Indobufen, a non-steroidal anti-inflammatory drug (NSAID), has demonstrated significant antiplatelet aggregation effects, making it widely used to prevent and treat cardiovascular diseases. Cardiovascular diseases, one of the leading causes of death and disability worldwide, are steadily increasing in prevalence. According to statistics from the World Health Organization (WHO), ischemic heart disease and stroke rank first among the top ten causes of death worldwide. Cardiovascular and cerebrovascular diseases cause approximately 14 million deaths annually, accounting for 23% of the total global mortality (1). With the aging population and lifestyle changes, the incidence of cardiovascular diseases is on the rise, highlighting the critical need for effective antithrombotic and antiplatelet therapies.

The formation of intravascular thrombosis is the primary cause of cardiovascular and cerebrovascular events (2). Arterial thrombosis primarily comprises platelets and forms at sites of atherosclerotic vascular injury under increased shear stress and disturbed blood flow (3). Antiplatelet drugs, which reduce thrombosis by inhibiting platelet aggregation, play a key role in significantly reducing the incidence of cardiovascular events and are an essential therapeutic approach for treating cardiovascular diseases. Indobufen exerts its antiplatelet effects by inhibiting cyclooxygenase activity (COX-1 and COX-2), thereby reducing the synthesis of platelet aggregation-promoting substances (4). In recent years, there have been an increasing number of studies assessing the effectiveness and safety of indobufen in treating cardiovascular conditions. However, results from various studies have been inconsistent; some demonstrate significant efficacy in preventing cardiovascular events (5), while others fail to confirm its superiority (6). Hence, a systematic evaluation of indobufen's role in cardiovascular disease treatment is crucial.

This study aims to assess the efficacy and safety of indobufen in treating cardiovascular diseases through a systematic review and meta-analysis systematic review of existing literature, thus exploring its potential clinical value. This provides a basis for further clinical research and offers valuable guidance for treating patients with cardiovascular diseases.

According to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), the protocol for this meta-analysis was registered on PROSPERO (Registration No: CRD42024587938) (7).

After screening the databases, 168 studies were initially identified. After 66 duplicate studies were removed, 37 irrelevant studies were excluded based on their titles and abstracts. Additionally, 37 articles were excluded because they were reviews or meta-analyses. The full texts of 28 articles were further reviewed, resulting in the exclusion of 16 articles. Among these, 3 trials lacked results, 4 were conference abstracts, and 9 studies had unavailable full texts, making data extraction impossible. Ultimately, 12 randomized controlled trials (RCTs) were included in this meta-analysis. A brief description of the literature screening process is shown in Figure 1, while a summary of the key characteristics of the included studies is provided in Table 1.

Based on meta-analysis, this study systematically evaluated the efficacy and safety of indobufen in treating cardiovascular diseases, cerebrovascular diseases, and thromboembolic diseases. Through this meta-analysis, we confirmed that indobufen demonstrates better clinical outcomes than other antiplatelet drugs in safety endpoints, including bleeding, gastrointestinal, and overall adverse reactions. Specifically, subgroup analyses of monotherapy or combination therapy with aspirin or clopidogrel, as well as cardiovascular disease subgroup analysis, revealed that indobufen had a significant advantage in bleeding events and gastrointestinal adverse reactions, which may be attributed to the reversible antiplatelet effect of indobufen. Regarding efficacy, no significant clinical superiority was observed for indobufen in MACE, myocardial infarction, angina, thrombosis, and mortality events compared to other antiplatelet therapies. However, in the case of stroke events, especially among cerebrovascular disease patients, indobufen demonstrated some risks.

Additionally, heterogeneity issues were of considerable concern in this study. Although studies with significant heterogeneity were excluded in the combined analysis, factors such as study design differences, participants' baseline characteristics, and drug dosages may still influence the results. The subgroup analyses in this study showed that heterogeneity in thrombotic events, gastrointestinal adverse reactions, and total adverse reaction outcomes were primarily caused by inconsistent disease types among the included studies. No significant heterogeneity was found in the outcomes mentioned above after performing subgroup analyses based on different disease types (Supplementary Figures S19–S22). For bleeding events, heterogeneity caused by the study by Morocutti et al. (14) and publication bias visible in the funnel plot were further explored. We speculated that the close monitoring of patients in this study during follow-up may have kept the relevant indicators within optimal ranges, which could explain why the original data from this study may not reflect the most realistic research situation compared to other studies.

