The Efficacy and Safety of Indobufen-Based DAPT in ACS Patients with a History of Gastrointestinal Damage Undergoing PCI: A Single-Center,Observational Study

Abstract

Purpose

Indobufen, an alternative to aspirin in acute coronary syndrome (ACS) patients with gastrointestinal damage undergoing percutaneous coronary intervention (PCI), has limited data on its efficacy and safety in long-term use. This study compared indobufen-based dual antiplatelet therapy (DAPT) to aspirin-based DAPT in such patients.

Methods

We retrospectively analyzed 255 PCI patients with a history of gastrointestinal damage, divided into indobufen (n = 90) and aspirin (n = 165) groups. We defined the composite of major adverse gastrointestinal events as a composite endpoint event of dyspepsia, peptic ulcer disease and gastrointestinal hemorrhage. Concurrently, the composite of clinically significant adverse gastrointestinal events has been designated as a composite endpoint comprising peptic ulcer disease and gastrointestinal hemorrhage.

Results

Indobufen significantly reduced the incidence of the composite of major adverse gastrointestinal events (25.6% vs 39.4%, HR = 0.58, 95% CI:0.36–0.94, P = 0.026) and the composite of clinically significant adverse gastrointestinal events (18.9% vs 33.3%, HR = 0.53, 95% CI:0.30–0.90, P = 0.020) compared to aspirin. There was no significant difference in major adverse cardiovascular events (MACE) incidence between the two groups (4.4% vs 6.7%, P = 0.400).

Conclusion

In conclusion, compared with aspirin, the use of indobufen-based DAPT was associated with a lower incidence of the composite of major adverse gastrointestinal events, which was mainly driven by a reduction in the clinical symptoms and an improvement in quality of life.

Keywords

indobufen dual antiplatelet therapy acute coronary syndrome gastrointestinal damage

Introduction

Aspirin and a P2Y12 inhibitor (clopidogrel or ticagrelor) have long been used as the preferred recommended (DAPT)^1,2 for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). As a kind of inhibitor of cyclooxygenase (COX), aspirin plays a role in inhibiting platelet aggregation by irreversibly blocking platelet COX-1 and thereby preventing thromboxane-A2 (TXA2) formation.³ Meanwhile, aspirin also inhibits the activity of COX-1 distributed in the gastrointestinal tract, which secretes prostacyclin (PGI2) to protect the gastrointestinal tract mucosa.⁴ Therefore, long-term use of aspirin easily leads to adverse reactions such as acid reflux, nausea, abdominal distention, and even gastrointestinal bleeding.⁵

The oral antiplatelet drug indobufen is also a kind of inhibitor of platelet COX-1, which has been used as an alternative to aspirin in DAPT because of its comparable inhibiting of platelet aggregation⁶ and better gastrointestinal tolerance.⁷ However, indobufen inhibits platelet COX-1 activity in a reversible manner and prevents the production of TXA2 to inhibit platelet activation, adhesion, and aggregation.^8,9 Without affecting PGI2 production, indobufen causes less damage to the gastrointestinal mucosa¹⁰ and has fewer adverse effects. For patients with a history of gastrointestinal mucosa damage, DAPT treatment based on indobufen instead of aspirin is also a good choice.¹¹

Previous studies indicated that indobufen has a comparable inhibitory effect on platelet aggregation to aspirin while reducing the undesirable side effects and resulting in a relatively low risk of bleeding.¹¹ However, there are few studies and clinical trials designed to explore the impact of indobufen-based DAPT on patients with a history of gastrointestinal mucosa damage and the gastrointestinal prognosis of long-term use of indobufen.¹² In present study, we retrospectively analyzed the use of indobufen-based DAPT on ACS patients with a history of gastrointestinal damage and compared the occurrence of gastrointestinal adverse events with aspirin-based DAPT, aiming to explore the efficacy and safety of indobufen-based DAPT on the gastrointestinal system and provide some reference opinions for the clinical application of indobufen.

