sample size needed in the current study. A propensity score matching was made to reduce the bias due to other cardiovascular risk factors-related variables. Kaplan–Meier curves were plotted for each of the two treatment groups and were compared using a Log rank test. The hazard ratios (HR) and 95% confidence intervals (CI) for MACCE were analyzed using Cox proportional-hazards analysis regression models. A P-value less than 0.05 was considered statistically significant.

Results Clinical and Laboratory Baseline Characteristics

Figure 1. shows the flow chart of the current study. In total 171,086 participants were initially enrolled in the Kailuan study. 937 patients with AF were initially enrolled in this study, among which, 87 participants with medical histories with MI or stroke were further excluded. Finally, 174 AF patients with ASA monotherapy (ASA group) were 1:4 matched with 676 AF patients without ASA monotherapy (non-ASA group). Table 1 shows the baseline characteristics.

Table 1 Baseline Characteristics

Figure 1 Flow chart of the prospective study.

Abbreviations: MI, myocardial infarction; ASA, aspirin; non-ASA, non-aspirin.

Incidence of MACCE

Figure 2. shows that during the 7.2-year follow-up, MACCE occurred 30 in the ASA group, and 101 in the non-ASA group, with a cumulative incidence of 19.88% vs 17.27%, P = 0.511; MI occurred 3 in the ASA group, and 18 in the non-ASA group, with a cumulative incidence of 1.78% vs 2.90%, P = 0.305. IS occurred 27 in the ASA group, and 84 in the non-ASA group, with a cumulative incidence of 1.78% vs 2.90%, P = 0.305. HS occurred 8 in the ASA group, and 13 in the non-ASA group, with a cumulative incidence of 5.01% vs 2.34%, P = 0.045. (Figure 2).

Figure 2 Cumulative incidence of (A) MACCE, (B) MI, (C) IS, (D) HS.

Abbreviations: MACCE, major cardiovascular and cerebrovascular events; MI, myocardial infarction; IS, ischemic stroke; HS, hemorrhagic stroke.

Regression Analysis of Factors Associated with Major Vascular Events

Table 2 shows that ASA therapy was not associated with MACCE in model 1 [hazard ratio (HR): 1.146, 95% confidence interval (CI): 0.763–1.723, P = 0.511], model 2 (HR: 1.152, 95% CI: 0.766–1.732, P = 0.497), and model 3 (HR: 1.130, 95% CI: 0.747–1.710, P = 0.562). Similarly, ASA therapy was not associated with MI in model 1 (HR: 0.635, 95% CI: 0.187–2.157, P = 0.467), model 2 (HR: 0.635, 95% CI: 0.187–2.155, P = 0.466), and model 3 (HR: 0.557, 95% CI: 0.161–1.931, P = 0.356). In addition, ASA therapy was not associated with IS in model 1 (HR: 1.254, 95% CI: 0.813–1.935, P = 0.306), model 2 (HR: 1.278, 95% CI: 0.828–1.973, P = 0.269), and model 3 (HR: 1.309, 95% CI: 0.843–2.034, P = 0.231). Except that, it shows that ASA therapy was not associated with HS in model 1 (HR: 2.393, 95% CI: 0.992–5.775, P = 0.052), and model 2 (HR: 2.387, 95% CI: 0.989–5.761, P = 0.053). However, it shows that ASA therapy was significantly associated with HS in model 3 (HR: 2.563, 95% CI: 1.024–6.418, P = 0.044).

Table 2 Cox Proportional Hazards Regression Analysis

There is no difference between MACCE with ASA therapy as compared with non-ASA therapy in subgroups. However, it shows that the association between IS with ASA therapy was stronger in diabetes patients (HR: 2.442, 95% CI: 1.184–5.035) than nondiabetic patients (HR: 0.940, 95% CI: 0.522–1.693) (P for interaction = 0.037). Similarly, it shows that the association between HS with ASA therapy was stronger in diabetes patients (HR: 6.857, 95% CI: 1.686–27.885) than nondiabetic patients (HR: 0.845, 95% CI: 0.158–4.513) (P for interaction = 0.045) (Table 3).

Table 3 Relative Risks for Various Subgroups

Discussion

Here, the results of our current study showed that there is no difference in the cumulative incidence of MACCE between the ASA therapy group and the non-ASA therapy group. ASA monotherapy is not significantly associated with MI and IS, but it is significantly associated with HS. Patients with AF are unlikely to benefit from ASA monotherapy.

In consist with our results, many studies suggested that ASA therapy is significantly associated with a higher risk of bleeding events, while without a lower risk of ischemic events in patients with AF. Here, Sato et al sought the efficacy of ASA for low-risk patients of AF, the superiority of ASA for prevention of primary end events (cardiovascular death, symptomatic brain infarction, or transient ischemic attack) was not confirmed. In addition, the risk of major bleeding in the ASA group was significantly higher than in the control group.12 Dewilde et al investigated the efficacy and safety of clopidogrel alone compared with clopidogrel plus ASA in patients undergoing percutaneous coronary intervention and receiving oral anticoagulants. Their results showed that clopidogrel plus ASA significantly increased bleeding complications compared with clopidogrel alone.13

In addition, Steinberg et al reported that 35% of 10,126 AF patients received a concomitant oral anticoagulant agents (OAC) and ASA therapy, in which, 39% of patients had no history of atherosclerotic disease. More major bleeding events were recorded in patients receiving combined OAC and ASA therapy.7 Lip et al demonstrated that the risks of stroke and bleeding events in low-risk patients are truly low. With 1 additional stroke risk factor, the event rates significantly increased in patients receiving anticoagulant therapy compared to patients without anticoagulation therapy. The superiority of the ASA treatment versus no treatment for the prevention of stroke was not confirmed in this study. Whereas, the bleeding events significantly increased in the ASA group versus no treatment. Furthermore, the stroke and death events were reduced in the warfarin group compared to the ASA or no treatment group, while the bleeding events showed no significant difference between warfarin and ASA.14 Flaker et al investigated the efficacy and safety of combining ASA and anticoagulant therapy in patients with AF, their results showed that the combination of ASA and anticoagulant therapy was not associated with any reduction in stroke, systemic embolism, or MI compared to anticoagulant therapy alone. In contrast, a combination of ASA and warfarin was associated with an increase in major bleeding events.15 Hansen et al demonstrated that triple therapy of warfarin, ASA, and clopidogrel is associated with an increased risk of bleeding events, carrying a more than 3-fold higher risk of bleeding events than warfarin monotherapy.16 In summary, concomitant anticoagulation and antiplatelet therapy are not suitable for AF patients without a recent cardiovascular event.17

Our study has several limitations. First, the ethnicity of people enrolled was Chinese Han, hence the results cannot apply to a general population. Second, the sample size is very limited. Third, patients were recruited consecutively, which may cause bias in research.

Conclusion

In summary, our study demonstrated that ASA therapy is significantly associated with a higher risk of bleeding events, while without a lower risk of ischemic events in patients with AF. Patients with atrial fibrillation are unlikely to benefit from aspirin monotherapy.

Data Sharing Statement

The original data are available from the corresponding author on reasonable request.

Statement of Ethics

The Kailuan study has been reviewed and approved by the ethics committee of Kailuan hospital (registration number in the Chinese clinical trial registry: ChiCTR-TNRC-11001489). An informed consent was obtained from the study participants. All procedures were performed in accordance with the declaration of Helsinki.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The present study was financially supported by key scientific research project of health commission of Hebei province, PR China. Project No.: 20231775.

Disclosure

The authors declare that they have no competing interests in this work.

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