Efficacy and Safety of Indobufen in Patients with Coronary Artery Disease: A Systematic Review and Meta-Analysis

Abstract

Purpose

Indobufen reversibly inhibits platelet aggregation and has potential efficacy in acute coronary syndrome and long-term cardiovascular prevention. As an alternative treatment for patients intolerant to other antiplatelet drugs, evidence-based medicine is insufficient. The purpose of this study was to evaluate the efficacy and safety of indobufen therapy in patients with coronary artery disease, and to provide reference for expanded clinical use.

Methods

We conducted a systematic review and meta-analysis of studies from the establishment of PubMed, EMBASE and other databases until their publication on November 21, 2024 The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), the primary safety index was the rate of hemorrhage of the Academic Research Consortium type 2, 3, or 5. The risk of ischemic stroke and myocardial infarction were used as the secondary indexes.

Results

This meta-analysis included eight studies with a total of 13,545 patients. According to subgroup analysis, there was no significant difference in the incidence of unconscious-cerebrovascular events between indobufen monotherapy and dual antiplatelet agents (OR 1.02, 95%CI 0.84-1.23, p = 0.84, I² = 48%). Indobufen reduced the bleeding risk in patients with coronary artery disease (OR 0.66, 95%CI 0.51-0.85, p = .001, I² = 0%). The risk of ischemic stroke for secondary indicators was comparable (OR 0.98, 95%CI 0.63-1.52, p = 0.92, I² = 3%). Similarly, the risk of myocardial infarction was comparable (OR 0.61, 95%CI 0.35-1.09, p = .10, I² = 0%).

Conclusions

According to the results of this meta-analysis, indobufen based treatment may reduce the bleeding risk with better efficacy than dual antiplatelet agents for the patients with coronary artery disease.

Introduction

Rapid urbanization and population aging have popularized unhealthy lifestyles (eg, poor diet, physical inactivity, smoking), contributing to a rising global burden of cardiovascular diseases (CVDs), including dyslipidemia, hypertension, and coronary heart disease (CHD). ¹ According to the World Health Statistics 2021 report by the WHO, CVDs remain a leading cause of mortality and morbidity worldwide. In China, CHD prevalence and mortality are substantial and increasing, with 2019 mortality rates at 121.59/100,000 (urban) and 130.14/100,000 (rural). ² However, adherence to standardized secondary prevention medications post-discharge has declined. ³ Antiplatelet therapy has significant benefits for the primary and secondary prevention of CVDs, especially in the treatment of CHD, ischemic cerebrovascular disease and peripheral artery disease.^4,5

Moreover, individual responses vary significantly. Aspirin intolerance causes or exacerbates gastrointestinal damage, bleeding, hyperuricemia and gout. Similarly, patients carrying loss-of-function alleles of CYP2C19 may experience reduced metabolic activation of clopidogrel, leading to impaired platelet inhibition and an elevated risk of ischemic events. ⁶

Indobufen, like aspirin, inhibits platelet cyclooxygenase (COX), reducing thromboxane A2 production and platelet aggregation. Unlike aspirin, however, its antiplatelet effect is reversible and diminishes within 24 h after discontinuation. ⁷ Moreover, indobufen appears to have minimal impact on prostacyclin levels, which may translate into a lower risk of gastrointestinal injury, bleeding, and renal impairment.

Current clinical guidelines recommend indobufen as an alternative antiplatelet agent for patients who are intolerant to conventional therapies, although supporting evidence remains limited. Therefore, this systematic review and meta-analysis therefore evaluates the efficacy and safety of indobufen (monotherapy and in dual regimens) for CVDs, in order to provide deeper insights for clinical decision-making.

Methods

This meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). ⁸ The protocol for this meta-analysis was registered on PROSPERO (ID: CRD42024626237).

Eligibility and Search Strategy

We performed the search in PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials from the inception dates to November 21,2024, using the Medical Subject Headings (MeSH)"Coronary Vessels”, OR “Vessel, Coronary” OR “Coronary Arteries “ OR “ Arteries, Coronary “ OR “Artery, Coronary” OR “Sinus Node Artery” OR “Arteries, Sinus Node” OR “Artery, Sinus Node” OR “Sinus Node Arteries” OR “Coronary Veins” OR “Coronary Vein” OR “Vein, Coronary"OR"Veins, Coronary” AND “indobufen[Mesh]”, OR “2-(4-(1-oxo-2-isoindolinyl)phenyl)butyric acid “ OR “ K 3920” OR “Ibustrin” OR “indobufen, (-)-isomer”.

