The occurrence of gastrointestinal bleeding after coronary revascularization represents a serious complication of cardiac surgery, associated with high mortality and disability rates [1]. Several retrospective studies have reported various bleeding-related complications after coronary revascularization [1, 2]. However, to our knowledge, no studies have specifically evaluated the risk factors for upper gastrointestinal bleeding after hybrid coronary revascularization (HCR), a combination of stent percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), primarily used to revascularize multivessel coronary artery disease [3]. HCR combines the minimally invasive features of PCI with the long-term patency of CABG grafts, effectively reducing the occurrence of postoperative major adverse cardiovascular and cerebrovascular events (MACCEs). HCR also shortens intensive care unit (ICU) and overall hospital stays, reduces ventilation time, lowers the perioperative period, decreases the need for blood transfusions, and reduces the incidence of atrial fibrillation; thus, HCR has become one of the main revascularization methods currently used to treat multivessel coronary artery disease [4]. As the clinical application of HCR increases, the safety of the associated perioperative management has attracted more attention, especially the balance between antithrombotic therapy and bleeding risk. Dual antiplatelet therapy (DAPT) is recommended after both CABG and PCI [5]. Similarly, antiplatelet therapy is commonly prescribed after percutaneous (transcatheter) heart valve replacement (i.e., transcatheter aortic valve replacement/implantation, TAVR/TAVI) to reduce thrombotic events and recurrent ischemic complications, with the choice between single and DAPT based on patient-specific ischemic and bleeding risk as well as current evidence and guidelines [6]. However, this increases the risk of bleeding-related complications after cardiac surgery. Although gastrointestinal bleeding after general coronary revascularization has been of concern, upper gastrointestinal bleeding, as a specific subtype characterized by more rapid progression and poorer prognosis, has not been specifically studied in the HCR population. Existing studies on bleeding complications after HCR have primarily focused on cardiovascular-related bleeding, such as mediastinal and wound bleeding, with limited systematic exploration of upper gastrointestinal bleeding. Consequently, the incidence rates, risk factors, and clinical impact of upper gastrointestinal bleeding in HCR patients remain unclear. Therefore, identifying the risk factors associated with upper gastrointestinal bleeding is necessary. Thus, this study aimed to review and collect relevant preoperative, intraoperative, and postoperative data from patients to identify risk factors for upper gastrointestinal bleeding after HCR, thereby helping surgeons identify high-risk patients early and implement timely, effective interventions to improve survival rates and quality of life.

Gastrointestinal bleeding is defined as a reduction in hemoglobin of at least 2 g/dL, accompanied by hematemesis or black stool, and is diagnosed accordingly [9]. In this study, the incidence of gastrointestinal bleeding in patients undergoing HCR was 5.2%, and the mortality rate among those who exhibited gastrointestinal bleeding was 25.0%. There was a significant difference in mortality between patients with and without gastrointestinal bleeding (25.0% vs. 3.2%; p = 0.011). Previous studies have reported an incidence of gastrointestinal bleeding after CABG of 1.1% [10]. Meanwhile, the incidence of gastrointestinal bleeding in patients treated with PCI was 0.6%. Compared with patients without gastrointestinal bleeding, the mortality rate was higher in those with gastrointestinal bleeding (9.7% vs. 1.1%; p = 0.001), as well as a longer median hospital stay (5.8 vs. 1.6 days) [11]. The incidence and mortality of gastrointestinal bleeding in this study were higher than those previously reported after CABG and PCI, potentially because HCR differs from traditional surgery; thus, HCR patients will be administered oral aspirin before the operation. Furthermore, heparin will be used on the day of operation to maintain an ACT $>$300 s during CABG, and patients will receive a loading dose of clopidogrel before the start of PCI. Postoperative anticoagulation includes the use of anticoagulants such as aspirin and heparin, all of which can increase the risk of postoperative gastrointestinal bleeding in patients with HCR and long-term antiplatelet drugs before operation.

