A retrospective study of the safety and efficacy of clopidogrel versus aspirin monotherapy one year after coronary stent implantation

Abstract

Background

The ideal single antiplatelet therapy for long-term maintenance after coronary stenting remains uncertain. In a head-to-head comparison, we aimed to evaluate the efficacy and safety profile of aspirin and clopidogrel as monotherapies in this patient cohort.

Method

We reviewed 1044 patients who underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES) at the Department of Cardiovascular Medicine, Jinshan Hospital of Fudan University, between January 2019 and December 2021 and completed a 12-month Dual Antiplatelet Therapy (DAPT) treatment. They were divided into two groups: 582 were assigned to the aspirin group (100 mg/day) and 422 to the clopidogrel group (75 mg/day). The primary endpoint was the composite cardiac death, ischemic stroke, myocardial infarction, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater. Secondary endpoint events included all-cause death, ischemic stroke, myocardial infarction, bleeding (defined as a BARC type ≥ 2 bleeding), and gastrointestinal complications.

Results

After a mean observation period of 25 ± 8.4 months, the primary endpoint event occurred in 29 (6.8%) patients in the clopidogrel group and 30 (5.1%) in the aspirin group, with no difference between the two groups (P = 0.253). In BARC type 2 or greater bleeding events, there were 9 (1.5%) in the aspirin group compared to 7 (1.7%) in the clopidogrel group, with no difference between the two groups (P = 0.160).

Conclusion

After 12-month DAPT in Chinese patients undergoing DES implantation, aspirin monotherapy versus clopidogrel monotherapy showed no significant difference between the two drugs in terms of safety and efficacy in terms of hemorrhage, myocardial infarction, ischemic stroke, cardiac death, and bleeding with BARC type 2 or greater.

Introduction

The incidence of cardiovascular diseases (CVDs) is on the rise with the aging of the population. Cardiovascular diseases are the leading cause of death worldwide, accounting for more than 30% of global deaths each year [1]. In China, coronary atherosclerotic heart disease is the most common cardiovascular disease, with a mortality rate of about 50% of cardiovascular diseases [2]. Atheromatous plaque rupture is the most common trigger for abnormal platelet activation, and percutaneous coronary intervention (PCI) is one of the most numerous treatments for coronary stenosis [3]. Postoperative antiplatelet therapy is crucial for preventing thrombosis in stents. The primary purpose of antiplatelet agents is to prevent or treat cardiovascular and cerebrovascular diseases by inhibiting platelet accumulation, activation, and adhesion. It can also reduce mortality rates to some extent. Drug-eluting stents (DES) have reduced the incidence of restenosis and repeat revascularization in patients undergoing PCI. However, excessive antiproliferative effects and hypersensitivity to DES increase the risk of complex thrombotic events. The mainstay of antiplatelet therapy currently involves aspirin or clopidogrel [4]. However, not all patients are suitable for treatment with these drugs.

Patients with a history of aspirin use may experience discomfort due to gastrointestinal intolerance, bleeding, or allergy [5]. According to the American College of Cardiology (ACC) Expert Consensus, treatment with dual antiplatelet therapy (DAPT) for 12 months is still usually recommended for patients with ACS. After 12 months of dual antiplatelet therapy, the recommendation for most patients is to continue aspirin. For patients who are aspirin intolerant, we have also recommended continuing with a P2Y12 receptor inhibitor (preferably clopidogrel) [6]. Numerous investigations are devoted to DAPT, yet scarce research exists that delves into the comparison of the likelihood and magnitude of adverse cardiovascular incidents (inclusive of all-cause mortality, myocardial infarction, or cerebral infarction) between oral administration of single-agent aspirin and single-agent clopidogrel, particularly one-year post-coronary stent placement. While the Korean HOST-EXAM study [7] suggests that clopidogrel surpasses aspirin as an antiplatelet drug in long-term maintenance, there is a lack of extensive randomized trials in the current era of DES that specifically address the optimal choice of monotherapy for indeterminate antiplatelet treatment in PCI recipients. This study aims to fill this gap by evaluating and contrasting the effectiveness and security of monotherapies with aspirin and clopidogrel in patients undergoing PCI for coronary artery disease and in need of sustained antiplatelet therapy.