No language restrictions were limited. Inclusion criteria were as follows: (1) indobufen (as single or dual therapy) was used as experimental observation group; (2) Confirmed coronary artery disease, with or without revascularization; (3) whether there are complete clinical and outcome data after discharge. Exclusion criteria were: (1) patients with less than 90% follow-up data; (2) ongoing studies or data that could not be retrieved; (3) letters, case reports, animal tests, posters; lack of control group studies; patients receiving oral or intravenous anticoagulant therapy; (4) follow-up ≤30 days. Other interventions including conventional antiplatelet therapy or placebo were used as controls.

Study Selection

Two researchers (NTT and SYL) screened the retrieved literature strictly against inclusion and exclusion criteria. The screening process involved an initial review of titles and abstracts, followed by a full-text assessment of potentially eligible studies. Any discrepancies between the two reviewers during the literature selection process were resolved through consultation with a senior researcher (WJB).

Outcome Measures

The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) (major cardio-cerebral adverse events were characterized by cardiogenic death, recurrent myocardial infarction, definite or probable stent thrombosis(ST), target lesion revascularization(TLR), and ischemic stroke). The primary safety index was the BARC type 2, 3 or 5 bleeding rate, and the secondary index was the risk of ischemic stroke and myocardial infarction.

Data Analysis

Statistical analysis was performed using Review Manager 5.4 free software package. Odds ratio (OR) and 95% confidence interval (95% CI) were used as pooled statistics. The Chi-Square test (χ²) test was used to test the heterogeneity of results. If P ≥ .1 and I² ≤ 50%, the fixed-effect model was used for meta-analysis. When P < .1 and I² > 50%, sensitivity analysis was performed. If heterogeneity persisted, the random effects model was used. Additionally, subgroup analyses based on treatment regimen (such as indobufen monotherapy vs dual antiplatelet therapy) were conducted to explore potential sources of statistical heterogeneity.

Risk of Bias Assessment

Each study was assessed for risk of bias. the Cochrane Bias Risk Tool 2.0(ROB 2) was used to evaluate randomized controlled trials, the Newcastle-Ottawa Scale (NOS) were used to evaluate cohort studies and case-control studies. NOS was evaluated using three blocks of eight items,including population selection, comparability, exposure or outcome evaluation. NOS uses the semi-quantitative principle of the star system to evaluate the quality of literature, with a full score of 9 stars. The risk of bias was assessed by two researchers working independently (WXN and CRN).

Results

Eligible Studies

After screening 312 studies, 234 duplicates,non-full-text articles, or no results evaluation articles were removed, as illustrated in Fig. 1. One trial was excluded because the control group used antiplatelet drugs plus oral anticoagulants, ⁹ and three studies lacked results exclusion.^10–12 Ultimately, the meta-analysis included eight trials,^13–20 including five randomized controlled trials (RCTs), two retrospective studies, and one prospective cohort study.

Figure 1.

Flow Diagram of the Systematic Overview Process.

In the eight studies included, the total population was 13,545 patients. Of these 9872 patients were male (72.88%). Indobufen monotherapy^13,14,16,17 and dual antiplatelet therapy^15,18,19,20 were studied in 4 studies with follow-up years of one year or more. The main characteristics of the included studies are presented in Table 1, and the relevant outcome measures are summarized in Table 2.

Table 1.

Characteristics of Included Studies.