Gastrointestinal bleeding after cardiac surgery is associated with increased mortality, prolonged ventilator use, pneumonia, wound infection, sepsis, acute renal injury, atrial fibrillation, MI, ICU treatment time, and prolonged hospital stay [12]. Previous studies have suggested several factors that increase the risk of bleeding during DAPT treatment, including a history of bleeding, oral anticoagulants, women, advanced age, low body weight, chronic renal insufficiency, diabetes, anemia, and long-term use of steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) [11, 13, 14]. Intraoperative blood loss and postoperative total drainage may lead to gastrointestinal perfusion deficiency, vasoconstrictive catecholamine release, weakening of the mucus–bicarbonate barrier, gastric acid emptying, and other factors, such as gastrointestinal mucosal damage and gastrointestinal ulcers, which may lead to gastrointestinal bleeding in the later stage [15]. After multivariate analysis, prior cerebrovascular disease and total drainage were established as independent predictors of postoperative gastrointestinal hemorrhage in patients undergoing HCR. Cerebrovascular diseases included hemorrhagic stroke and ischemic stroke. In this study, 6 of 12 patients with gastrointestinal hemorrhage had a history of cerebral infarction and had been administering antiplatelet drugs for a long time. Therefore, it is considered that patients with previous cerebrovascular diseases may increase the risk of postoperative gastrointestinal bleeding due to long-term use of antiplatelet drugs before the operation. Indeed, long-term antiplatelet therapy (e.g., aspirin) may impair gastrointestinal mucosal repair and increase the risk of bleeding by disrupting the mucus–bicarbonate barrier and inhibiting platelet aggregation [16]. However, this mechanism must be considered alongside alternative explanations, such as generalized atherosclerosis, vascular frailty, and unmeasured confounders. Meanwhile, increased total drainage can also lead to a higher risk of postoperative gastrointestinal hemorrhage, primarily by inducing perioperative hypovolemia, which exacerbates gastrointestinal hypoperfusion, impairs mucosal barrier function, and promotes stress ulcer formation.

The results of this study are similar to those of previous studies, which have focused more on preoperative baseline data [17]. In contrast, this study includes many factors, such as intraoperative anticoagulant use and operation time, perioperative blood transfusion and postoperative drainage, and postoperative ICU length of stay. The results show that patients with previous cerebrovascular diseases have a relatively high risk of gastrointestinal bleeding after HCR. For these patients, attention should be paid to adjusting antiplatelet and prevention strategies to reduce the risk of gastrointestinal bleeding after the operation and discharge. Furthermore, caution is required in interpreting these findings. The wide CIs of the OR and the limitations of this study (small sample size, low event rate, unmeasured confounding factors) mean that the observed association cannot be definitively attributed solely to long-term antiplatelet therapy. Instead, these findings may reflect a combination of direct (mucosal damage caused by antiplatelet drugs) and indirect (systemic vascular dysfunction, unmeasured confounding factors) effects.

The use of dual antiplatelet drugs after coronary revascularization can reduce mortality and the incidence of ischemic events, but also increase the corresponding risk of bleeding [18]. DAPT generally uses aspirin and clopidogrel. Previous studies and guidelines recommend that aspirin be continued indefinitely after CABG, and that in patients with acute coronary syndrome (ACS) who are treated with DAPT and subsequently undergo CABG, P2Y12 inhibitor therapy be resumed after surgery to complete 12 months of DAPT following the ACS event. DAPT has been shown to reduce the risk of in-stent thrombosis by 0.4%, MI by 1.1%, and moderate-to-severe bleeding by 1.2% [13]. Since HCR combines CABG and PCI, balancing anticoagulation and bleeding risk is a major challenge for both surgeons and anesthesiologists.

After coronary revascularization, the generally recommended antiplatelet strategy is DAPT, which can significantly reduce mortality and MACCEs. Common DAPT regimens include aspirin plus ticagrelor or clopidogrel. Aspirin plus ticagrelor is the best combination for reducing bridge restenosis, mortality, and MACCEs, but this combination is associated with increased risk of bleeding during use [19]. Aspirin directly acts on the phospholipid layer of gastric mucosa, destroys the hydrophobic protective barrier of gastric mucosa [20], promotes the release of cytotoxic substances such as leukotrienes, resulting in direct mucosal loss; meanwhile, aspirin also reduces prostaglandin synthesis, gastric mucosal blood flow, and mucosal protection by inhibiting mucosal cyclooxygenase (COX)-1 and COX-2 activity [21]. Clopidogrel noncompetitively inhibits adenosine diphosphate (ADP) receptors and platelet aggregation. However, it has been reported to delay gastrointestinal mucosal healing, which may contribute to an increased risk of gastrointestinal bleeding [22]. The AUGUSTUS trials have shown that aspirin use for 30 days or longer can seriously increase the risk of bleeding. After 30 days, continued aspirin therapy further increases the risk of bleeding without reducing the risk of ischemic events [23]. Almost all patients receiving antiplatelet therapy have varying degrees of gastrointestinal injury. The bleeding risk of aspirin or clopidogrel alone was lower than that of aspirin combined with clopidogrel (0.6% vs. 5.4%; p 0.001) [24]. Indobufen is a reversible COX-1 inhibitor, with lower inhibition of prostacyclin, fewer gastrointestinal reactions, and a lower risk of hemorrhage. For patients with high risk of bleeding, the OPTION studies have shown that the incidences of cardiovascular death, non-fatal MI, ischemic stroke, and in-stent thrombosis were similar and low (1.40% vs. 1.51%; p = 0.76). The incidence of bleeding decreased significantly by 37% (2.97% vs. 4.71%; p = 0.002) when the indole buffer combined with clopidogrel is compared with aspirin combined with clopidogrel [25]. In addition, for patients at high risk of bleeding, the addition of a proton pump inhibitor (PPI), histamine-2 receptor antagonist (H2RA), or gastric mucosal protective agents is necessary to prevent gastrointestinal bleeding. PPIs can inhibit gastric acid secretion to a large extent, promote ulcer healing, and effectively prevent the gastrointestinal toxicity of antiplatelet drugs such as aspirin. PPI, as the first choice for the prevention and treatment of upper gastrointestinal bleeding, is superior to H2RAs in preventing gastrointestinal bleeding (OR = 2.102, 95% CI: 1.008–4.385) and ulcer formation (OR = 2.257, 95% CI: 1.277–3.989) [26].