Method

Study population

We reviewed 1055 patients who underwent PCI at the Department of Cardiovascular Medicine, Jinshan Hospital of Fudan University, between January 2019 and December 2021 and completed a 12-month DAPT treatment. The DAPT regimen was aspirin 100 mg and clopidogrel 75 mg per day. The operator decided on DES, and PCI was performed using a standard technique. Exclusion criteria (1) Patients with any ischemic or bleeding complications before enrolment (fatal myocardial infarction, revascularization, readmission for cardiovascular reasons, and bleeding defined as a Bleeding Academic Research Consortium type ≥ 2 bleeding) (2) Patients with known allergies or contraindications to aspirin and clopidogrel; patients with atrial fibrillation who are currently taking oral anticoagulants (3) No other antiplatelet agents allowed during follow-up (4) Pregnant women (5) Patients with combined hyperthyroidism, severe hepatic or renal insufficiency, severe respiratory diseases, malignant tumors, severe left heart insufficiency, and psychiatric diseases (6) Pulmonary embolism, aortic dissection within six months (7) Patients refused to follow up. Event-free patients at 12-month follow-up were allocated to either the aspirin or the clopidogrel group. A window of 3 months before and after the 12-month follow-up was accepted for this classification because of possible time variation in the follow-up process.

Data collection

We reviewed their demographic characteristics and vital signs at admission, including respiration, heart rate, systolic blood pressure, diastolic blood pressure, BMI, history, and comorbidities such as history of hypertension, diabetes mellitus, hyperlipidemia, nephropathy, atrial fibrillation, previous infarction, previous stent implantation, and history of smoking; diagnosis at admission; laboratory investigations, post-procedure medications, and coronary angiography-related data. The protocol was approved by the Ethics Committee of Jinshan Hospital, Fudan University (JIEC 2024-S40).

Definitions and follow-up

The primary endpoint was the composite cardiac death, ischemic stroke, myocardial infarction, and Bleeding Academic Research Consortium (BARC) type 3 or greater. Secondary endpoint events included all-cause death, ischemic stroke, myocardial infarction, bleeding (defined as a BARC type ≥ 2 bleeding), and gastrointestinal complications.

Myocardial infarction (MI) was characterized by raised cardiac biomarkers (troponin or the myocardial segment of creatine kinase exceeding the 99th percentile of the upper limit of normal) accompanied by ischemic symptoms or electrocardiogram results suggesting ischemia, excluding those linked to the primary intervention. Ischemic stroke was verified through the emergence of novel neurological impairments, confirmed both by a neurologist and imaging studies. Hemorrhage events were evaluated based on the BARC classification system [8]. Revascularization was defined as the interruption of myocardial blood supply due to stenosis or occlusion of the coronary arteries supplying myocardial perfusion for various reasons and using PCI to restore blood supply, including at the original stent site or in a newly developed target vessel. Gastrointestinal symptoms include gastrointestinal bleeding, black stools, dyspepsia, nausea, vomiting, bloating, and abdominal pain due to the medication. The treating physicians initially identified all endpoints and scrutinized them by an author with complete access to the patient’s clinical and laboratory data.

Patient management involved a multifaceted approach, including telephone calls, use of community health services, and review of hospital outpatient and inpatient records, with consistent monitoring at 3-month, 6-month, and then 6-month intervals. We were primarily interested in patients’ adherence to medication and the incidence of ischemic and bleeding events. During follow-up, we assessed their ongoing antiplatelet therapy regimen, including medication consistency, any unmonitored dose changes or discontinuations, motivating factors, and the addition of other anticoagulants. We also documented ischemic events such as cardiac death, non-fatal myocardial infarction, ischemic stroke, revascularization procedures, and ischemia-related readmissions. We also recorded bleeding events such as gastrointestinal bleeding, intracranial bleeding, and epistaxis. We also monitored non-hemorrhagic side effects such as flatulence, abdominal discomfort, and rash. If we couldn’t contact a patient using the contact information they provided, or if we couldn’t retrieve their outpatient or inpatient information after three consecutive attempts, it was considered a missed visit. In cases where a patient experienced multiple endpoint events during follow-up, the time of the first event was recorded, and follow-up was discontinued.

