Is it time to recommend dual antiplatelet therapy for all following coronary artery bypass graft surgery?—an updated review of clinical trials

Introduction

The optimal antithrombotic therapy for patients following coronary artery bypass grafting (CABG) remains unclear. Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor such as clopidogrel, or more recently ticagrelor, has been well-established in the setting of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI) (1-4). However, its role in patients with stable ischaemic heart disease without recent ACS, who undergo CABG is less well-defined.

The recent Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Grafting (DACAB) study by Zhu et al. (5) has further fuelled the discussion by demonstrating significantly superior outcomes following elective CABG in patients treated with aspirin and ticagrelor DAPT, without the increased risk of bleeding reported by some. The primary endpoint assessed was the occurrence of major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, myocardial infarction, stroke, and the need for coronary revascularization. Secondary endpoints included an extended composite outcome incorporating all-cause death, myocardial infarction, stroke, coronary revascularization, and hospital admission for unstable angina, as well as a more restrictive composite outcome consisting of cardiovascular mortality, myocardial infarction, and stroke. The 5-year outcomes reported, are a follow up to the DACAB trial (6) which found that DAPT had a better outcome in terms of MACE as compared to either aspirin or ticagrelor monotherapy (22.6% with DAPT vs. 29.9% with aspirin, P=0.04 vs. 32.9% with ticagrelor, P=0.05). In addition, DAPT with aspirin and ticagrelor did not result in significantly higher major bleeding rates (9.3% in the DAPT group, vs. 2.5% in the aspirin group, P=0.80 vs. 4.3% in the ticagrelor group, P=0.26) (5).

Traditionally, aspirin has been the cornerstone of antiplatelet therapy following CABG, given its ability to inhibit platelet aggregation by irreversibly blocking cyclooxygenase-1 (COX-1) and reducing thromboxane-A2 (TXA2) production. This antithrombotic effect helps to prevent saphenous vein graft (SVG) occlusion. Despite the widespread use of aspirin, graft failure remains a concern, with studies reporting a 7–11% occlusion rate within the first-year post-surgery (7,8). This has led to exploration of whether the addition of a second antiplatelet agent, such as clopidogrel or ticagrelor, could offer additional protective benefits by targeting a different pathway in platelet activation potentially reducing graft occlusion and improving long-term outcomes.

The rationale behind DAPT is based on the synergistic inhibition of platelet aggregation: while aspirin inhibits TXA2-mediated platelet activation, P2Y12 inhibitors block adenosine diphosphate (ADP)-mediated platelet activation (9). This dual blockade may theoretically provide superior antithrombotic effects, reducing the risk of graft occlusion more effectively than aspirin alone. The development of aspirin resistance in a certain subset of patients can also explain the better outcomes from DAPT than single antiplatelet therapy (10).

However, the use of DAPT is not without its risks. The most significant concern is the increased risk of bleeding, which can offset the potential benefits of reducing thrombotic events. Although the difference in major bleeding between DAPT and aspirin monotherapy in the study by Zhu et al. (5) was not statistically significant, the absolute difference (9.3% vs. 2.5%) remains clinically relevant. In elective CABG patients, who typically have stable coronary disease compared to those undergoing surgery after ACS, the tolerance for bleeding complications is lower. Therefore, even a modest increase in major bleeding warrants careful consideration.

Balancing the reduction of thrombotic complications with minimising bleeding risk is crucial to optimising postoperative outcomes. Surgeons and cardiologists must assess each patient’s bleeding risk individually, particularly in those with prior bleeding events, advanced age, renal dysfunction, or other risk factors for perioperative haemorrhage. If the ischaemic benefit of DAPT in preventing MACE is marginal, the associated bleeding risk may not justify routine use, especially in lower-risk patients. However, for those with complex coronary disease, extensive grafting, or prior PCI with stents, the potential benefits of DAPT may outweigh bleeding concerns.

The study by Zhu et al. (5) highlights a critical evidence gap regarding the role of DAPT in elective CABG. Future research should focus on identifying subgroups most likely to benefit from prolonged DAPT while maintaining an acceptable bleeding risk. Additionally, strategies such as lower-dose P2Y12 inhibitors or tailoring therapy based on platelet function testing could help optimise outcomes. While the bleeding difference in this study was not statistically significant, it underscores the importance of an individualised approach to DAPT in elective CABG, weighing risks and benefits on a case-by-case basis. Therefore, the decision to initiate DAPT in the surgical patient population must be carefully balanced against the potential for harm, particularly in those with a high bleeding risk.

Building on the findings of the most recent clinical trials, this review aims to provide a comprehensive and updated summary of the current evidence regarding DAPT following CABG surgery.

Conduits used in CABG

The choice of conduits plays a crucial role in determining long-term graft patency and patient outcomes. The left internal mammary artery (LIMA) is widely considered the gold standard conduit, particularly for the left anterior descending (LAD) artery, due to its superior long-term patency and resistance to atherosclerosis. The right internal mammary artery (RIMA) is another arterial option that can be used as a second arterial graft, often in a Y- or T-graft configuration. The radial artery (RA) is a versatile conduit with good long-term patency, particularly when used in patients with appropriate target vessels and adequate competitive flow reduction. The SVG remains the most used venous conduit due to its availability and ease of harvest, although it is prone to atherosclerosis and occlusion over time. Less commonly, the right gastroepiploic artery (RGEA) and the inferior epigastric artery (IEA) may be utilized, particularly in cases where other conduits are unsuitable. The choice of conduit depends on multiple factors, including patient comorbidities, target vessel characteristics, and surgeon preference, with an increasing trend toward multiple arterial grafting to improve long-term outcomes.