Among the patients undergoing HCR surgery, those with a history of cerebrovascular diseases exhibited a higher risk of postoperative gastrointestinal bleeding. For these patients, antithrombotic strategies should be adjusted, and appropriate preventive measures should be implemented to reduce the risk of gastrointestinal bleeding.

Most previous studies have focused on CABG and PCI; to our knowledge, there are currently no relevant studies on gastrointestinal bleeding after HCR. This study, as the first report analyzing risk factors for gastrointestinal bleeding after HCR, provides new insights and lays the foundation for future preventive strategies. However, this study has certain limitations. First, the critically low number of gastrointestinal bleeding events (n = 12) leads to insufficient statistical power for definitive analysis. The event-per-variable (EPV) ratio in the multivariable logistic regression model is only ~6, which is below the commonly recommended threshold of 10 EPVs. This may lead to model instability, potential overfitting, overestimated odds ratios, and wide confidence intervals, rendering the findings preliminary and unreliable for definitive conclusions. Second, this was a single-center retrospective study with a small overall sample size (n = 231). Moreover, patient selection and perioperative management may be specific to our institution, limiting the generalizability of the results. Third, due to the small number of events and sample size, we were unable to conduct subgroup analyses (e.g., differentiating types of cerebrovascular disease) or adjust for all potential confounders (e.g., severity of comorbidities, non-steroidal anti-inflammatory drug use, or gastrointestinal mucosal status). Additionally, the analysis of factors such as gender, age, and smoking history was inconsistent with previous studies, possibly due to insufficient statistical power required to detect true associations.

ACT, Activated Clotting Time; CABG, Coronary Artery Bypass Grafting; CI, Confidence Interval; CRD, Chronic Respiratory Disease; CVD, Cerebrovascular Disease; DAPT, Dual Antiplatelet Therapy; DCB, Drug-Coated Balloon; DES, Drug-Eluting Stent; eGFR, estimated Glomerular Filtration Rate; GIB, Gastrointestinal Bleeding; HCR, Hybrid Coronary Revascularization; HGB, Hemoglobin; ICU, Intensive Care Unit; LAD, Left Anterior Descending Artery; LIMA, Left Internal Mammary Artery; LMCA, Left Main Coronary Artery; LVED, Left Ventricular End-Diastolic Diameter; LVEF, Left Ventricular Ejection Fraction; MACCEs, Major Adverse Cardiovascular and Cerebrovascular Events; MIDCABG, Minimally Invasive Direct Coronary Artery Bypass Grafting; OR, Odds Ratio; PCI, Percutaneous coronary intervention; PLT, Platelet Count; PPI, Proton Pump Inhibitor; PVD, Peripheral Vascular Disease; SD, Standard Deviation; SEM, Standard Error of the Mean; TTFM, Transit-Time Flow Measurement.

The datasets used and analysed during the current study were available from the corresponding author on reasonable request.

PS designed the study, secured funding, and oversaw the implementation of the project. ZF and YX managed the data. ZF collected demographic characteristics and wrote the initial draft, YX and PS revised it. All authors have accessed and verified the data and collectively decided to submit the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study was approved by the Ethics Committee of the Beijing Chao-Yang Hospital, Capital Medical University (Approval No.: 2023-673). All methods were carried out in accordance with Declaration of Helsinki, and all of the participants provided signed informed consent.

Not applicable.

This work was supported financially by National clinical key specialty construction project Cardiovascular Surgery.

The authors declare no conflict of interest.