Statistical analysis

All clinical data were consolidated and subjected to an extensive analysis. The presentation of measurement data was in the form of mean ± standard deviation (x ± s), with a t-test employed for inter-group comparison. For data count, percentages or composition ratios were utilized, and the groups were compared. The survival rates were assessed using the Kaplan-Meier method, while Log-rank tests were executed to examine differences. Correlative examinations were carried out for clinical incidents occurring at various time intervals. Subgroup investigations were further conducted using the Cox proportional hazards model, considering factors such as age (categorized as less than 70 or 70 years and above), hypertension, Diabetes Mellitus (DM), acute coronary syndromes (ACS), hyperlipidemia, previous MI, DES implantation history, chronic kidney disease, and smoking status. The hazard ratios (HRs) for the primary efficacy endpoint (a composite of all-cause death, myocardial infarction, and stroke complications) in both groups are shown according to prespecified and post-hoc subgroups. Statistical computations were executed using SPSS software, version 29.0, and R software, version 4.3.1. A significance level of P < 0.05 was adopted to denote statistical relevance.

Results

Patient demographics are detailed in Table 1. From the initial 1055 participants, 41 were omitted due to incomplete data (n = 33) or inability to continue follow-up within our facility (n = 18), as illustrated in Fig. 1. The study ultimately comprised 1004 subjects, divided into two groups: 582 were assigned to the aspirin group (100 mg/day) and 422 to the clopidogrel group (75 mg/day). Following DES implantation PCI, we ensured a mean observation period of 25 ± 8.4 months, with all patients completing 12 months of DAPT (Fig. 1).

Table 1 Baseline characteristics of the intention-to-treat population

Fig. 1

The flowchart of study participants

The basic characteristics of the subjects were compared, and there were significantly more male participants than females in both groups, 77.8% in the aspirin group and 76.1% in the clopidogrel group, with no statistically significant difference in gender distribution. The mean age of the aspirin group was 62.62 years, while the mean age of the clopidogrel group was higher at 66.38 years, and the difference in age between the two groups was statistically significant (p = 0.001). Further divided by 70 years of age, the age difference between the two groups remained significant in those over 70 years of age (p = 0001). There was no difference in heart rate, systolic blood pressure, diastolic blood pressure, respiratory rates, BMI, smoking habits, diabetes, hyperlipidemia, history of myocardial infarction, history of stent implantation, or between-group comparison. For hypertensive disorders and in the history of atrial fibrillation, the difference was statistically significant. There were no statistically significant differences between the two groups in laboratory tests related to biochemical indices of total cholesterol, triglycerides, fasting blood glucose, glycosylated hemoglobin, and platelets. At the same time, there were statistical differences in LDL-c and HDL-c. None of the clinical classifications of coronary artery disease reached statistical significance according to the clinical presentation at the beginning of the disease. The aspirin and clopidogrel groups showed a non-significant difference in terms of the number of stents implanted and the location of their distribution. In comparing coronary lesions, no statistically significant differences were found between the two groups for patients with lesions involving one or two vessels. However, when lesions involved three vessels, the proportion of patients in the clopidogrel group significantly exceeded that of the aspirin group, with statistically significant differences of 44.3% and 33.8%, respectively. There was no statistically significant difference between the aspirin and clopidogrel groups when comparing the two groups concerning the use of ACEI/ARB drugs, beta-blockers, and statins (Table 1).

After a mean observation period of 25 ± 8.4 months, the two groups had no statistical differences concerning the primary endpoint events, all-cause mortality, myocardial infarction, ischemic stroke, revascularizations, and all-cause mortality. For the endpoint of bleeding, ten patients in both groups experienced bleeding (statistically BARC type 1 or greater). There were no statistical differences in BARC bleeding type or gastrointestinal bleeding (Table 2).

Table 2 Results for the efficacy endpoint follow up after DAPT

Survival analysis curves were plotted for the aspirin group versus the clopidogrel group, and Log-Rank tests were performed by Kaplan-Meier for all-cause mortality events (survival), primary endpoint events (including the combination of cardiac death, ischemic stroke, and myocardial infarction), and BARC bleeding events of type 2 or greater in both groups. The two groups had no statistically significant differences regarding all-cause mortality, primary endpoint events, and bleeding events of BARC type 2 or greater (Fig. 2a, b and c).