Graft failure can occur due to a variety of mechanisms, including early thrombosis, intimal hyperplasia, and progressive atherosclerosis (11-14). While arterial conduits such as the LIMA generally demonstrate superior long-term patency, they are still susceptible to failure due to factors such as competitive flow, vasospasm, or anastomotic site complications (15-19). Venous grafts, particularly SVGs, are more prone to failure in the long term due to their tendency to develop intimal hyperplasia and accelerated atherosclerosis. Other factors influencing conduit failure include technical aspects of graft harvesting and anastomosis (11-14), post-operative medical therapy, and patient-specific variables such as diabetes, hyperlipidaemia, and smoking. Understanding the mechanisms of conduit failure is crucial in optimising graft selection, surgical technique, and postoperative management to enhance graft longevity and improve patient outcomes.

SVG failure

SVG occlusion is a significant complication following CABG surgery, leading to adverse cardiovascular events and the need for repeat revascularisation. The mechanism and pathophysiology of SVG occlusion are complex, involving a combination of early thrombosis, intimal hyperplasia, and late atherosclerosis (11). Understanding these processes is crucial for developing strategies to improve graft patency and long-term outcomes in patients undergoing CABG. Figure 1 summarises these processes.

Figure 1 Molecular processes contributing to graft failure. This figure was informed by (11-14).

Early thrombosis

The initial phase of SVG occlusion typically occurs within the first month after surgery and is primarily driven by technical failure or thrombosis, primarily at the site of anastomosis. The process begins with the initial harvesting of the saphenous vein, which disrupts the vasa vasorum and adventitia. This disruption compromises the vessel’s nutrient supply and can result in localised hypoxia, leading to endothelial injury (12). Moreover, high-pressure distension of the vein during intra-operative assessment of graft integrity can induce endothelial injury. When a vein graft is harvested and implanted in the arterial circulation, it is exposed to arterial pressures and shear forces that are much higher than those encountered in the venous system. This sudden change in the hemodynamic environment leads to endothelial injury, platelet activation, and the initiation of the coagulation cascade. The damaged endothelium becomes prothrombotic, promoting platelet aggregation and fibrin deposition, which can rapidly lead to graft occlusion if not adequately controlled (13). Aspirin, an inhibitor of platelet aggregation, is commonly used to mitigate this risk by irreversibly acetylating the COX-1 enzyme, hence reducing TXA2 production from arachidonic acid, and thereby decreasing platelet activation and thrombus formation (12,14).

Intimal hyperplasia

Beyond the first month, the pathophysiology of SVG occlusion shifts towards intimal hyperplasia, a process that typically occurs between 1 month and 1-year post-CABG. Intimal hyperplasia is characterized by the proliferation of smooth muscle cells (SMCs) from the medial layer of the vein graft into the intima, leading to the thickening of the vessel wall and narrowing of the lumen (12). This response is driven by the mechanical stress of arterial pressures, endothelial dysfunction, and the release of growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β). These growth factors stimulate SMC migration and proliferation, as well as the deposition of extracellular matrix components, which further contribute to intimal thickening. While intimal hyperplasia is a natural adaptive response to the arterialisation of the vein, excessive hyperplasia can lead to significant stenosis and eventual occlusion of the graft (14).

Late atherosclerosis

The long-term failure of SVGs, typically occurring several years after surgery, is primarily due to the development of atherosclerosis within the graft. Unlike native coronary arteries, where atherosclerosis primarily affects the proximal segments, SVG atherosclerosis tends to occur diffusely throughout the graft and is often more aggressive. It is often concentric, with a less well-defined or absent fibrous cap, more prone to rupture (14). The pathogenesis of graft atherosclerosis involves endothelial dysfunction, lipid accumulation, inflammation, and the formation of fibro-fatty plaques. The vein graft’s endothelial cells, which are not as well-adapted to the high-pressure arterial environment as arterial endothelial cells, become dysfunctional and lose their protective anti-thrombotic and anti-inflammatory properties. This dysfunction facilitates the uptake of low-density lipoprotein (LDL) cholesterol into the vessel wall, where it becomes oxidized and triggers an inflammatory response. Macrophages infiltrate the intima, ingest oxidized LDL, and transform into foam cells, leading to the development of atherosclerotic plaques. These plaques can eventually rupture, causing acute thrombotic occlusion of the graft (14).

RA graft failure

The RA has emerged as a valuable conduit in CABG due to its superior long-term patency compared to SVG (15-17,20). However, despite its advantages, the RA is more susceptible to failure than the LIMA (18), primarily due to its muscular wall, higher propensity for vasospasm, and increased sensitivity to competitive flow (19). Various factors influence the long-term success of RA grafts, including anatomical considerations, surgical technique, competitive flow from the native coronary artery, endothelial function, and postoperative pharmacological management.

Anatomical and physiological considerations

The RA is a muscular artery, unlike the LIMA, which is an elastic artery (21). This distinction has significant implications for graft patency, as muscular arteries are more prone to vasospasm and intimal hyperplasia. The RA also has a smaller diameter than the saphenous vein, which may contribute to higher resistance and flow limitations in certain circumstances. Some studies suggest that chronic exposure to systemic hypertension may predispose the RA to medial thickening, which could negatively affect long-term patency (22).

Competitive flow and target vessel selection

One of the most critical determinants of RA graft patency is the degree of competitive flow from the native coronary artery. Competitive flow occurs when the target coronary vessel has only moderate stenosis, leading to inadequate utilisation of the graft (23-25). This results in functional closure or atrophy of the RA over time. Several studies have demonstrated that RA grafts perform best when anastomosed to coronary arteries with at least 80–90% stenosis. Moderate lesions (50–70% stenosis) are associated with a higher risk of graft failure due to persistent native coronary flow, which limits graft recruitment (23-25). The choice of the target vessel also plays a role. The RA has been successfully used for grafting to the left circumflex and right coronary arteries, particularly in patients with high-grade lesions. However, it has lower patency when used to bypass the LAD artery, where the LIMA remains the preferred conduit (23-25).