Methods

Study Design

The current study was involving a total of 392 consecutive after PCI patients combined with gastrointestinal damage history, during the period from August 2021 to August 2022 (Figure 1). Patients who were at least 18 years of age were enrolled if they had a history of gastrointestinal tract damage, including ulcerative dyspepsia, peptic ulcer disease, gastrointestinal bleeding, or other gastrointestinal damage diseases. They were also required to have a confirmed final diagnosis of ACS and undergo PCI with a sirolimus-eluting stents (DES), taking aspirin or indobufen with a P2Y12 inhibitor (ticagrelor or clopidogrel) upon admission and at discharge. Patients were ineligible if they underwent unsuccessful PCI or experienced severe or urgent PCI complications (acute coronary occlusion, no-reflow, coronary artery perforation, contrast induced acute injury, loss of stents and other equipment, acute thrombosis of the stent, non gastrointestinal bleeding). Patients who needed oral anticoagulant drugs and those who discontinued or switched between indobufen and aspirin were also excluded. Finally, patients were also disqualified if they had any of the following basic diseases: known relevant hematological deviations, active major bleeding (Bleeding Academic Research Consortium, BARC II or worse),¹³ severe liver dysfunction¹⁴ and renal insufficiency,¹⁵ severe valvular heart disease,¹⁶ dilated or hypertrophic cardiomyopathy,¹⁷ atrial fibrillation,¹⁸ active tumors, pulmonary embolism,¹⁹ hyperthyroidism, clinically important thrombocytopenia (ie, plate-let <100 × 109/L) or anemia (ie, hemoglobin <90 g/L).

Figure 1.

The flow chart with the population before and after applying the inclusion and exclusion criteria.

Population

Patients were categorized into two groups based on their medication at discharge: the indobufen group (n = 90) and the aspirin group (n = 165). All data on baseline characteristics, medication, and clinical follow-up including the study endpoints were routinely collected using the cv-net clinical data collection system (Beijing Crealife Technology Co., Ltd) by a specialized clinical research team. All patients were followed up for one year from the time of admission.

Dual antiplatelet agents were administered to all patients according to the current guidelines for the diagnosis and management of ACS. The patients in the indobufen group received a 200-mg loading dose of indobufen plus either a 180-mg loading dose of ticagrelor or a 300-mg loading dose of clopidogrel upon admission. Following PCI, they also received 100 mg of indobufen twice daily indefinitely along with either 75 mg of clopidogrel once daily or 90 mg of ticagrelor twice daily for at least a year. The patients in the aspirin group received a 300-mg loading dose of aspirin plus either a 180-mg loading dose of ticagrelor or a 300-mg loading dose of clopidogrel upon admission. Following PCI, they received 100 mg of aspirin once daily indefinitely along with either 75 mg of clopidogrel once daily or 90 mg of ticagrelor twice daily for at least a year. According to the current guidelines for the diagnosis and management of ACS, all patients underwent a coronary angiography during PCI, in which the specific PCI techniques and stent types for coronary lesions were identified by interventional cardiologists. For the secondary prevention of coronary artery disease, all patients received standard medical attention and medications.

Study Endpoints

The primary endpoints were the composite of major adverse gastrointestinal events, defined as a composite of ulcerative dyspepsia, peptic ulcer disease, and gastrointestinal bleeding. Besides, the composite of clinically significant adverse gastrointestinal events were defined as a composite of peptic ulcer disease and gastrointestinal bleeding. Dyspepsia was defined as a common chronic gastrointestinal disorder defined by upper abdominal symptoms originating from the gastroduodenal region with no structural disease on routine investigations.²⁰ Patients with dyspepsia as referred to in the study were specifically defined as those who had previously experienced damage to the gastrointestinal tract mucosa, but were currently in a state of relative remission regarding their symptoms, while still experiencing distinct symptoms of dyspepsia. Peptic ulcer disease refers to an inflammatory reaction of the gastrointestinal mucosa with necrosis, detachment, and ulcer formation under the action of various pathogenic factors, which may occur in the esophagus, stomach, or duodenum, or in the vicinity of the gastrojejunal anastomosis.²¹ Gastrointestinal bleeding was defined as bleeding from the esophagus, stomach, or intestine, including symptoms like hematemesis (vomiting of red blood or coffee grounds material), melena (black, tarry stool), or hematochezia (passage of red or maroon material per rectum), among others.²²