Fig. 2

Kaplan-Meier for primary end-point events, all-cause mortality events, and BARC bleeding events of type 2 or greater

Subgroup analysis

There was no statistically significant difference between the aspirin and clopidogrel groups for the primary endpoint event. Subgroup assessments comprised factors such as age, hypertension, diabetes mellitus, hyperlipidemia, previous infarction, history of DES, chronic kidney disease, ACS, and smoking. In these subgroups, there were no differences in incidence rates between the two groups. There were no significant interactions between several subgroups and the primary efficacy endpoint (Fig. 3).

Fig. 3

The hazard ratios for the primary efficacy endpoint (a composite of all-cause death, myocardial infarction, and stroke complications) in both groups are shown according to prespecified and post-hoc subgroups. DM diabetes mellitus, hyperlipemia, MI history previous infarction, DES Drug-eluting stent history, chronic kidney disease, ACS acute coronary syndrome

Discussion

This study was conducted in patients taking clopidogrel or aspirin one year after coronary stent implantation. After a median follow-up of 25 ± 8.4 months, no significant differences were found between the two drugs in preventing ischemia and reducing the incidence of MACE events. No significant differences were found between the two drugs in terms of safety. Subgroup analyses reported no significant interaction between the treatment effect and various subgroups, such as age, hypertension, and MI history. Current ACC/AHA guidelines recommend at least six months of DAPT with aspirin and a P2Y12 inhibitor for patients with stable CAD and at least 12 months of DAPT with aspirin and a P2Y12 inhibitor for patients with ACS who undergo PCI with a DES. In many randomized trials, aspirin is the best cardiovascular secondary prevention drug. It is also recommended as a priority for patients completing DAPT after PCI [9, 10]. We studied patients undergoing PCI in our hospital who were treated with DAPT for one year and then switched to aspirin or clopidogrel. Depending on the drug, the patients were divided into two groups: aspirin and clopidogrel. The occurrence of ischemic events with adverse drug effects was observed between the groups. Regarding the choice of drug, although the current guidelines firstly recommend the use of aspirin after the completion of DAPT, some patients have many side effects from aspirin, such as vomiting blood, black stools, abdominal distension, and other gastrointestinal symptoms; the most common and severe side effect is gastrointestinal hemorrhage [11]. So, in our study, the medical staff unintentionally gave clopidogrel to the senior citizens. Therefore, the mean age in the clopidogrel group was higher than the aspirin group.

The U.S. Preventive Services Task Force (USPSTF) [12] included 14 randomized controlled trials to assess the bleeding hazards of aspirin, with endpoints for all types of bleeding, including all major bleeding, gastrointestinal bleeding, extracranial bleeding, hemorrhagic stroke, and intracranial bleeding. One of the meta-analysis studies that included 119,130 patients found a 58% increased risk of gastrointestinal bleeding due to aspirin use. Meanwhile, another meta-analysis that included 134,470 patients showed a 31% increased risk of intracranial hemorrhage due to aspirin. Although these studies showed no significant association between aspirin and age, gender, or diabetes, the risk of bleeding increased significantly with age, especially in adults older than 60 years [13]. Therefore, clopidogrel has been used as an alternative to aspirin in people with aspirin intolerance or allergy. Aspirin and clopidogrel were included in this study for analysis of antiplatelet effectiveness, and based on a median time of 25 ± 8.4 months of follow-up, there was no statistical difference between the two groups in terms of the occurrence of ischemic events, either in terms of the primary endpoint event or the secondary endpoint events (including sudden cardiac death, myocardial infarction, and cerebral infarction). There was also no significant difference between the two drugs in terms of adverse effects and bleeding events above BARC type 2. Thus, in our study, it is possible to find that both aspirin and clopidogrel have similar efficacy in preventing ischemia during the chronic maintenance period.

