Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by refractory hypoxemia, respiratory distress, and non-cardiogenic pulmonary edema, triggered by pulmonary factors such as aspiration and pneumonia, or by extrapulmonary factors like severe infection, shock, and major trauma (1). The pathophysiological of ARDS centers on severe inflammatory responses and coagulation abnormalities. This processes damage the alveolar epithelium and pulmonary vascular endothelium, ultimately leading to microthrombosis and increased alveolar-capillary permeability. The resultant pulmonary interstitial edema, and ventilation-perfusion mismatch are key contributors to refractory hypoxemia (2). ARDS is a major cause of respiratory failure in critically ill patients, with an incidence of up to 23% in mechanically ventilated patients and a mortality rate exceeding 30%, where pulmonary microthrombosis is a leading cause of death (3). Therefore, developing effective treatments for ARDS and improving patient outcomes remain key challenges in current research.

Activated platelets play a regulatory role in alveolar-capillary permeability, neutrophil infiltration, and endothelial barrier function, all of which influence the progression of ARDS (4). Recent studies have demonstrated that modulating coagulation and antiplatelet therapy may improve the condition and prognosis of ARDS patients. Looney et al. (5) found that aspirin reduces platelet aggregation in pulmonary vessels, mitigating transfusion-related acute lung injury. Hayes et al. (6) confirmed that acetylsalicylic acid alleviates pulmonary edema and improves survival by inhibiting platelet activation and reducing inflammatory responses. Hamid et al. (7) showed that aspirin decreases lipopolysaccharide-induced neutrophil accumulation in the lungs, attenuating pulmonary inflammation. Thus, suppressing platelet activation may improve outcomes in ARDS.

The potent antiplatelet effect of eptifibatide, a glycoprotein IIb/IIIa receptor inhibitor (GPI), is mediated by its competitive inhibition of fibrinogen and other adhesive ligand binding to this integrin receptor (8). It exhibits high selectivity and short duration of action (half-life ~2.5 h, with antiplatelet effects diminishing within 4 h after discontinuation), along with low immunogenicity and favorable biosafety (9, 10). Currently, eptifibatide is extensively used as an antiplatelet agent in patients with acute coronary syndrome (ACS), covering the full spectrum of STEMI, NSTEMI, and unstable angina, primarily to reduce ischemic complications. Beyond ACS, its therapeutic potential is being investigated in a range of other thromboinflammatory disorders, such as stroke, ARDS, and septic shock (11–13). It is also used as an adjunctive antiplatelet agent in percutaneous coronary intervention (PCI) to minimize perioperative thrombosis risk, often in combination with aspirin, heparin, or P2Y12 inhibitors clopidogrel (14). The IMPACT II trial, a randomized, double-blind, placebo-controlled Phase III study involving 4,010 patients undergoing elective, urgent, or emergency PCI across 84 U.S. centers (November 1993–November 1994), demonstrated that eptifibatide significantly reduced the composite endpoint of death, myocardial infarction, and urgent revascularization (10). Adeoye et al. (15) reported that eptifibatide combined with recombinant tissue-type plasminogen activator (r-tPA) showed promising efficacy in acute ischemic stroke. Berthelsen et al. (16) found that eptifibatide significantly improved Sequential Organ Failure Assessment (SOFA) scores in septic shock. Lê et al. (17) observed that eptifibatide suppressed influenza virus-induced lung injury in mice. Collectively, these data underscore a promising therapeutic rationale for the potential use of eptifibatide in ARDS treatment.

Due to its rapid onset and reversible inhibition, eptifibatide is well-suited for short-term antiplatelet therapy and is widely used as an intravenous antiplatelet agent in ACS interventions. Its main adverse effects include bleeding (e.g., access site hemorrhage, gastrointestinal bleeding), thrombocytopenia (incidence 1%−2%), and hypotension, with dose adjustments required in renal impairment (halved if CrCl < 50 ml/min) to avoid accumulation. In clinical practice, it is often combined with dual antiplatelet therapy and anticoagulants, necessitating careful monitoring of bleeding risks and drug interactions. The FDA Adverse Event Reporting System (FAERS), the world's largest pharmacovigilance database, provides critical post-marketing drug safety data. This study aims to systematically analyze eptifibatide-related adverse events (AEs) in FAERS using data mining techniques and disproportionality measures to identify potential safety signals, thereby offering evidence-based guidance for clinical use.