The secondary endpoints were major adverse cardiovascular events (MACE), defined as a composite of all-cause death, myocardial infarction (MI), stroke, and any revascularization. MI was defined according to the Fourth Universal Definition of Myocardial Infarction (2018).²³ Any revascularization was defined as revascularization involving either the target or nontarget vessels.²⁴ Stroke was defined as the focal loss of neurologic function caused by either ischemia or hemorrhage, with residual symptoms lasting at least 24 h or leading to death.²⁵

Statistical Analysis

Continuous variables with normal distributions were summarized as the mean ± standard deviation, which were compared by the Student's t-test. Continuous variables with non-normal distributions were summarized as the median (interquartile range), which were compared by the Mann–Whitney U test. Besides, categorical variables were summarized as frequencies with percentages, which were compared by the chi-square test or Fisher's exact test. We employed the Kaplan–Meier method to establish survival plots with gastrointestinal adverse events and used the log-rank test to evaluate the difference between curves. The Cox proportional hazards model was employed to compute the hazard ratios (HR) and 95% confidence intervals (CI) for the two groups, which were utilized to evaluate the impact of medication grouping on the primary endpoint. A two-sided P value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed using R version 4.1.2.

Results

Population Characteristics

From August 2021 to August 2022, a total of 255 ACS patients with a history of gastrointestinal damage who underwent PCI were consecutively enrolled in this study. Based on the dual antiplatelet therapy, 90 patients were assigned to the indobufen plus P2Y12 inhibitor group, and 165 patients received aspirin plus a P2Y12 inhibitor.

Baseline characteristics were well-balanced between the two groups, including baseline demographics, laboratory data, PCI characteristics and medication, as summarized in Table 1. However, patients in the indobufen group had a longer history of ACS, and higher use of bivalirudin and clopidogrel, whereas the aspirin group showed greater use of beta-blockers, diuretics, nitrates, and ticagrelor.

Table 1.

Baseline Demographics and Clinical Characteristics.