Vasospasm and endothelial function

RA vasospasm is a major concern owing to its muscular nature and propensity for contraction in response to various stimuli, including catecholamines, mechanical manipulation, and cold temperatures (26,27). Intraoperative and postoperative strategies to prevent vasospasm are crucial for optimizing graft patency. During harvesting, meticulous handling of the artery and the use of vasodilatory agents such as nitroglycerin, verapamil, and papaverine help reduce the risk of spasm. Additionally, ensuring adequate intraoperative blood flow and avoiding excessive arterial traction can preserve endothelial integrity and reduce the risk of early graft failure. Postoperatively, calcium channel blockers (CCBs) such as diltiazem and amlodipine are commonly prescribed to maintain graft patency by preventing vasospasm. The effectiveness of these agents in improving long-term RA patency is supported by multiple studies (28,29).

Systemic haemodynamics and graft adaptation

RA grafts require adequate blood pressure to maintain flow and prevent hypoperfusion. The reaction of RA grafts to fluctuations in blood pressure is not very well documented or understood. It is thought that hypotension in the early postoperative period can lead to thrombosis or graft spasm, whereas uncontrolled hypertension may contribute to endothelial damage and intimal hyperplasia (30,31). The process of graft adaptation, where the RA undergoes structural changes to accommodate the higher flow conditions in the coronary circulation, is another critical factor. Over time, RA grafts typically develop a more compliant wall structure, improving their hemodynamic performance. Ensuring optimal systemic haemodynamics, with high flow rates through the RA graft, in the postoperative period can facilitate this adaptation process and enhance long-term patency (32,33).

Role of antiplatelets in radial arterial grafts

The superior endothelial function of the RA, compared to venous grafts, contributes to its relative resistance to thrombosis, which may explain why aspirin alone is often sufficient. Within the RAPS and RAPCO trials, all patients were discharged with at least aspirin monotherapy (34,35). The role of DAPT in CABG, particularly in arterial grafts, is less clear. Several studies have explored the potential benefits of DAPT in improving RA patency. The DACAB trial demonstrated that ticagrelor-based DAPT improved graft patency compared to aspirin alone, particularly for non-LIMA grafts such as the RA. Sun et al. suggested that the addition of clopidogrel may potentially enhance the patency of RA grafts (36). Other observational studies have reported similar findings, suggesting that DAPT may enhance RA graft function by reducing platelet activation and thrombotic complications.

Among the P2Y12 inhibitors, clopidogrel has been most widely studied in the CABG population. However, its efficacy is limited by interindividual variability in drug metabolism due to genetic polymorphisms affecting CYP2C19 enzyme activity, as will be described below. Ticagrelor has shown superior platelet inhibition compared to clopidogrel and may be a better option in certain patients. This will be discussed below in more detail. Some studies suggest that ticagrelor-based DAPT may improve arterial graft patency more effectively than clopidogrel, though further research is needed to confirm these findings (11).

LIMA graft failure

The LIMA is the preferred conduit for CABG owing to its superior long-term patency rates compared to SVG and RA grafts. LIMA grafts maintain patency rates of over 90% at 10 years postoperatively, significantly improving survival and reducing the need for repeat revascularisation (37). However, despite its durability, several factors influence LIMA graft patency, including patient-specific characteristics, surgical technique, anatomical considerations, competitive flow from the native coronary artery, and postoperative pharmacological management. Understanding these factors is crucial to optimising graft longevity and patient outcomes.

Anatomical and physiological advantages of LIMA

The LIMA differs from other arterial conduits owing to its unique histological composition and intrinsic resistance to atherosclerosis (33). Unlike muscular arteries such as the RA, the LIMA is an elastic artery with a thinner medial layer and a well-developed internal elastic lamina. These characteristics contribute to its enhanced resistance to intimal hyperplasia and atherosclerotic degeneration, key factors in graft longevity. Moreover, the LIMA has a robust endothelial function, with a higher production of nitric oxide (NO) and prostacyclin, both of which contribute to vasodilation and thrombosis prevention. These properties provide a natural resistance to graft occlusion and make the LIMA the conduit of choice for bypassing the LAD artery, where it demonstrates optimal flow dynamics and superior long-term outcomes (33).

Harvesting technique—skeletonised versus pedicled grafts

The method used to harvest the LIMA has a direct impact on its patency. Traditionally, the LIMA has been harvested as a pedicled graft, meaning it is dissected along with its surrounding veins, fascia, and connective tissue. However, skeletonised harvesting, where the artery is dissected free from the surrounding tissue, has gained popularity in recent years. Advantages of skeletonisation include increased graft length, preservation of sternal blood supply and improved endothelial function (38,39). Skeletonised LIMA grafts are longer, allowing greater flexibility in grafting options, particularly in multi-arterial revascularisation. Studies suggest that skeletonised harvesting reduces the risk of sternal wound complications, particularly in diabetic and obese patients, by preserving collateral blood flow from the intercostal arteries, although this was not found to be the case in the Arterial Revascularisation Trial (ART) by Benedetto et al. (39). Some studies indicate that skeletonised grafts retain better endothelial function and have better flow, leading to enhanced long-term patency rates (40). Despite these advantages, concerns remain regarding the increased technical difficulty of skeletonised harvesting and the potential risk of graft trauma, which could negatively impact early patency. However, a post-hoc analysis of the COMPASS trial seemed to suggest that skeletonisation of the LIMA has worse patency outcomes (41). More randomised data is required in this field.

