Indobufen versus Aspirin After CABG in Septuagenarians: A Propensity Score–Matched Cohort Study

Introduction

Coronary artery bypass grafting (CABG) remains a key treatment option for patients with three-vessel or left main coronary artery disease.^1–4 As the population ages and coronary artery disease becomes more prevalent, septuagenarians comprise an expanding proportion of the CABG population, creating new challenges for postoperative medical management.⁵ These patients often present with multimorbidity, compromised renal and gastrointestinal functions, polypharmacy, and frailty, which increase their susceptibility to both bleeding and ischemic complications.⁶ These age-related physiological changes substantially narrow the therapeutic window for antiplatelet therapies.

Aspirin remains the standard antiplatelet agent following CABG, and dual antiplatelet therapy (DAPT) is reserved primarily for patients with acute coronary syndromes and off-pump CABG.^1,7–12 However, guideline recommendations are largely derived from mixed-age or younger cohorts, providing limited insight into optimal antiplatelet strategies for septuagenarians. Aspirin intolerance, gastrointestinal bleeding risk, and reduced tolerance to bleeding-related complications are particularly relevant in this population, underscoring a clear unmet need for safer and more individualized postoperative regimens.

Indobufen, a reversible inhibitor of cyclooxygenase-1 (COX-1), effectively reduced the production of thromboxane A₂ while preserving prostacyclin levels.¹³ Prior studies in percutaneous coronary intervention (PCI) populations have demonstrated ischemic protection comparable to that of aspirin and reduced gastrointestinal bleeding.^14,15 However, evidence in elderly patients undergoing CABG, who may differ significantly in bleeding vulnerability, platelet biology, and exposure duration, is limited.

To address this gap, we compared the efficacy and safety of sequential antiplatelet therapy with indobufen and standard aspirin following CABG in patients aged 70–79 years at our institution. We aimed to provide clinically relevant evidence for individualized antiplatelet decision-making in this geriatric high-risk population.

Materials and Methods

Study Design and Population

We conducted a retrospective cohort study of consecutive patients aged 70–79 years who underwent isolated CABG at our institution between January 2020 and December 2022. Exclusion criteria included: (1) failure to complete 12 months of dual antiplatelet therapy (DAPT); (2) use of alternative antiplatelet monotherapy between 12 and 24 months; (3) oral anticoagulant use; (4) changes in antiplatelet therapy during follow-up; and (5) severe baseline comorbidities associated with limited life expectancy. Antiplatelet regimen selection was determined by the treating physicians. All procedures were conducted in compliance with the Declaration of Helsinki and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The study protocol received approval from the Institutional Review Board of our institution (no. B2025-377).

Perioperative Management

DAPT consisted of clopidogrel plus either indobufen (100 mg twice daily) or aspirin (100 mg once daily), initiated within 24 hours after hemostasis and continued for 12 months. After the 12-month DAPT period, clopidogrel was discontinued, and patients were maintained on monotherapy with their respective baseline agent (indobufen or aspirin) for an additional year.^1,7,16 Proton pump inhibitors (PPIs) were routinely administered during early recovery for gastrointestinal protection. The bleeding management adhered to the Bleeding Academic Research Consortium (BARC) criteria.

Data Collection and Outcomes

Baseline demographics, comorbidities, laboratory values, and surgical details were extracted from the medical records. Patients were systematically monitored at our outpatient clinic at 1, 6, 12, and 24 months, with additional telephone outreach. For patients with multiple events, the first occurrence of each outcome of interest was used in the time-to-event analyses. The primary endpoint of this study was the incidence of major adverse cardiac and cerebrovascular events (MACCE), encompassing cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and clinically indicated repeated revascularization over a 2-year follow-up period. The primary safety endpoint was major clinically relevant bleeding, as defined by the BARC criteria, encompassing types 2, 3, or 5.¹⁷ Type 4 bleeding is procedure-related and not attributable to postoperative antiplatelet therapy. The secondary endpoints included (1) all-cause death, (2) individual components of MACCE, and (3) BARC-classified bleeding by site and severity (types 1, 2, 3, or 5).¹⁸

Statistical Analysis

Propensity score matching (PSM) was performed using demographics (sex, age, body mass index [BMI]), comorbidities (hypertension, hyperlipidemia, diabetes, chronic kidney disease), surgical factors (on-pump/off-pump procedures, left internal mammary artery use, and graft number), and medications (β-blockers, ACE inhibitors/ARBs, and statins), as used in the CHARISMA trial.¹⁹ Matching (1:2, caliper = 0.25 SD) was used to retain patients with indobufen while improving balance. Absolute standardized mean difference (SMD) <0.1 indicated adequate matching.^19,20

Competing risk analyses (Fine–Gray models) accounted for death as a competing event. Continuous data were presented as mean ± SD or median (interquartile range) following an assessment of normality using Q-Q plots. Group comparisons were conducted using t-tests or the Mann–Whitney U-test. Categorical data were analyzed using the χ² or Fisher’s exact test. Statistical significance (two-tailed p <0.05) was assessed using R v4.4.3 (The R Foundation, Austria) and SPSS v25.0 (IBM Corp., Armonk, New York, USA).