Characteristic	Indobufen (n = 90)	Aspirin (n = 165)	P
Demographic Characteristics
Age (years)	64.46 ± 10.41	63.42 ± 9.39	0.421
Male,n. (%)	65(72.2)	121(73.3)	0.849
Height (cm)	168.72 ± 8.46	168.56 ± 7.27	0.871
Body weight (kg)	71.33 ± 12.52	71.32 ± 10.61	0.990
BMI (kg/m²)	24.96 ± 3.65	25.06 ± 3.11	0.823
Heart rate (beats/min)	74.64 ± 13.82	75.78 ± 11.86	0.493
Systolic blood pressure（mm Hg）	134.44 ± 20.20	131.82 ± 19.86	0.320
Diastolic blood pressure（mm Hg）	78.36 ± 8.75	79.12 ± 11.24	0.576
Course of CHD（years）	3.00(0.50,7.25)	1.00(0.15,7.00)	0.035
Previous medical characteristics
Smoking status, n (%)
No	45(50.0)	83(50.3)
Current	22(24.4)	46(27.9)	0.737
Previous	23(25.6)	36(21.8)
Drinking status, n (%)
No	60(66.7)	102(61.8)
Current	15(16.7)	41(24.8)	0.296
Previous	15(16.6)	22(13.4)
Hypertension, n (%)	59(65.6)	107(64.8)	0.910
Diabetes mellitus, n (%)	33(36.7)	53(32.1)	0.463
Stroke, n (%)	21(23.3)	27(16.4)	0.174
CKD, n (%)	4(4.4)	8(4.8)	1.000
Peripheral vascular disease, n (%)	4(4.4)	4(2.4)	0.611
MI history, n (%)	25(27.8)	49(29.7)	0.747
PCI history, n (%)	34(37.8)	60(36.4)	0.823
CABG history, n (%)	6(6.7)	4(2.4)	0.183
Laboratory and examination data
White blood cells (10⁹/l)	6.65(5.30,8.20)	6.90(5.60,8.30)	0.358
Hemoglobin (g/l)	131.16 ± 24.83	136.85 ± 21.31	0.056
HCT(%)	40.09 ± 4.42	41.18 ± 4.21	0.057
Total platelets (10⁹/l)	223.36 ± 59.53	217.61 ± 58.50	0.457
Blood glucose (mmol/l)	6.55 ± 2.42	6.87 ± 2.89	0.375
LDL-C (mmol/L)	2.25 ± 0.77	2.19 ± 0.76	0.545
HDL-C (mmol/L)	0.99(0.84,1.10)	0.94(0.81,1.10)	0.233
TG (mmol/L)	1.50(1.06,1.90)	1.45(1.07,2.04)	0.698
CHOL (mmol/L)	3.86 ± 1.03	3.79 ± 0.95	0.572
NT-proBNP (pg/mL)	192.50(60.58,484.38)	185.10(83.51,625.60)	0.343
cTnT (ng/L)	0.02(0.01,7.60)	0.02(0.01,7.00)	0.546
CK-MB (U/L)	12.80(10.68,16.40)	14.00(11.30,17.75)	0.088
Scr (umol/L)	76.50(66.54,90.28)	75.80(63.65,91.25)	0.508
Ccr (ml/min)	73.12 ± 26.91	76.37 ± 23.47	0.317
LVEF (%)	60.56 ± 5.95	59.38 ± 7.98	0.221
GRACE	104.00(92.00,114.25)	101.00(89.50,117.00)	0.964
CRUSED	28.07 ± 12.22	26.53 ± 9.55	0.267
PCI characteristics
Number of diseased vessels, n (%)			0.132
One-vessel disease	16(17.8)	36(21.8)
Two-vessel disease	35(38.9)	49(29.7)
Three-vessel disease	36(40.0)	63(38.2)
Left main disease	3(3.3)	17(10.3)
Number of stents	1.00(1.00,2.00)	1.00(1.00,3.00)	0.595
Stent diameter (mm)	2.39 ± 1.30	2.42 ± 1.36	0.872
Total stent length (mm)	33.00(15.00,58.75)	37.00(15.00,72.00)	0.360
Radial artery access, n (%)	75(83.3)	146(88.5)	0.247
Tirofiban, n (%)	14(15.6)	26(15.8)	0.966
Bivalirudin, n (%)	42(46.7)	55(33.3)	0.036
Medication
ACEI/ARB, n (%)	41(45.6)	88(53.3)	0.235
Beta-blocker, n (%)	44(48.9)	106(64.2)	0.017
Statin, n (%)	89(98.9)	165(100)	0.758
Diuretics, n (%)	6(6.7)	26(15.8)	0.036
Nitrate, n (%)	70(77.8)	148(89.7)	0.010
Clopidogrel, n (%)	89(98.9)	150(90.9)	0.012
Ticagrelor, n (%)	2(2.2)	18(90.0)	0.026
Calcium channel blockers, n (%)	40(44.4)	61(37.0)	0.243
Proton pump inhibitor, n (%)	88(97.8)	163(98.8)	0.926

Data are expressed as mean ± standard deviation, or number (percentage).

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CHD, coronary heart disease; CKD, chronic kidney disease; CABG, coronary artery bypass grafting; CHOL, total cholesterol; CK-MB, creatine kinase-MB; Ccr, creatinine clearance; cTnT, troponinT; HCT, hematocrit; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal Pro-B-type natriuretic peptide; PCI, percutaneous coronary intervention; TG, triglyceride; Scr, serum creatinine.

Gastrointestinal History

To specifically evaluate gastrointestinal effects, we compared relevant baseline gastrointestinal characteristics between the groups, including laboratory data, medicine use and the previous gastrointestinal characteristics (Dyspepsia, Peptic ulcer disease, Gastrointestinal bleeding, Other gastrointestinal diseases, Time of gastrointestinal tract damage).

As presented in Table 2, the two groups were comparable in all assessed gastrointestinal history measures except for a significantly higher rate of previous gastrointestinal bleeding in the indobufen group compared to the aspirin group (23.3% vs 13.3%, P = 0.042).

Table 2.

Gastrointestinal Characteristics.