Competitive flow and target vessel selection

Competitive flow from the native coronary artery is one of the most critical determinants of LIMA graft patency. If the native coronary artery has moderate stenosis (50–70%), the physiological resistance to graft flow can lead to underutilisation of the LIMA, resulting in functional occlusion or atrophy over time. LIMA patency is highest when grafted to arteries with severe stenosis (>80–90%), ensuring maximal flow through the graft (32,38). Bypassing a vessel with mild disease (<50%) leads to competitive flow, increasing the risk of graft failure. The LIMA performs best when grafted to the LAD, where it experiences optimal flow dynamics and shear stress conditions that promote long-term function (32,38).

What is the rationale for DAPT?

Aspirin is a cornerstone therapy in preventing graft occlusion following CABG. However, the phenomenon of aspirin resistance—where patients exhibit a diminished biological response to aspirin—may pose significant challenges to graft patency and patient outcomes post-CABG. Aspirin resistance can result from various factors, including genetic polymorphisms, drug interactions, noncompliance, and comorbid conditions such as diabetes mellitus (13). These factors undermine aspirin’s efficacy in preventing platelet aggregation and thrombus formation, thus increasing the risk of early and late SVG occlusion.

The pathophysiology of aspirin resistance is multifaceted, but there is a genetic basis in some cases. Genetic polymorphisms, affecting both the COX-1 enzyme and platelet glycoprotein receptors, such as GPIIb/IIIa, have been shown to lead to reduced inhibition of TXA2 synthesis, thus allowing continued platelet activation despite aspirin therapy. For example, a study in 2007 in a Chinese population found that the presence of the P2Y1 893CC genotype in healthy Chinese volunteers confers an attenuated antiplatelet effect with aspirin (42). Another study showed a similar situation for carriers of polymorphisms of PY21 893T and 1622G alleles (43). Moreover, upregulation of alternative pathways for platelet activation, such as those mediated by ADP or collagen, can bypass the inhibitory effects of aspirin on TXA2, leading to continued platelet aggregation.

There is some evidence that there may be transient aspirin resistance in some patients following CABG, reaching up to 90% in the early post-operative period but slowly fading out by 6 months post-surgery. Whether this is because of a transient effect of surgery, including cardiopulmonary bypass, or genetic polymorphisms, remains yet to be determined (43). Drug interactions, particularly with nonsteroidal anti-inflammatory drugs (NSAIDs), can further exacerbate aspirin resistance. Similarly, proton pump inhibitors (PPIs) have been implicated in diminishing aspirin’s antiplatelet effect by interfering with its absorption or metabolic activation.

To address the issue of aspirin resistance and therefore potentially prolong patency of bypass grafts and improve long term outcomes following CABG, several strategies have been explored. These include the use of higher doses of aspirin (44) or combination therapy with other antiplatelet agents such as clopidogrel as DAPT.

Although use of DAPT appears to be the favoured strategy, a recent randomised trial by Kim et al. (45), suggested that some patients can demonstrate clopidogrel resistance. This is often secondary to a CYP2C19 genetic polymorphism (46) and has been seen to be associated with increased rates of MACE in patients following CABG and PCI (46). The prevalence of the CYP2C19 allele varies significantly across populations, affecting approximately 15% of White and African American individuals and up to 35% of Asians (47,48). This underscores the importance of considering patient ethnicity when interpreting trial outcomes, as variations in genetic polymorphisms across different populations could influence the generalisability of observed findings across different populations.

As a result of these observations, some advocate that platelet function testing may be the best way of guiding optimal antiplatelet therapy as it can identify patients with suboptimal response to antiplatelet therapies, allowing for personalised adjustments which may improve clinical outcomes.

While DAPT has been extensively studied in the context of CABG, alternative antithrombotic strategies have also been explored to improve graft patency. In particular, the potential role of oral anticoagulants, such as factor Xa inhibitors, has been investigated as an adjunct or alternative to aspirin-based therapy. However, evidence suggests that graft thrombosis is primarily a platelet-driven process, limiting the efficacy of anticoagulation in this setting. This was highlighted in a sub-study of the COMPASS trial, which evaluated the impact of rivaroxaban on graft patency following CABG. In a sub-study of the COMPASS trial (49) involving 1,448 patients who underwent CABG, the use of the factor Xa inhibitor rivaroxaban, either as monotherapy or in combination with aspirin, did not lead to a significant reduction in graft failure at one year when compared to aspirin alone. The incidence of graft failure was 9.1% in the rivaroxaban-plus-aspirin group versus 8.0% in the aspirin-alone group [odds ratio (OR): 1.13, 95% confidence interval (CI): 0.82–1.57; P=0.45]. Similarly, in the rivaroxaban monotherapy group, the graft failure rate was 7.8% compared to 8.0% in the aspirin group (OR: 0.95, 95% CI: 0.67–1.33; P=0.75). These findings indicate that graft thrombosis is predominantly driven by platelet activation rather than thrombin-mediated mechanisms, thereby supporting current guidelines which do not recommend the use of oral factor Xa inhibitors for the prevention of graft failure.

Current guideline recommendations

The European and American guidelines on antiplatelet therapy following elective CABG offer recommendations that are both similar and nuanced, reflecting the current evidence and patient-specific considerations.

The European guidelines, as detailed by the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery (ESC/EACTS) in 2018 (50), recommend lifelong aspirin therapy at a dose of 75–100 mg daily for all patients after CABG. While the use of DAPT, combining aspirin with a P2Y12 inhibitor like clopidogrel, can be considered for up to one year, this is primarily advised for patients at higher risk, such as those with ACS or complex coronary anatomy. However, for patients undergoing elective CABG for stable ischaemic heart disease, DAPT is not routinely recommended.