Results

Baseline Characteristics and Matching

Among the 618 screened patients, 296 were eligible for analysis (indobufen = 46; aspirin = 250) (Figure 1). Propensity score matching (1:2, caliper 0.25 SD) yielded 104 well-balanced patients (indobufen = 36; aspirin = 68) (Absolute SMD < 0.1; Table 1). Before matching, indobufen recipients had more baseline bleeding risk factors (eg, anemia and prior gastrointestinal bleeding). These differences were eliminated after adjustment, confirming adequate covariate balance (Figure 2).

Table 1 Baseline Characteristics Before and After Propensity Score Matching

Figure 1 Study flowchart of patient selection and propensity score matching. Abbreviations: CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy.

Figure 2 Love plot of baseline covariate balance before and after propensity score matching. Absolute standardized mean difference (SMD) for baseline covariates are shown before and after matching. An absolute SMD < 0.1 was considered indicative of adequate balance. Abbreviations: LVEF, left ventricular ejection fraction; GI, gastrointestinal; ARNI, angiotensin receptor–neprilysin inhibitor; CCB, calcium channel blocker; RCA, right coronary artery; LDL-C, low-density lipoprotein cholesterol; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BMI, body mass index; FOBT, fecal occult blood test; MI, myocardial infarction; PPI, proton pump inhibitor; LCX, left circumflex artery; LIMA, left internal mammary artery; LAD, left anterior descending artery; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; CKD, chronic kidney disease; CABG, coronary artery bypass grafting.

Outcomes

During the 2-year follow-up, the cumulative incidence of MACCE was comparable between the groups after matching (8.3% vs. 10.3%; sHR 0.81, 95% CI 0.21–3.10; p = 0.76). Similar findings were observed before matching. In the matched cohort, the indobufen group had a lower cumulative incidence of BARC type 2, 3, or 5 bleeding than the aspirin group (2.8% vs. 11.8%; sHR 0.24, 95% CI 0.03–1.87; p = 0.14), corresponding to a 9% absolute reduction (number needed to treat [NNT] ≈ 11), despite limited power. A similar trend was observed in the overall cohort (2.2% vs. 6.8%; sHR 0.32, 95% CI 0.04–2.38; p = 0.23). Most bleeding events occurred during the first postoperative year of DAPT. BARC type 4 (CABG-related) bleeding was excluded because it represents intraoperative events rather than antiplatelet-related events (Table 2 and Figure 3).

Table 2 Primary and Secondary Endpoints Analyzed by Fine–Gray Competing Risk Model

Figure 3 Cumulative incidence of MACCE and BARC type 2, 3, or 5 bleeding. Cumulative incidence was estimated using Fine–Gray competing risk models, which accounted for death as a competing event. (A and B) show MACCE before and after propensity score matching, respectively. (C and D) show BARC 2, 3, or 5 bleeding before and after matching. Abbreviations: MACCE, major adverse cardiac and cerebrovascular events; BARC, Bleeding Academic Research Consortium; sHR, subdistribution hazard ratio; CI, confidence interval; CABG, coronary artery bypass grafting.

Subgroup Analyses

No significant heterogeneity was observed across age, sex, diabetes, anemia, chronic kidney disease, graft number, pump status, or PPI use. A consistent trend toward a lower bleeding risk with indobufen was observed across the subgroups. Full forest plots of the subgroup analyses are presented in Supplementary Figures S1–S4.

Discussion

Effective antiplatelet therapy is crucial after coronary revascularization to prevent thrombotic complications and to maintain graft patency.^7,16,21 In septuagenarians, frailty, multimorbidity, polypharmacy, and age-related changes in gastrointestinal and renal physiology further narrow the margin between therapeutic benefits and potential harm. These patients often exhibit impaired drug metabolism, reduced physiological reserve, chronic low-grade inflammation, and high rates of comorbidities, such as iron-deficiency anemia and chronic kidney disease, which increase susceptibility to bleeding, drug toxicity, and perioperative complications.^22–27 The optimal post-CABG antiplatelet strategy in septuagenarians remains uncertain, given the need to balance ischemic protection against an inherently higher bleeding risk. Aspirin intolerance, affecting approximately 10% of patients after PCI, often leads to poor adherence and increased ischemic risk, whereas current strategies, such as PPI co-therapy or desensitization, have important safety and practical limitations.^28–30 Given the lack of suitable alternatives, such as cilostazol, in routine practice,³¹ there is a pressing need for safer and more effective substitutes.

In our cohort, indobufen-based sequential therapy provided ischemic protection comparable to aspirin while showing a lower cumulative incidence of BARC type 2, 3, or 5 bleeding over two years, particularly during the first postoperative year under DAPT. These findings suggest that indobufen can offer ischemic protection similar to that of aspirin in septuagenarians, potentially improving net clinical outcomes by avoiding bleeding events. Competing risk modeling reinforces this observation by accounting for the nontrivial proportion of septuagenarians who die from noncardiac causes.