Characteristic	Indobufen (n = 90)	Aspirin (n = 165)	P
Laboratory data
FOB, n (%)	15(16.7)	26(15.8)	0.850
Transferrin, n (%)	12(13.3)	31(18.8)	0.266
Medication
Proton pump inhibitor, n (%)	88(97.8)	163(98.8)	0.926
Previous gastrointestinal characteristics
Dyspepsia, n (%)	28(31.1)	65(39.4)	0.189
Peptic ulcer disease, n (%)	38(42.2)	68(41.2)	0.876
Gastrointestinal bleeding, n (%)	21(23.3)	22(13.3)	0.042
Other gastrointestinal diseases, n (%)	16(17.8)	25(15.2)	0.585
Time of gastrointestinal tract damage, (years)	4.88 ± 3.85	5.21 ± 4.21	0.533

Data are expressed as number (percentage).

FOB, Fecal Occult Blood.

Primary Endpoints

The primary endpoint, a composite of major adverse gastrointestinal events, occurred in 23 patients (25.6%) in the indobufen group and 65 patients (39.4%) in the aspirin group. The incidence was significantly lower in the indobufen group (HR = 0.58, 95% CI: 0.36-0.94; Log-rank P = 0.026) (Table 3, Figure 2).

Figure 2.

Kaplan-Meier estimates of the major adverse gastrointestinal events.

Table 3.

Primary Endpoints.

	Indobufen (n = 90)	Aspirin (n = 165)	p
the composite of major adverse gastrointestinal events, n (%)	23 (25.6)	65 (39.4)	0.026
the composite of clinically significant adverse gastrointestinal events, n (%)	17 (18.9)	55 (33.3)	0.014
Ulcerative dyspepsia	6 (6.7)	10 (6.1)	0.849
Peptic ulcer disease	12 (13.3)	39 (23.6)	0.049
Gastrointestinal hemorrhage	5 (5.6)	16 (9.7)	0.250

Data are expressed as number (percentage).

the composite of major adverse gastrointestinal events：Dyspepsia, Peptic ulcer disease and Gastrointestinal hemorrhage.

the composite of clinically significant adverse gastrointestinal events：Peptic ulcer disease and Gastrointestinal hemorrhage.

Similarly, the composite of clinically significant gastrointestinal events was also significantly reduced in the indobufen group (18.9% vs 33.3%; HR = 0.53, 95% CI: 0.30-0.90; Log-rank P = 0.020) (Table 3, Figure 3).

Figure 3.

Kaplan-Meier estimates of the clinically significant gastrointestinal events.

Notably, indobufen was associated with a lower incidence of peptic ulcer disease compared to aspirin (13.3% vs 23.6%). Besides, despite a higher prevalence of previous gastrointestinal bleeding in the indobufen group, the incidence of gastrointestinal bleeding events during follow-up was significantly lower in patients receiving indobufen compared to those receiving aspirin (3.3% vs 9.7%).

Secondary Endpoints

MACE occurred in 4 patients (4.4%) in the indobufen group and 11 patients (6.7%) in the aspirin group, with no statistically significant difference between the groups (P = 0.400) (Table 4). No cases of all-cause mortality, myocardial infarction, or stent thrombosis were reported during the follow-up period.

Table 4.

Secondary Endpoints.

	Indobufen (n = 90)	Aspirin (n = 165)	p
MACEs, n (%)	4 (4.4)	11 (6.7)	0.400
All-cause death	0	0	-
MI	0	0	-
Stroke	0	0	-
Any revascularization	4 (4.4)	11 (6.7)	0.400

Data are expressed as number (percentage).

MACEs, major adverse cardiovascular and cerebrovascular events; MI, myocardial infarction.

Discussion

In present study, we sought to compare the occurrence of the composite of major adverse gastrointestinal events between indobufen-based DAPT and aspirin-based DAPT in ACS patients with a history of gastrointestinal damage, aiming to explore the efficacy and safety of indobufen-based DAPT on the gastrointestinal system. In ACS patients with a history of gastrointestinal damage who have undergone PCI, indobufen plus a P2Y12 inhibitor DAPT for 12 months may have better gastrointestinal safety and tolerability than aspirin plus a P2Y12 inhibitor with respect to the primary endpoint. This is mainly due to the fact that the incidence of the composite of major adverse gastrointestinal events was significantly lower in the Indobufen group compared with that in the Aspirin group (P = 0.026). Besides, the incidence of the composite of clinically significant adverse gastrointestinal events was also significantly lower in the Indobufen group compared with that in the Aspirin group (P = 0.020). This decrease was mainly driven by a significantly reduced risk of the clinical symptoms and an improvement in quality of life.