Similarly, the American guideline focused update on the duration of DAPT in patients with coronary artery disease provided by the American College of Cardiology and the American Heart Association (ACC/AHA) in 2016 (51) recommend DAPT for 12 months in patients who have had CABG following ACS, as a class I indication, recognising the heightened risk of recurrent events in this population. The 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularisation also endorse lifelong aspirin therapy post-CABG and recommend aspirin at a slightly broader dosage range of 100–325 mg daily (52). For patients who undergo elective CABG for stable coronary artery disease, aspirin monotherapy is typically deemed sufficient. Nonetheless, DAPT may be considered in select cases, particularly in high-risk individuals, in patients undergoing off-pump surgery (53) and those with higher SYNTAX scores, or in those with specific graft characteristics, such as poor-quality SVGs.

Debate regarding the use of DAPT post elective surgery

The role of DAPT after elective CABG remains controversial due to conflicting trial results (Table 1). The CURE (54,55) and PLATO (2) trials, which focused on ACS patients, suggested improved outcomes with DAPT; however, their applicability to stable patients undergoing elective CABG is unclear. In the CURE trial, during the initial hospitalisation for CABG, the incidence of cardiovascular death, myocardial infarction, or stroke prior to the surgery was 4.7% in the placebo group compared to 2.9% in the clopidogrel group [relative risk (RR) 0.56, 95% CI: 0.29 to 1.08]. Among those who underwent CABG, life-threatening bleeding occurred in 5.6% of patients treated with clopidogrel and 4.2% of those given placebo (RR 1.30, 95% CI: 0.91 to 1.95). Both differences were statistically nonsignificant (55). Meanwhile, the PLATO trial established ticagrelor as a superior alternative to clopidogrel in patients with ACS due to its greater efficacy in reducing cardiovascular events and mortality, leading to changes in clinical guidelines recommending ticagrelor as the preferred antiplatelet agent in this setting (2). The CASCADE trial (56), which studied aspirin with or without clopidogrel post-CABG, showed no significant difference in SVG patency rates, challenging the routine use of DAPT in this setting. Conversely, the DACAB trial (5,6) demonstrated that adding ticagrelor to aspirin post-CABG reduced SVG occlusion rates, but this came with a higher risk of bleeding. The TICAB trial (57) supported the benefit of DAPT in improving graft patency, particularly in high-risk patients, but again raised concerns about bleeding complications. However, due to the early termination of recruitment, the trial lacked sufficient power and was ultimately inconclusive.

A recent paper by Olufade et al. in 2021 (59) assessed the relative effectiveness of ticagrelor compared to clopidogrel in reducing hospitalisations for MI in patients with ACS. The research found that patients treated with ticagrelor had lower hospitalisation rates for MI compared to those receiving clopidogrel, suggesting that ticagrelor may be more effective in preventing recurrent ischaemic events.

The variation in patient populations between studies, timing of DAPT initiation, and differing endpoints across studies contribute to the ongoing debate. Current guidelines, as outlined above, are cautious, generally recommending aspirin monotherapy for most post-elective CABG patients, reserving DAPT for those with high thrombotic risk or prior ACS. The results of the TACSI (Ticagrelor and ASA vs. ASA only after Isolated Coronary Artery Bypass Grafting in Patients with Acute Coronary Syndrome) trial are eagerly anticipated. With a planned enrolment of 2,200 patients, the study is set to complete recruitment by December 2024, and its findings will offer valuable insights into the 10-year outcomes for these patients (60).

The 5-year follow up of the DACAB trial—revolutionary or not?

Zhu et al.’s recent paper (5) provides long-term outcomes of the DACAB trial, focusing on the effectiveness and safety of DAPT versus aspirin monotherapy after CABG. The study evaluated 500 patients randomised 1:1:1 to either DAPT (aspirin 100 mg + ticagrelor 90 mg twice daily), ticagrelor monotherapy (90 mg twice daily) or aspirin alone (100 mg daily) for one year, followed by a five-year follow-up.

At five years, the primary endpoint—MACE—occurred in 22.6% of patients in the DAPT group, versus 32.9% in the ticagrelor monotherapy group versus 29.9% in the aspirin monotherapy group, showing a continued significant reduction in occlusion rates with DAPT. In the study, the five-year event rates for extended MACE, the secondary endpoint, were 22.6% for DAPT, 32.9% for ticagrelor monotherapy, and 30.5% for aspirin monotherapy. The risk of experiencing extended MACE was significantly lower in the DAPT group compared to the aspirin monotherapy group, with a hazard ratio of 0.64 (95% CI: 0.43 to 0.96; P=0.03). Similarly, the DAPT group had a lower risk compared to the ticagrelor monotherapy group, with a hazard ratio of 0.65 (95% CI: 0.43 to 0.98; P=0.04) (56).

The five-year bleeding event rates were 4.9% for DAPT, 2.5% for ticagrelor monotherapy, and 4.3% for aspirin monotherapy. The analysis revealed no significant difference in the risk of major bleeding between the DAPT group and the aspirin monotherapy group, with a hazard ratio of 1.14 (95% CI: 0.42 to 3.14; P=0.80). Similarly, the comparison between the DAPT group and the ticagrelor monotherapy group showed no significant difference in bleeding risk, with a hazard ratio of 1.99 (95% CI: 0.60 to 6.61; P=0.26).

The DACAB trial’s five-year results are consistent with earlier findings regarding SVG patency but with a noticeably lower bleeding risk associated with DAPT. The study also noted that patency of SVG was less in off-pump vs. on-pump.