Our results align with and extend the evidence from previous studies conducted in other settings. In the OPTION trial (>4500 PCI patients with negative troponin), indobufen-based DAPT was noninferior to aspirin-based DAPT for cardiovascular death, MI, stroke, or stent thrombosis at 12 months (1.51% vs. 1.40%; HR 1.08, p = 0.76) and significantly reduced bleeding (BARC type 2, 3, or 5 bleeding 2.97% vs. 4.71%; HR 0.63).¹⁴ Similarly, the ASPIRATION registry (n = 7135) showed identical 1-year MACCE rates (6.5% vs. 6.5%; HR 0.99) but a significant 75% relative risk reduction in BARC 2–5 bleeding with indobufen (3.0% vs. 11.9%; HR 0.24, p < 0.001), including patients with aspirin intolerance.¹⁵ Despite the lack of randomized trials specifically in post-CABG patients, few studies have provided supportive signals. For instance, Cataldo et al reported comparable 1-year graft patency with fewer GI bleeding events using indobufen (1.2% vs. 3.5%).³¹ In a multicenter analysis of aspirin-intolerant CABG patients, Ren et al found no MACCE events and markedly lower bleeding with indobufen (15.8% vs. 55%).³² Despite methodological limitations, these findings align with our observations and suggest that indobufen may offer a better-tolerated antiplatelet option for surgical patients at an elevated bleeding risk.

Indobufen’s reversible COX-1 inhibition and shorter half-life may offer practical advantages in older adults who require longer periods of DAPT or are sensitive to bleeding and gastrointestinal toxicity. Pharmacodynamic studies demonstrating aspirin-equivalent COX-1 suppression but greater prostacyclin preservation provide a plausible mechanism for the clinically observed lower GI risk in some clinical settings.¹³ Despite its long clinical history, indobufen has received comparatively limited research attention over the past three decades. Most advances in antiplatelet therapy have focused on P2Y12 receptor antagonists, whereas inhibitors of the thromboxane A₂ pathway other than aspirin have remained relatively understudied. Several factors may explain this disparity, including the widespread availability and low cost of aspirin, the substantial financial investment required for large randomized clinical trials, and the limited commercial incentive to investigate older agents. Consequently, indobufen has often been used empirically despite its well-described pharmacologic properties. Recently, however, interest in indobufen has re-emerged, particularly as a potential alternative antiplatelet agent for patients with aspirin intolerance or increased bleeding risk. A systematic review has highlighted that indobufen represents a “neglected” antiplatelet agent whose pharmacological profile may offer advantages in selected patient populations.³³ From a pharmacodynamic perspective, indobufen differs from aspirin in several important ways. It acts as a reversible and noncompetitive inhibitor of cyclooxygenase-1 (COX-1), suppressing thromboxane A₂ synthesis and thereby inhibiting platelet activation. Unlike aspirin, which irreversibly acetylates platelet COX-1, indobufen produces transient inhibition and has a relatively short half-life of approximately 6–7 hours, allowing platelet function to recover more rapidly after drug discontinuation. In addition, experimental data suggest that indobufen may partially preserve prostacyclin production and exert modest inhibitory effects on ADP-induced platelet aggregation, characteristics that may contribute to improved gastrointestinal tolerability.^31,33–35 Conversely, the INSURE trial reported that indobufen failed to meet noninferiority to aspirin in preventing recurrent stroke after moderate-to-severe ischemic stroke,³⁶ a result likely driven by disease-specific cerebrovascular mechanisms rather than its intrinsic antiplatelet potency. Taken together, these findings highlight the need for further evidence in surgical populations.

This study has several limitations. Due to the retrospective single-center design and the limited number of patients receiving indobufen, the study may have been underpowered to detect modest differences in low-frequency outcomes, and the relatively small indobufen cohort limited the precision of effect estimates. Residual confounding may still exist despite propensity score matching and competing-risk modeling. The single-center setting may also limit generalizability, and treatment adherence was self-reported rather than objectively verified. Measures of frailty, mobility, and functional recovery were not available, which restricted our ability to assess patient-centered geriatric outcomes. Prospective randomized trials focusing on septuagenarians undergoing CABG are therefore warranted, ideally incorporating functional status, quality of life, and treatment tolerability. Until such data become available, our findings support an individualized approach to post-CABG antiplatelet therapy, recognizing that indobufen may be a reasonable alternative for septuagenarians who are not well suited to long-term aspirin therapy.

Conclusion

Indobufen may serve as a viable alternative to aspirin for secondary prevention in septuagenarians undergoing CABG. Over 2 years, indobufen-based therapy achieved comparable protection against MACCE, with a trend toward fewer clinically relevant bleeding events, particularly during the early postoperative phase. Although not statistically significant, this safety signal merits further investigation. Larger multicenter randomized trials are warranted to confirm these findings and define the role of indobufen in individualized post-CABG antiplatelet strategies.