For patients with acute coronary syndrome undergoing percutaneous coronary intervention, aspirin and a P2Y12 inhibitor (clopidogrel or ticagrelor) have long been the recommended DAPT.^1,2 However, the long-term use of aspirin has also led to many side effects, which has limited the clinical use of this DAPT. In a multicenter observational study by Tournoij et al, low-dose aspirin significantly increased the risk of gastrointestinal bleeding (pooled OR: 1.5-2.0), peptic ulcer (OR: 1.3), and upper gastrointestinal symptoms (OR: 1.7).²⁶ The most common side effects of aspirin are gastrointestinal intolerance. The OPT-PEACE trial, which employed magnetically controlled capsule endoscopy, demonstrated that continued use of aspirin-based dual antiplatelet therapy (DAPT) beyond 6 months was significantly associated with the formation of new ulcers (38.1%; P = 0.009) in patients initially free from gastrointestinal injury.⁵ The gastrointestinal side effects of aspirin not only raise the risk of bleeding incidents, but also decrease the medicine adherence of DAPT or even lead to discontinuation,²⁷ which significantly raises the risk of ischemic events.^28,29 For those ACS patients with a history of gastrointestinal damage, receiving aspirin-based DAPT may lead to a worse result.³⁰

The oral antiplatelet drug indobufen is a reversible inhibitor of platelet COX-1, which has comparable effects on inhibiting platelet aggregation and better gastrointestinal tolerance to those of aspirin. The OPTION trials indicated that indobufen-based DAPT significantly reduced the risk of 1-year net clinical outcomes. This reduction in risk was primarily due to a decrease in bleeding events without an increase in ischemic events.³¹ In clinical practice, indobufen-based DAPT was usually used to treat those ACS patients with a history of gastrointestinal damage by physicians based on clinical experience. However, there is less clinical evidence and randomized controlled trials have been taken to investigate the efficacy and safety on the gastrointestinal system of this strategy

The gastrointestinal damage severely affects not only medication compliance in patients receiving DAPT for ACS but also their long-term prognosis and quality of life.³² Previous studies have typically focused more on the outcomes associated with MACE events and gastrointestinal bleeding. However, there are only a few studies that have focused on the damage caused by DAPT to the patient's gastrointestinal system.³³ Our study classified the gastrointestinal impairment into three degrees based on the clinical symptoms and quality of life of these patients: the first is ulcerative dyspepsia, the second is peptic ulcer and the third is gastrointestinal bleeding. By statistically analyzing the patients’ gastrointestinal symptom histories and the three degrees of gastrointestinal symptom outcomes that occurred after receiving DAPT for 1 year, we further compared the effects of indobufen-based DAPT and aspirin-based DAPT on the gastrointestinal system in detail. In the present study, apart from the fact that patients in the indobufen group had a higher rate of previous gastrointestinal hemorrhage (P = 0.042) than those in the aspirin group, the history of gastrointestinal damage did not differ between the two groups. However, after 1 year DAPT, the patients in indobufen group had relatively less gastrointestinal damage than those in aspirin group.

Our study has several limitations. Firstly, the sample size of our study is small, and the follow-up period was short; as a result, a larger and better-quality randomized controlled trial with longer follow-up periods is required to validate our findings. Secondly, there were several differences in the administering of clopidogrel and ticagrelor across the indobufen and aspirin groups during follow-up, which might impact our results. Thirdly, the study was non-randomized, which raises the possibility of selection bias. Fourthly, patients usually receive DAPT for at least 1 year following PCI, but recent guidelines^34,35 have suggested reducing the length of DAPT for patients with ACS, which could affect our findings. Finally, our study only included Chinese patients, so the findings may not be generalizable to all populations.