The DACAB trial provides valuable insights into the role of DAPT after elective CABG, but like any study, it has both strengths and limitations. One of its major strengths is its randomised design. Additionally, the trial specifically focuses on patients undergoing elective CABG, addressing an important but under-researched area. The inclusion of multiple centres enhances the generalisability of the findings within the Chinese population, while the use of angiographic follow-up provides objective data on graft patency, a critical endpoint in surgical revascularisation. Moreover, the study evaluates both clinical outcomes and graft failure, offering a comprehensive assessment of DAPT’s impact beyond traditional endpoints like MACE.

However, the DACAB trial also has limitations that must be considered when interpreting its findings. The sample size, while reasonable, may still be underpowered to detect smaller but clinically relevant differences in graft patency or long-term outcomes. Additionally, the follow-up duration, although sufficient to capture early graft failure, may not fully reflect long-term benefits or risks associated with prolonged DAPT use. Another key limitation is the lack of a pre-specified subgroup analysis differentiating between vein grafts and arterial grafts, as DAPT may have distinct effects on different conduit types. Furthermore, the study does not account for variations in surgical techniques, such as the use of skeletonised versus pedicled grafts, which could influence outcomes. The absence of platelet function testing also means that the study could not assess whether a more personalised approach to antiplatelet therapy might yield better results. Lastly, while the trial reports no statistically significant difference in major bleeding, the absolute difference in bleeding rates raises concerns about the safety of DAPT in this setting, warranting further investigation.

This extended follow-up of the DACAB trial, with a notably high rate of patient inclusion, adds strength to the findings by ensuring robust and comprehensive data analysis. The consistent engagement of patients over this extended period provides valuable insights into the long-term effects of the use of DAPT post CABG. However, while the current results are promising, it would be particularly insightful to observe the outcomes with an even longer follow-up, such as at the 10-year mark. This would allow for a more definitive understanding of the durability and clinical significance of the observed increased SVG patency and reduced MACE rate. Furthermore, for the study to be repeated in different populations to confirm the generalisability of the results.

However, the study by Zhu et al. (5) represents the largest to date demonstrating such a stark difference in graft patency rates following elective CABG when comparing aspirin monotherapy, ticagrelor monotherapy, and the combination of aspirin and ticagrelor therapy. Most previous studies evaluating antiplatelet strategies in CABG patients have been conducted in the context of ACS, making this study particularly significant in addressing outcomes in the elective surgical population.

Conclusions

Early intervention with antiplatelet therapy, strategies to minimise intimal hyperplasia, and long-term management of atherosclerotic risk factors are essential to improving outcomes for patients undergoing CABG.

Both the European and American guidelines emphasise aspirin monotherapy as the primary antiplatelet strategy post-elective CABG in patients with stable ischaemic heart disease. DAPT is generally reserved for patients with recent ACS or other high-risk features. The decision to use DAPT in elective cases remains a matter of individual patient assessment, balancing the potential advantages in graft patency against the risk of bleeding. The guidelines reflect the ongoing debate within the field, as clinical trials like CASCADE, PLATO, TICAB, and others have yielded mixed results regarding the overall benefit of DAPT in the context of elective stable CABG patients.

The DACAB-FE study has made a significant contribution to the literature by providing valuable insights into the long-term outcomes of DAPT following CABG in the elective setting. The extended follow-up period of the original DACAB trial offered a more comprehensive understanding of the benefits and risks associated with DAPT compared to aspirin monotherapy in post-CABG patients. By highlighting the reduction in MACE with DAPT, the DACAB-FE study reinforces the potential benefits of prolonged antiplatelet therapy, especially in patients undergoing elective CABG, at high risk of graft failure. Previous clinical trials mentioned above did not focus on the use of DAPT in elective patients. Additionally, the study’s findings help to clarify the balance between the protective effects of DAPT and the increased risk of bleeding, contributing to more informed clinical decision-making regarding post-CABG antiplatelet strategies. These extended follow-up data also add depth to the discussion on optimal antiplatelet therapy duration, influencing future guidelines and clinical practices.

However, there is still a lack of consistent, robust evidence supporting a clear benefit of DAPT in elective CABG patients and this underscores the need for more targeted research to define the optimal approach.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-180/prf

Funding: None.