Study	Type	Mean Age, y	Total Patients, No	Male, N/%	Dose
					experimental	control
Fornaro G, et al, 1993	RCT	62	196	100 (51.02)	indobufen 0.1 g bid	placebo
Rajah SM, et al, 1994	RCT	54.6 ± 8.3	803	684 (85.18)	indobufen 0.2 g bid	aspirin 0.3 g tid + s dipyridamole 75 mg tid
Barilla F, et al, 2013	RCT	61.7 ± 22.1	42	30 (71.43)	indobufen 0.1 g bid + clopidogrel 75 mg qd	clopidogrel 75 mg qd
Yang1 MW, et al, 2021	RCT	61.2 ± 9.4	218	119 (55)	indobufen 0.1 g bid	aspirin 0.1 g qd;0.1 g qod;0.1 g q72 h;50 mg bid;75 mg qd;50 mg qd
Chen B, et al, 2022	prospective cohort study	60 ± 6.9	152	119 (78.29)	indobufen 0.1 g bid	clopidogrel 75 mg qd
Wu HY, et al, 2023	RCT	61.1	4551	2968 (65.22)	indobufen 0.1 g bid + clopidogrel 75 mg qd	aspirin 0.1 g + clopidogrel 75 mg qd
Dai CF, et al, 2024	retrospective study	63.5 ± 10.5	7135	5561 (77.94)	indobufen 0.1 g bid + P2Y12 receptor antagonist)	aspirin 0.1 g qd + P2Y12 receptor antagonist
Dai WB, et al, 2024	retrospective study	72 ± 10	448	291 (64.60)	indobufen 0.1 g bid + clopidogrel 75 mg qd	aspirin 0.1 g + clopidogrel 75 mg qd

Table 2.

Correlation Outcome Indicator.

Study	MACCE (N/%)			BARC type 2, 3,			Ischemic stroke (N/%)			Myocardial infarction (N/%)
				or 5 bleeding (N/%)
	experimental	control	P	experimental	control	P	experimental	control	P	experimental	control	P
Fornaro G, et al, 1993	6(6.12)	17 (17.35)	<0.05	1 (1.02)	0 (0.00)	0.23	1 (1.02)	5 (5.10)	0.21	1 (1.02)	2 (2.04)	1.00
Rajah SM, et al, 1994				2 (0.50)	2 (0.50)	1.00				9 (2.22)	23 (5.76)	<0.05
Barilla F, et al, 2013	0 (0.00)	3 (14.29)	0.25							0 (0.00)	3 (14.29)	0.25
Yang1 MW, et al, 2021				1 (3.13)	6 (3.23)	1.00
Chen B, et al, 2022	4 (5.41)	5 (6.67)	1.00	0 (0.00)	2 (2.67)	0.5				0 (0.00)	1 (1.33)	1.00
Wu HY, et al, 2023	34 (1.51)	32 (1.40)	0.76	67 (2.97)	108 (4.70)	<0.05	18 (0.80)	19 (0.83)	0.91	9 (0.40)	10 (0.44)	0.84
Dai CF, et al, 2024	88 (6.51)	449 (6.32)	0.79	41 (3.03)	497 (6.70)	<0.05	7 (0.52)	25 (0.35)	0.36	6 (0.44)	63 (0.87)	0.10
Dai WB, et al, 2024	45 (20.09)	33 (14.73)	0.14	36 (16.07)	46(20.54)	0.22	8 (3.57)	8 (3.57)	1.00

Risk of Bias

The risk of bias in the five randomized controlled trials was assessed using the Cochrane Risk of Bias Tool (version 2), and in one study ¹³ withdrawal of the study drug due to adverse effects and refusal to continue treatment may have a depletion bias; One study ¹⁴ may have differences when considering sample size calculation and statistical analysis methods; One study ¹⁸ may have biases in the reporting and determination of results; One study ¹⁶ lacked blinded procedures and the analysis of clinical outcomes could have been biased. Overall, the five RCTs exhibited some risk of bias across various domains, as summarized in Fig. 2. The three observational studies^17,19,20 were evaluated using the NOS, and detailed information on risk bias was shown in Table 3.

Figure 2.

Risk of bias summary: review authors’ judgements about each risk of bias item for RCTs.

Table 3.

The Newcastle-Ottawa Scale was Used to Assess the Risk of Bias.

Study	Study population selection	Comparability between groups	Outcome measurement	Total
Chen B, et al, 2022	****	*	**	*******
Dai CF, et al, 2024	****	*	***	********
Dai WB, et al, 2024	***	*	**	******

Main Therapeutic index

According to subgroup analysis, four studies showed that indobufen dual antiplatelet drugs had a similar risk of MACCE in patients with coronary artery disease (4.33% (167/3853) versus 5.36% (517/9646), OR = 1.08, 95% CI [0.89-1.31], p = .42, I² = 12%, Fig. 3).

Figure 3.

Forest Plot Comparing MACCE Risk in Coronary Atherosclerosis Patients Receiving Indobufen-Based Monotherapy Versus Dual Antiplatelet Therapy. Odds Ratios (OR) with 95% Confidence Intervals (CIs) are Shown. The Size of Each Square Corresponds to the Statistical Weight of the Study in the meta-Analysis. The Dashed Vertical Line Indicates no Effect (OR = 1).