This investigation comprehensively evaluated AEs associated with eptifibatide since its market launch in 2004. Through analysis of the FAERS database, the study confirmed common AEs listed in the drug label, including bleeding (puncture site hemorrhage, gastrointestinal hemorrhage, hematuria, intracranial hemorrhage, gingival bleeding, and epistaxis), thrombocytopenia, and hypotension, as well as severe bleeding (intracranial hemorrhage, retroperitoneal hematoma) and acute severe thrombocytopenia. Additionally, potential AEs not listed in the label were identified, such as hemorrhagic pancreatitis, coronary artery reocclusion, vascular stent thrombosis, anisocoria, brain herniation, and cardiac arrest. These results highlight the importance of enhanced drug monitoring, particularly during the initial administration of eptifibatide, to effectively manage potential side effects.

Our findings suggest that eptifibatide use may be associated with hemorrhagic pancreatitis, a severe pancreatic pathology involving tissue damage, inflammation, and necrosis, consistent with the clinical spectrum of acute or chronic pancreatitis (18). Hemorrhagic pancreatitis is a severe form of pancreatitis, possibly related to pancreatic ischemia and hypoxia, activation of pancreatic enzymes, inflammatory mediators, and increased intrapancreatic tissue pressure (19). These factors lead to vascular damage and bleeding, with severe cases resulting in shock and multiple organ failure. Studies have found that known adverse reactions of eptifibatide include bleeding (20). A plausible explanation is that eptifibatide administration may cause pancreatic tissue ischemia and hypoxia, leading to pancreatic enzyme activation and inflammatory responses that promote the development of hemorrhagic pancreatitis. Alternatively, bleeding may induce inflammatory responses and pancreatic enzyme activation, exacerbating pancreatitis. The relationship between eptifibatide and hemorrhagic pancreatitis requires further research to confirm. Therefore, awareness of this potential adverse effect underscores the importance of monitoring pancreatic function during eptifibatide therapy in ARDS to enable timely intervention and prevent hemorrhagic pancreatitis. Coronary artery reocclusion represents another potential adverse reaction, referring to the recurrence of vascular occlusion detected during follow-up angiography after successful thrombolysis of occluded arteries in AMI (21). This complication predominantly occurs within 1 week post-thrombolysis with an incidence of approximately 5%−15%, increasing to about 35% at 6 months after thrombolytic therapy, and is clinically associated with post-thrombolytic angina, arrhythmias, cardiac function deterioration, and mortality (22). The underlying mechanism involves thrombolytic therapy dissolving clots at ruptured plaques while leaving the original plaques intact, combined with residual coronary stenosis, highly thrombogenic residual thrombi, and re-exposure of ruptured surfaces, ultimately leading to thrombus reformation (23). These pathophysiological processes correlate with eptifibatide resistance, plaque rupture, and persistent coagulation activation of residual mural thrombi. Consequently, eptifibatide administration may result in suboptimal antiplatelet effects, thereby elevating patients' risk of coronary reocclusion. Therefore, clinicians should exercise particular caution regarding this potential adverse reaction when prescribing eptifibatide.

Stent thrombosis has been identified as a potential adverse effect of eptifibatide, manifesting as acute or subacute in-stent thrombosis following emergency percutaneous intervention and antiplatelet therapy in AMI patients, representing a serious post-procedural complication (24). The etiology is multifactorial, potentially involving inappropriate stent sizing, vascular dissection formation, incomplete plaque coverage, antiplatelet drug resistance, and drug interactions (25). Some patients exhibit inadequate suppression of platelet aggregation despite long-term standard-dose clopidogrel therapy, a phenomenon termed clopidogrel hypo-responsiveness or resistance (26). Eptifibatide may demonstrate analogous drug resistance patterns. The identification of stent thrombosis as a potential eptifibatide-related adverse reaction, distinct from its established post-marketing adverse effects, provides valuable guidance for clinical safety monitoring during eptifibatide therapy.