Although no other meaningful results could be obtained in this study apart from the findings mentioned above, several interesting issues were observed. In cerebrovascular diseases, indobufen treatment may lead to higher risks of thrombosis and gastrointestinal adverse reactions. Further analysis of the included studies suggests that the high risk could be attributed to the few included studies (only two), which may have led to biased results and cannot be generalized. Furthermore, in subgroup analyses of cerebrovascular diseases and Asian patients, indobufen exhibited a higher risk in MACE events and stroke events, which is consistent with the conclusions from the study by Morocutti et al. (14). However, no statistical differences were found between the treatment groups after adjusting for prognostic factors. Multivariable analysis revealed that these factors were female sex, history of stroke, and myocardial infarction at admission (14). It is also well-known that antiplatelet drugs may show low responsiveness in certain diseases or populations due to metabolic pathways or genetic effects, such as the CYP2C19 enzyme for clopidogrel metabolism and the COX-1 gene and P2Y12 gene polymorphisms for aspirin metabolism (19–23). Due to variations in drug dosages, potential drug synergistic effects, the polymorphisms of the genes mentioned above, and the larger weight of findings from studies with large sample sizes, the higher risk associated with indobufen may have been influenced.

Our meta-analysis confirmed that indobufen has certain advantages for patients with gastrointestinal dysfunction or aspirin intolerance in cardiovascular diseases, consistent with expert consensus in clinical guidelines (19). Previous clinical studies, such as OPTION (indobufen or aspirin with clopidogrel for coronary artery drug-eluting stent implantation) and INSURE (indobufen vs. aspirin in acute ischemic stroke), large multi-center clinical trials comparing indobufen and aspirin, reported similar results to our meta-analysis. Indobufen demonstrated advantages in bleeding outcomes compared to other antiplatelet drugs, but for preventing recurrence in cerebrovascular diseases, especially in stroke patients, indobufen was not superior to aspirin. Moreover, a series of previous systematic reviews evaluating the efficacy and safety of indobufen have also pointed out that its effectiveness is significantly lower than other antiplatelet therapies in patients with gastrointestinal discomfort or those at risk of bleeding (24–26).

This meta-analysis comprehensively analyzed the efficacy and safety of indobufen in cardiovascular and cerebrovascular diseases, as well as thromboembolic diseases, and conducted subgroup analyses with possible explanations for significant results. However, due to differences in study designs, such as varied inclusion and exclusion criteria, baseline characteristics of patient populations, and differences in the diseases studied [e.g., coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and non-rheumatic atrial fibrillation (AF)], as well as time spans between studies (from 1993 to 2024). Inconsistent definitions of outcome assessment, these factors could have influenced the final results of the meta-analysis. Nevertheless, it cannot be denied that indobufen shows advantages compared to other antiplatelet drugs in safety outcomes.

Several limitations remain in this study. Firstly, the open-label design of some randomized trials may potentially influence the outcomes and introduce bias into the results. Additionally, Different studies used various metrics to assess treatment efficacy, and the statistical forms of these metrics were inconsistent across studies, such as the thromboxane B2 (TXB2) levels in plasma and urine, making it difficult to compare the outcomes of these studies. Therefore, the research focuses only on safety indicators, such as bleeding events and adverse reactions, as well as efficacy indicators, such as cardiovascular events and stroke.

Third, the included studies had inconsistent dosing regimens and insufficient studies with the same dosing protocols. This inconsistency in dosing regimens limits the interpretation of differences between the two groups in the final pooled analysis and introduces bias. In particular, the limited number of studies related to thromboembolic diseases included in this research made it difficult to evaluate the efficacy and safety of indobufen in treating thromboembolic diseases. Fourth, the studies from Asian countries included in this research were limited to China. While these studies provide valuable references for indobufen use in China and other Asian countries, future research should involve more countries and ethnic groups to obtain better results.

There are several antiplatelet drugs currently available in clinical practice, including aspirin, clopidogrel, and warfarin. Indobufen, as a secondary medication for preventing cardiovascular and cerebrovascular diseases, exhibits high selectivity and reversible binding to its receptor (27), offering certain advantages over other anticoagulants. However, compared to other anticoagulants, indobufen is used for a shorter duration, and there are fewer large-scale clinical studies, which limits the strength of the available evidence. Additionally, the increased risk of MACE and stroke observed in the indobufen group in this study suggests that, in specific conditions such as cerebrovascular diseases, these risks may be more pronounced. In conclusion, indobufen may be a suitable choice for certain populations. Its low association with bleeding events and adverse reactions provides some guidance for clinical antiplatelet therapy in patients at potential risk of bleeding or adverse reactions. Nevertheless, compared to widely recognized antiplatelet drugs like aspirin and clopidogrel, indobufen still shows certain limitations in clinical efficacy. Therefore, using indobufen should be based on carefully assessing its effectiveness and safety with individualized treatment decisions. Further research focusing on different disease types and populations will be crucial for better defining the indications and scope of use for indobufen in future clinical practice.