A significant difference in MACCE risk was observed between the two indobufen monotherapy treatments (5.81% (10/172) versus 12.72% (22/173), OR = 0.42, 95% CI [0.19-0.92], p = .03, I² = 19%). Evaluate publication bias through funnel plots (Fig. 4), although there was heterogeneity between the two groups (p = .02, I² = 81.1%), there was no significant difference in overall risk of MACCE in patients with coronary artery disease treated with indobufen (4.40% (177/4025) versus 5.49% (539/9819), OR = 1.02, 95% CI [0.84-1.23], p = .84, I² = 48%).

Figure 4.

Funnel Plot Assessing Publication Bias for MACCE Risk in Coronary Heart Disease Patients. Comparison: Indobufen Monotherapy versus Dual Antiplatelet Therapy. Log Odds Ratios (OR) Plotted Against Precision (1/standard error). Solid Center Line: Pooled OR; Dotted Curves: Expected 95% Confidence Intervals under Null Bias. Circles Denote Indobufen Combination; Diamonds Denote Indobufen Monotherapy.

Main Safety index

Among the primary safety endpoints observed, three studies showed a significant reduction in the risk of type 2, 3 OR 5 bleeding with indobufen dual antiplatelet agents in patients with coronary artery disease (3.76% (144/3833) versus 6.76% (651/9625), OR = 0.53, 95% CI [0.43-0.65], p < .00001, I² = 60%), Fig. 5), sensitivity analysis was used to exclude one ¹⁶ observational study involving those who were intolerant to aspirin, but not the entire PCI population due to heterogeneity.

Figure 5.

Forest Plot Comparing Clinically Relevant Bleeding Risk (BARC Type 2, 3, or 5) in Coronary Artery Disease Patients Receiving Indobufen Monotherapy Versus Dual Antiplatelet Therapy. Odds Ratios (OR) with 95% Confidence Intervals (CIs) are Shown. The Size of Each Square Corresponds to the Statistical Weight of the Study in the meta-Analysis. The Dashed Vertical Line Indicates no Effect (OR = 1).

The risk of bleeding was comparable among the four indobufen monotherapy treatments(0.66% (4/608) versus 1.32% (10/758), OR = 0.84, 95% CI [0.27-2.61], p = .76, I² = 0%). Overall indobufen was associated with a reduced risk of bleeding in patients with coronary artery disease(3.33% (148/4441) versus 6.37% (661/10383), OR = 0.54, 95% CI [0.44-.65], p < .00001, I² = 15%).

Secondary Marker–Ischemic Stroke

A total of 91 patients (0.67% of the population) had ischemic stroke data from the four studies.There were 34 patients in the experimental group and 57 patients in the control group. Patients treated with indobufen had a comparable risk of ischemic stroke compared with controls (0.86% (34/3931) versus 0.59% (57/9723), OR = 0.98, 95% CI [0.63-1.52], p = .92, I² = 3%, Fig. 6).

Figure 6.

Forest Plot of Ischemic Stroke Risk in Coronary Artery Disease Patients Receiving Indobufen Therapy. Odds Ratios (OR) with 95% Confidence Intervals (CIs) are Shown. The Size of Each Square Corresponds to the Statistical Weight of the Study in the Meta-analysis. The Dashed Vertical Line Indicates no Effect (OR = 1).

Secondary Marker–Myocardial Infarction

Four studies observed myocardial infarction data in 92 patients (0.89% of the population). There were 16 patients in the experimental group and 76 patients in the control group. Indobufen treated patients had a comparable risk of myocardial infarction compared with controls (0.42% (16/3781) versus 0.79% (76/9574), OR = 0.61, 95% CI [0.35-1.09], p = .10, I² = 0%, Fig. 7).

Figure 7.

Forest Plot of Myocardial Infarction Risk in Coronary Artery Disease Patients Receiving Indobufen Therapy. Odds Ratios (OR) with 95% Confidence Intervals (CIs) are Shown. the Size of Each Square Corresponds to the Statistical Weight of the Study in the meta-Analysis. the Dashed Vertical Line Indicates no Effect (OR = 1).