Conclusions

In this single-center, observational study involving ACS patients with a history of gastrointestinal damage who underwent PCI, indobufen-based dual antiplatelet therapy (DAPT) demonstrated superior gastrointestinal safety profiles compared to conventional aspirin-based DAPT. Specifically, the incidence of composite major adverse gastrointestinal events—including dyspepsia, peptic ulcer disease, and gastrointestinal hemorrhage—was significantly lower in the indobufen group. This reduction was primarily attributable to a marked decrease in clinically significant gastrointestinal complications, such as peptic ulcer formation and overt bleeding, rather than mild dyspeptic symptoms alone. Importantly, the gastrointestinal benefits of indobufen were achieved without compromising cardiovascular efficacy, as both groups exhibited comparable rates of major adverse cardiovascular events (MACE). These findings suggest that indobufen may serve as a safer alternative to aspirin in this high-risk patient population, potentially improving medication adherence and long-term quality of life by mitigating gastrointestinal morbidity. Further large-scale randomized trials are warranted to validate these results and refine patient selection criteria for indobufen-based antiplatelet strategies.

Footnotes

List of Abbreviations

Acknowledgements

We acknowledge the support and assistance of all participating patients.

Ethical Approval

This retrospective study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China, and an exemption for informed consent was approved simultaneously.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent to Publish

The authors confirm that the research participants gave informed consent for the publication of the figures and tables in the study.

Author's Contribution

Wenjun Yan conceived the idea and designed the trial. Ruilin Chen, Xiaoming Xu and Quanchi Liu performed the study and collected the data. Zihan Qin and Qi Shen scrubbed data and maintained research data. Ruilin Chen and Yunlong Xia wrote the manuscript. Wenjun Yan and Dongtao Yang revised the paper.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the the Program for National Science Funds of China, (grant number 82370252).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

ORCID iDs

Quanchi Liu

Ruilin Chen

Xiaoming Xu

Yunlong Xia

Zihan Qin

Wenjun Yan

References

Atherosclerosis and Coronary Heart Disease Working Group of Chinese Society of Cardiology, Interventional Cardiology Working Group of Chinese Society of Cardiology, Specialty Committee on Prevention and Treatment of Thrombosis of Chinese College of Cardiovascular Physicians , et al. Chinese Society of cardiology and Chinese college of cardiovascular physicians expert consensus statement on dual antiplatelet therapy in patients with coronary artery disease. Zhonghua Xin Xue Guan Bing Za Zhi. 2021;49(5):432–454.

Valgimigli

Bueno

Byrne

, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur J Cardiothorac Surg. 2018;53(1):34–78.

Schrör

. Aspirin and platelets: The antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost. 1997;23(4):349–356.

Devillier

. Pharmacology of non-steroidal anti-inflammatory drugs and ENT pathology. Presse Med. 2001;30(39-40 Pt 2):70–79.

Han

Liao

, et al. Magnetically controlled capsule endoscopy for assessment of antiplatelet therapy-induced gastrointestinal injury. J Am Coll Cardiol. 2022;79(2):116–128.

Lee

Sung

Choi

. Comparison of aspirin and indobufen in healthy volunteers. Platelets. 2016;27(2):105–109.

Barillà

Pulcinelli

Mangieri

, et al. Clopidogrel plus indobufen in acute coronary syndrome patients with hypersensitivity to aspirin undergoing percutaneous coronary intervention. Platelets. 2013;24(3):183–188.

De Caterina

Giannessi

Bernini

, et al. A prostacyclin-sparing effect of indobufen vs. Aspirin. Thromb Haemost. 1996;75(3):510–514.

Yang

Mei

, et al. Pharmacodynamic effects of indobufen compared with aspirin in patients with coronary atherosclerosis. Eur J Clin Pharmacol. 2021;77(12):1815–1823.

10.

Marzo

Crestani

Fumagalli

, et al. Endoscopic evaluation of the effects of indobufen and aspirin in healthy volunteers. Am J Ther. 2004;11(2):98–102.

11.

Zhao

, et al. Indobufen or aspirin on top of clopidogrel after coronary drug-eluting stent implantation (OPTION): a randomized, open-label, endpoint-blinded, non-inferiority trial. Circulation. 2023;147(3):212–222.