Our research additionally suggests anisocoria (a pupillary diameter disparity exceeding 1 mm between eyes) as a potential risk associated with eptifibatide (27). While physiological causes include hereditary factors, aging, and light adaptation, pathological etiologies encompass cerebral hemorrhage, brain tumors, iritis, mydriatic agents (e.g., atropine), and Horner's syndrome (28). Clinicians should remain vigilant for accompanying symptoms such as acute visual deterioration, eyelid dysfunction, sudden dizziness, headache, and nausea (29), which correlate with eptifibatide's known adverse effects of severe bleeding and intracranial hemorrhage. Intracranial hemorrhage-induced anisocoria signifies critical illness, often indicating direct brainstem or thalamic hemorrhage affecting pupillary regulatory centers, oculomotor nerve compression from elevated intracranial pressure, or cerebral herniation compressing cranial nerves and brainstem (30). Vigilant monitoring for pupillary changes, particularly anisocoria as a potential indicator of intracranial hemorrhage, is critical during eptifibatide infusion, and patients should be counseled accordingly about this risk. Our study identified brain herniation as a potential adverse reaction to eptifibatide. The cranial cavity is a fixed-volume enclosed space containing brain tissue, cerebrospinal fluid, and blood, where any increase in intracranial components can elevate local or generalized pressure, causing displacement of brain tissue to lower-pressure areas and forming life-threatening herniation, with the most common types being transtentorial, subfalcine, and tonsillar herniation (31). Common etiologies include intracranial hematomas, tumors, abscesses, parasitic infections, and congenital malformations, which correlate with eptifibatide's known adverse effect of intracranial hemorrhage (32). A plausible explanation is that eptifibatide administration may induce intracranial hemorrhage, with blood accumulation increasing local pressure that compresses and damages brain tissue, promoting displacement and herniation (33). While further research is needed to confirm the relationship between eptifibatide and brain herniation, this finding provides clinicians with a rationale for monitoring intracranial pressure and preventing herniation in patients receiving eptifibatide therapy.

Cardiac arrest, also known as asystole, was identified as another potential adverse reaction, representing complete loss of cardiac electrical activity and a primary cause of sudden cardiac arrest (34). Etiologies can be cardiac (e.g., coronary artery disease, cardiomyopathy, myocarditis) or non-cardiac (e.g., severe cerebral hemorrhage, pulmonary embolism, acute poisoning, hemorrhagic shock, anaphylaxis, electrocution, hyperkalemia, severe acidosis), corresponding with eptifibatide's known effects, including severe bleeding, allergic reactions, and intracranial hemorrhage (35). The pathways to cardiac arrest in this setting include exsanguination leading to hemorrhagic shock, anaphylaxis culminating in distributive and cardiogenic shock, and intracranial hemorrhage causing cerebral herniation via elevated intracranial pressure. Although more clinical studies are needed to investigate this association, our findings suggest cardiac arrest represents a potential eptifibatide-related adverse event warranting close cardiac monitoring and prompt intervention during treatment.

Through disproportionality analysis of FAERS data, we characterized the cumulative incidence and temporal patterns of adverse reactions primarily attributed to eptifibatide. These results emphasize the importance of early detection and management of treatment-related complications following eptifibatide administration for ARDS and other conditions, providing valuable evidence for adverse reaction prevention and mitigation to improve clinical outcomes.

This study has limitations inherent to its data source. The FAERS database, which relies on spontaneous reports, is susceptible to under-reporting, reporting biases, and variable data quality, which may affect the completeness and accuracy of our analysis. We implemented rigorous quality control measures, including correction of obvious data entry errors and duplicate report removal, to enhance reliability. Second, the exclusively U.S.-derived data may limit generalizability to other regions like Asia, Africa, and Latin America. Finally, while FAERS effectively identifies potential adverse reaction risks, its utility for epidemiological analysis remains limited.

This study utilized FAERS data to conduct disproportionality analysis of eptifibatide-related adverse events, focusing on all reports from the first quarter of 2004 to the fourth quarter of 2024. The analysis not only confirmed known adverse reactions of eptifibatide including bleeding (puncture site hemorrhage, gastrointestinal hemorrhage, hematuria, intracranial hemorrhage, gingival bleeding, and epistaxis), thrombocytopenia, and hypotension, as well as severe bleeding (intracranial hemorrhage, retroperitoneal hematoma) and acute severe thrombocytopenia, but also identified several potential adverse reactions such as hemorrhagic pancreatitis, coronary artery reocclusion, vascular stent thrombosis, anisocoria, brain herniation, and cardiac arrest. These findings underscore the necessity for early monitoring of adverse reactions in patients to ensure the safe application of eptifibatide in treating ARDS and other conditions.