However, a multicenter prospective study conducted at HOST-EXAM in Korea compared two medications used for chronic maintenance therapy after completion of DAPT. A total of 5348 patients were recruited and then assigned to 2780 (50.2%) in the aspirin group and 2710 (49.8%) in the clopidogrel group. During the 24-month follow-up period, the primary outcome occurred in 152 (5.7%) patients in the clopidogrel group versus 207 (7.7%) in the aspirin group (HR 0.73 [95% CI 0.59–0.90]; P = 0.0035), so, in their opinion, clopidogrel alone compared with aspirin alone significantly reduced the number of post-PCI DES risk of all-cause death, non-fatal myocardial infarction, cerebral infarction, readmission for acute coronary syndrome, and BARC bleeding. Clopidogrel monotherapy is more effective in patients requiring lifelong single-agent antiplatelet therapy after percutaneous coronary intervention [7]. Similar conclusions were demonstrated in Teak’s [14] 2016 trial and a meta-analysis by Bryan [15] in 2022 for clopidogrel to be superior to aspirin in chronic maintenance. However, an alternative perspective is presented by Doo [14] and Natsuaki [15], who observed comparable clinical efficacy of clopidogrel monotherapy in patients with acute myocardial infarction after DAPT in comparison to aspirin in their trial and did not identify significant differences between the two drugs. These findings are consistent with the results of our trial, which demonstrated no significant differences between the two drugs with regard to ischemic versus bleeding events and adverse drug reactions over a median follow-up period of 25 ± 8.4 months.

In our study, we found that bleeding cases such as gastrointestinal bleeding, nasal bleeding, gingival bleeding, and cerebral hemorrhage occurred in both aspirin and clopidogrel groups. However, the chances of their occurrence were not high. There were ten cases of bleeding in both aspirin and clopidogrel groups, accounting for 1.7% and 2.3% of the total, respectively. In the aspirin group, there were 8 cases of BARC2 bleeding events, one case of BARC3 bleeding events, and no bleeding events above BARC4; seven cases of BARC2 bleeding events in the clopidogrel group, and no bleeding events above BARC3 in the clopidogrel group, and no differences between groups existed. We performed a post-Kaplan-Meier analysis for bleeding events of BARC type 2 and greater, and there was no difference between the two groups (P = 0.160). However, the HOST-EXAM [7] study stated that clopidogrel was superior to aspirin in secondary prevention after PCI. Nevertheless, there are also studies [16] that have found consistent benefits of clopidogrel over aspirin monotherapy regardless of clinical risk or relative ischemia and bleeding risk. Therefore, when we choose a drug after PCI, clopidogrel can also be used as a new replacement option if the patient is intolerant to aspirin or has severe adverse effects. In conjunction with the patient’s condition, more emphasis should be placed on personalizing antiplatelet therapy to the individual’s role with P2Y12 receptor inhibitors [17].

A comparative analysis was conducted to evaluate the distinct effects, drug safety, and efficacy of these two pharmaceutical agents during the maintenance phase in patients who had undergone percutaneous coronary intervention. The risk of adverse cardiovascular events was reduced by reducing the risk of bleeding in patients without increasing the risk of ischemia, thereby achieving the greatest net clinical benefit. No significant difference was identified between the two drugs.

In conclusion, the results of our experiment demonstrated that aspirin and clopidogrel exhibited comparable efficacy in preventing ischemia in the chronic maintenance phase. Consequently, novel recommendations have been proposed for the selection of antiplatelet agents for patients in the chronic maintenance phase. Clopidogrel may be the preferred option for patients with an aspirin allergy or contraindications.

Our study has several limitations. Firstly, this experiment is a single-center retrospective study with the main population in Shanghai, and there is a gap between the reliability and multicenter, prospective, double-masked studies. In the future, if the opportunity arises, a multicenter collaborative study may be undertaken. Secondly, we also do not have genetic testing for clopidogrel. It has been demonstrated that the CYP2C19 non-functional allele results in impaired conversion of clopidogrel to active metabolites and diminished inhibition of platelet reactivity [18,19,20]. Therefore, clopidogrel-treated patients carrying one or both CYP2C19 nonfunctioning alleles are at a higher risk of developing MACE after PCI [21]. However, the clinical significance of clopidogrel resistance remains controversial, and current guidelines do not recommend routine platelet function testing when creating individualized treatment regimens [4]. Third, this study had a short follow-up of up to three years, and patients may be followed for longer to compare the two drugs further.

In conclusion, after 12-month DAPT in Chinese patients undergoing DES implantation, aspirin monotherapy versus clopidogrel monotherapy showed no significant difference between the two drugs in terms of safety and efficacy in terms of hemorrhage, myocardial infarction, ischemic stroke, cardiac death, and bleeding with BARC type 2 or greater.