12.

Bhana

McClellan

. Indobufen: An updated review of its use in the management of atherothrombosis. Drugs Aging. 2001;18(5):369–388.

13.

Mehran

Rao

Bhatt

, et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the bleeding academic research consortium. Circulation. 2011;123(23):2736–2747.

14.

Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association, et al. Guideline for diagnosis and treatment of liver failure. Zhonghua Gan Zang Bing Za Zhi. 2019;27(1):18–26.

15.

Chen

Knicely

Grams

. Chronic kidney disease diagnosis and management: a review. JAMA. 2019;322(13):1294–1304.

16.

Vahanian

Beyersdorf

Praz

, et al. 2021 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J. 2022;43(7):561–632.

17.

Guidelines for the diagnosis and treatment for Chinese adult patients with hypertrophic cardiomyopathy. Zhonghua Xin Xue Guan Bing Za Zhi. 2017;45(12):1015–1032.

18.

Hindricks

Potpara

Dagres

. Corrigendum to: 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association of cardio-thoracic surgery (EACTS). Eur Heart J. 2021;42(5):546–547.

19.

Konstantinides

Meyer

Becattini

, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European respiratory society (ERS). Eur Heart J. 2020;41(4):543–603.

20.

Stanghellini

Chan

FKL

Hasler

, et al. Gastroduodenal disorders. Gastroenterology. 2016;150(6):1380–1392.

21.

Tarasconi

Coccolini

Biffl

, et al. Perforated and bleeding peptic ulcer: WSES guidelines. World J Emerg Surg. 2020;15:3.

22.

Laine

Barkun

Saltzman

, et al. ACG Clinical guideline: Upper gastrointestinal and ulcer bleeding. Am J Gastroenterol. 2021;116(5):899–917.

23.

Thygesen

Alpert

Jaffe

. Fourth universal definition of myocardial infarction (2018). Rev Esp Cardiol (Engl Ed). 2019;72(1):72.

24.

Cutlip

Windecker

Mehran

, et al. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation. 2007;115(17):2344–2351.

25.

Qiu

Yan

, et al. Efficacy and safety of ticagrelor and clopidogrel in patients with stable coronary artery disease undergoing percutaneous coronary intervention. J Atheroscler Thromb. 2021;28(8):873–882.

26.

Tournoij

Peters

RJG

Langenberg

, et al. The prevalence of intolerance for low-dose acetylsalicylacid in the secondary prevention of atherothrombosis. Eur J Vasc Endovasc Surg. 2009;37(5):597–603.

27.

Cayla

Collet

Silvain

, et al. Prevalence and clinical impact of upper gastrointestinal symptoms in subjects treated with low dose aspirin: The UGLA survey. Int J Cardiol. 2012;156(1):69–75.

28.

Sundström

Hedberg

Thuresson

, et al. Low-Dose aspirin discontinuation and risk of cardiovascular events: A Swedish nationwide, population-based cohort study. Circulation. 2017;136(13):1183–1192.

29.

Biondi-Zoccai

GGL

Lotrionte

Agostoni

, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006;27(22):2667–2674.

30.

Herlitz

Tóth

Naesdal

. Low-dose aspirin therapy for cardiovascular prevention: Quantification and consequences of poor compliance or discontinuation. Am J Cardiovasc Drugs. 2010;10(2):125–141.

31.

Zhao

, et al. Indobufen or aspirin on top of clopidogrel after coronary drug-eluting stent implantation (OPTION): A randomized, open-label, End point-blinded, noninferiority trial. Circulation. 2023;147(3):212–222.

32.

Geraghty

Mehta

, et al. Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: A population-based cohort study. Lancet. 2017;390(10093):490–499.

33.

Veitch

Vanbiervliet

Gershlick

, et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British society of gastroenterology (BSG) and European society of gastrointestinal endoscopy (ESGE) guidelines. Endoscopy. 2016;48(4):385–402.

34.

Knuuti

Wijns

Saraste

, et al. ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407–477.

35.

Nakamura

Kimura

, et al. JCS 2020 Guideline focused update on antithrombotic therapy in patients with coronary artery disease. Circ J. 2020;84(5):831–865.