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References

1. Solo K, Lavi S, Kabali C, et al. Antithrombotic treatment after coronary artery bypass graft surgery: systematic review and network meta-analysis. BMJ 2019;367:l5476. [Crossref] [PubMed]
2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57. [Crossref] [PubMed]
3. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800. [Crossref] [PubMed]
4. Angiolillo DJ, Galli M, Collet JP, et al. Antiplatelet therapy after percutaneous coronary intervention. EuroIntervention 2022;17:e1371-96. [Crossref] [PubMed]
5. Zhu Y, Zhang W, Dimagli A, et al. Antiplatelet therapy after coronary artery bypass surgery: five year follow-up of randomised DACAB trial. BMJ 2024;385:e075707. [Crossref] [PubMed]
6. Zhao Q, Zhu Y, Xu Z, et al. Effect of Ticagrelor Plus Aspirin, Ticagrelor Alone, or Aspirin Alone on Saphenous Vein Graft Patency 1 Year After Coronary Artery Bypass Grafting: A Randomized Clinical Trial. JAMA 2018;319:1677-86. [Crossref] [PubMed]
7. Gaudino M, Antoniades C, Benedetto U, et al. Mechanisms, Consequences, and Prevention of Coronary Graft Failure. Circulation 2017;136:1749-64. [Crossref] [PubMed]
8. Antonopoulos AS, Odutayo A, Oikonomou EK, et al. Development of a risk score for early saphenous vein graft failure: An individual patient data meta-analysis. J Thorac Cardiovasc Surg 2020;160:116-127.e4. [Crossref] [PubMed]
9. Takahashi Y, Nishida Y, Nakayama T, et al. Comparative effect of clopidogrel and aspirin versus aspirin alone on laboratory parameters: a retrospective, observational, cohort study. Cardiovasc Diabetol 2013;12:87. [Crossref] [PubMed]
10. Thet MS, Khosravi A, Egbulonu S, et al. Antiplatelet Resistance in Coronary Artery Bypass Grafting: A Systematic Review. Surg Res Pract 2024;2024:1807241. [Crossref] [PubMed]
11. Sandner S, Redfors B, Gaudino M. Antiplatelet therapy around CABG: the latest evidence. Curr Opin Cardiol 2023;38:484-9. [Crossref] [PubMed]
12. DeStephan CM, Schneider DJ. Antiplatelet therapy for patients undergoing coronary artery bypass surgery. Kardiol Pol 2018;76:945-52. [Crossref] [PubMed]
13. Storey RF. Exploring mechanisms of graft occlusion toward improved outcomes in coronary artery bypass graft surgery. J Am Coll Cardiol 2011;57:1078-80. [Crossref] [PubMed]
14. Xenogiannis I, Zenati M, Bhatt DL, et al. Saphenous Vein Graft Failure: From Pathophysiology to Prevention and Treatment Strategies. Circulation 2021;144:728-45. [Crossref] [PubMed]
15. Baikoussis NG, Papakonstantinou NA, Apostolakis E. Radial artery as graft for coronary artery bypass surgery: Advantages and disadvantages for its usage focused on structural and biological characteristics. J Cardiol 2014;63:321-8. [Crossref] [PubMed]
16. Desai ND, Cohen EA, Naylor CD, et al. A randomized comparison of radial-artery and saphenous-vein coronary bypass grafts. N Engl J Med 2004;351:2302-9. [Crossref] [PubMed]
17. Gaudino M, Benedetto U, Fremes S, et al. Association of Radial Artery Graft vs Saphenous Vein Graft With Long-term Cardiovascular Outcomes Among Patients Undergoing Coronary Artery Bypass Grafting: A Systematic Review and Meta-analysis. JAMA 2020;324:179-87. [Crossref] [PubMed]
18. Khot UN, Friedman DT, Pettersson G, et al. Radial artery bypass grafts have an increased occurrence of angiographically severe stenosis and occlusion compared with left internal mammary arteries and saphenous vein grafts. Circulation 2004;109:2086-91. [Crossref] [PubMed]
19. Cheng K, Rehman SM, Taggart DP. A Review of Differing Techniques of Mammary Artery Harvesting on Sternal Perfusion: Time for a Randomized Study? Ann Thorac Surg 2015;100:1942-53. [Crossref] [PubMed]
20. Audisio K, Halbreiner MS, Chadow D, et al. Radial artery or saphenous vein for coronary artery bypass grafting. Trends Cardiovasc Med 2022;32:479-84. [Crossref] [PubMed]
21. Panagiotopoulos I, Leivaditis V, Sawafta A, et al. The choice of conduits in coronary artery bypass surgery. Arch Med Sci Atheroscler Dis 2023;8:e83-8. [Crossref] [PubMed]
22. Martinez-Quinones P, McCarthy CG, Watts SW, et al. Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall. Am J Hypertens 2018;31:1067-78. [Crossref] [PubMed]
23. Glineur D, Hanet C. Competitive flow in coronary bypass surgery: is it a problem?. Curr Opin Cardiol 2012;27:620-8. [Crossref] [PubMed]
24. Nappi F, Bellomo F, Nappi P, et al. The Use of Radial Artery for CABG: An Update. Biomed Res Int 2021;2021:5528006. [Crossref] [PubMed]
25. Sousa-Uva M, Gaudino M, Schwann T, et al. Radial artery as a conduit for coronary artery bypass grafting: a state-of-the-art primer. Eur J Cardiothorac Surg 2018;54:971-6. [Crossref] [PubMed]
26. Verma S, Szmitko PE, Weisel RD, et al. Should radial arteries be used routinely for coronary artery bypass grafting? Circulation 2004;110:e40-6. [Crossref] [PubMed]
27. Kharabsheh S, Al-Halees Z. The radial artery as a coronary bypass conduit: dealing with hypereactivity. Ann Saudi Med 2005;25:70-2. [Crossref] [PubMed]
28. Gaudino M, Benedetto U, Fremes SE, et al. Effect of Calcium-Channel Blocker Therapy on Radial Artery Grafts After Coronary Bypass Surgery. J Am Coll Cardiol 2019;73:2299-306. [Crossref] [PubMed]
29. Bond BR, Zellner JL, Dorman BH, et al. Differential effects of calcium channel antagonists in the amelioration of radial artery vasospasm. Ann Thorac Surg 2000;69:1035-40; discussion 1040-1. [Crossref] [PubMed]
30. Schwann TA, Gaudino M, Baldawi M, et al. Optimal management of radial artery grafts in CABG: Patient and target vessel selection and anti-spasm therapy. J Card Surg 2018;33:205-12. [Crossref] [PubMed]