Discussion

This study evaluated the prognostic impact of indobufen-based therapy in patients with CAD, including those with acute coronary syndrome or stable CAD. Our findings reaffirm that indobufen is associated with a reduced risk of bleeding events (BARC types 2, 3, or 5), underscoring its superior safety profile compared to other antiplatelet agents. In terms of effectiveness, the characteristics of indobufen in MACCE such as cardiogenic death, recurrence of myocardial infarction, confirmed or probable ST, TLR, and ischemic stroke were comparable to those of other antiplatelet agents.

Our results are consistent with previous investigations. Yang et al reported indobufen's superiority over placebo/no treatment in preventing thromboembolism, with lower bleeding and gastrointestinal adverse event rates than other antiplatelet drugs. ²¹ Similarly, Xu et al found indobufen non-inferior to aspirin for preventing cardiovascular events (recurrent angina, non-fatal MI, cardiac death), yet with reduced overall bleeding and gastrointestinal reactions, suggesting better platelet selectivity and gastrointestinal tolerability.^22,23 Further supporting this improved safety profile, endoscopic studies in healthy volunteers have demonstrated reduced gastrointestinal toxicity with indobufen relative to aspirin. ²⁴

A key finding from our subgroup analysis is the potential enhanced efficacy and safety of indobufen-based dual antiplatelet therapy compared to monotherapy. The results of a clinical trial conducted by Liu et al ¹⁶ showed that for patients with mild stroke and high-risk transient ischemic attacks(TIA), the effect of aspirin dual antiplatelet therapy was not as effective as that of indobufen dual therapy combined therapy. This may be attributable to the relatively high prevalence of aspirin resistance in Asian populations, which can diminish aspirin's efficacy in preventing atherosclerotic events.^25–27

On the other hand, subgroup analysis of this difference may be related to the pharmacodynamics and pharmacokinetics of indobufen. As a reversible cyclooxygenase inhibitor, indobufen suppresses thromboxane A2 production and platelet aggregation induced by agonists like ADP and epinephrine. Other effects of indobufen include reduced platelet adhesion and enhanced erythrocyte deformability. ²⁸ Mechanistically, Shi et al ¹² showed that the arachidonic acid induced platelet aggregation (AA-PAR) in the indobufen group alone was lower than that in the aspirin group alone [5.21% (3.39-7.98) versus5.27% (4.06-6.60), p = .038], though this marginal difference may not be clinically significant. Conversely, ADP-induced platelet aggregation (ADP-PAR) was lower with clopidogrel monotherapy than with indobufen monotherapy. In vitro and in vivo studies, Li et al ²⁹ showed that indobufen dual therapy had a higher inhibitory effect on adenosine-induced platelet aggregation than aspirin dual therapy.

Of course, there are limitations in our study. Included studies (RCTs, retrospective, prospective) involved heterogeneous patient populations (eg,differing revascularization statuses–no intervention, PCI, CABG) and baseline characteristics (age, sex). Variability in efficacy endpoints (eg, revascularization rates, coagulation indices, thromboxane B2 levels, platelet aggregation) and treatment regimens (indobufen mono- vs dual therapy, varying dosages) complicates direct comparisons and introduces potential bias. Incomplete reporting in some studies also limited the depth of our analysis.

Despite these differences, through detailed analysis of the different characteristics of the included studies, subgroup analysis was conducted to analyze the main safety endpoint and observe the heterogeneity of indobufen dual antiplatelet therapy, confirming that indobufen dual antiplatelet therapy may have more obvious advantages in efficacy and safety than single therapy. Furthermore, our results reinforce that indobufen is associated with a superior safety profile compared to other antiplatelet agents in patients with coronary atherosclerosis. The stability of these findings was confirmed through sensitivity analyses.

Therefore, indobufen's unique pharmacodynamic profile-offering effective platelet inhibition with potentially improved tolerability and safety, particularly regarding bleeding-supports its role, as recognized in US and European guidelines，as a valuable alternative for CAD patients intolerant to other antiplatelet agents.^30,31

Conclusions

Our study suggests that indobufen-based regimens offer a potential benefit in reducing bleeding risk while maintaining comparable efficacy to other antiplatelet agents for MACCE in patients with CAD. However, the limited number of randomized controlled trials and heterogeneity among the included studies necessitate cautious interpretation. Based on the current evidence, indobufen represents a promising alternative option for CAD patients intolerant to other antiplatelet therapies, such as aspirin. Further large-scale, prospective randomized controlled trials are warranted to more definitively establish the role and optimal use of indobufen in this patient population.