31. Tatoulis J. The radial artery: An important component of multiarterial coronary surgery and considerations for its optimal harvest. JTCVS Tech 2020;5:46-55. [Crossref] [PubMed]
32. Szafron JM, Heng EE, Boyd J, et al. Hemodynamics and Wall Mechanics of Vascular Graft Failure. Arterioscler Thromb Vasc Biol 2024;44:1065-85. [Crossref] [PubMed]
33. Gharibeh L, Ferrari G, Ouimet M, et al. Conduits’ Biology Regulates the Outcomes of Coronary Artery Bypass Grafting. JACC Basic Transl Sci 2021;6:388-96. [Crossref] [PubMed]
34. Buxton BF, Raman JS, Ruengsakulrach P, et al. Radial artery patency and clinical outcomes: five-year interim results of a randomized trial. J Thorac Cardiovasc Surg 2003;125:1363-71. [Crossref] [PubMed]
35. Deb S, Cohen EA, Singh SK, et al. Radial artery and saphenous vein patency more than 5 years after coronary artery bypass surgery: results from RAPS (Radial Artery Patency Study). J Am Coll Cardiol 2012;60:28-35. [Crossref] [PubMed]
36. Sun JC, Teoh KH, Lamy A, et al. Randomized trial of aspirin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study. Am Heart J 2010;160:1178-84. [Crossref] [PubMed]
37. Zeff RH, Kongtahworn C, Iannone LA, et al. Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery: prospective randomized study with 10-year follow-up. Ann Thorac Surg 1988;45:533-6. [Crossref] [PubMed]
38. Dreifaldt M, Samano N, Geijer H, et al. Pedicled versus skeletonized internal thoracic artery grafts: a randomized trial. Asian Cardiovasc Thorac Ann 2021;29:490-7. [Crossref] [PubMed]
39. Benedetto U, Altman DG, Gerry S, et al. Pedicled and skeletonized single and bilateral internal thoracic artery grafts and the incidence of sternal wound complications: Insights from the Arterial Revascularization Trial. J Thorac Cardiovasc Surg 2016;152:270-6. [Crossref] [PubMed]
40. Mannacio V, Di Tommaso L, De Amicis V, et al. Randomized flow capacity comparison of skeletonized and pedicled left internal mammary artery. Ann Thorac Surg 2011;91:24-30. [Crossref] [PubMed]
41. Lamy A, Browne A, Sheth T, et al. Skeletonized vs Pedicled Internal Mammary Artery Graft Harvesting in Coronary Artery Bypass Surgery: A Post Hoc Analysis From the COMPASS Trial. JAMA Cardiol 2021;6:1042-9. Correction appears in JAMA Cardiol 2021;6:1223.
42. Li Q, Chen BL, Ozdemir V, et al. Frequency of genetic polymorphisms of COX1, GPIIIa and P2Y1 in a Chinese population and association with attenuated response to aspirin. Pharmacogenomics 2007;8:577-86. [Crossref] [PubMed]
43. Al Jaaly E, Zakkar M, Pufulete M, et al. Dual antiplatelet therapy after coronary artery bypass grafting Do we have a consensus? Journal of Integrative Cardiology 2015;1:90-3. [Crossref]
44. Goldman S, Copeland J, Moritz T, et al. Starting aspirin therapy after operation. Effects on early graft patency. Department of Veterans Affairs Cooperative Study Group. Circulation 1991;84:520-6. [Crossref] [PubMed]
45. Kim HH, Yoo KJ, Youn YN. A Randomized Trial of Clopidogrel vs Ticagrelor After Off-Pump Coronary Bypass. Ann Thorac Surg 2023;115:1127-34. [Crossref] [PubMed]
46. Sheng XY, An HJ, He YY, et al. High-Dose Clopidogrel versus Ticagrelor in CYP2C19 intermediate or poor metabolizers after percutaneous coronary intervention: A Meta-Analysis of Randomized Trials. J Clin Pharm Ther 2022;47:1112-21. [Crossref] [PubMed]
47. Krishnan K, Nguyen TN, Appleton JP, et al. Antiplatelet Resistance: A Review of Concepts, Mechanisms, and Implications for Management in Acute Ischaemic Stroke and Transient Ischaemic Attack. Stroke: Vascular and Interventional Neurology 2023;3. [Crossref]
48. Islam MR, Nova TT, Momenuzzaman N, et al. Prevalence of CYP2C19 and ITGB3 polymorphisms among Bangladeshi patients who underwent percutaneous coronary intervention. SAGE Open Med 2021;9:20503121211042209. [Crossref] [PubMed]
49. Lamy A, Eikelboom J, Sheth T, et al. Rivaroxaban, Aspirin, or Both to Prevent Early Coronary Bypass Graft Occlusion: The COMPASS-CABG Study. J Am Coll Cardiol 2019;73:121-30. [Crossref] [PubMed]
50. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87-165. Correction appears in Eur Heart J 2019;40:3096.
51. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischaemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016;134:e123-55. [PubMed]
52. Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022;145:e18-e114. [Crossref] [PubMed]
53. Deo SV, Dunlay SM, Shah IK, et al. Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis. J Card Surg 2013;28:109-16. [Crossref] [PubMed]
54. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. [Crossref] [PubMed]
55. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) Trial. Circulation 2004;110:1202-8. [Crossref] [PubMed]
56. Kulik A, Le May MR, Voisine P, et al. Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) Trial. Circulation 2010;122:2680-7. [Crossref] [PubMed]
57. Schunkert H, Boening A, von Scheidt M, et al. Randomized trial of ticagrelor vs. aspirin in patients after coronary artery bypass grafting: the TiCAB trial. Eur Heart J 2019;40:2432-40. [Crossref] [PubMed]
58. Kulik A, Abreu AM, Boronat V, et al. Ticagrelor versus aspirin 2 years after coronary bypass: Observational analysis from the TARGET trial. J Card Surg 2022;37:1969-77. [Crossref] [PubMed]
59. Olufade T, Atreja N, Bhalla N, et al. Hospitalization for Myocardial Infarction with Ticagrelor or Clopidogrel in Patients with Acute Coronary Syndrome: An On-Treatment Comparative Effectiveness Analysis. Cardiol Ther 2021;10:515-29. [Crossref] [PubMed]
60. Malm CJ, Alfredsson J, Erlinge D, et al. Dual or single antiplatelet therapy after coronary surgery for acute coronary syndrome (TACSI trial): Rationale and design of an investigator-initiated, prospective, multinational, registry-based randomized clinical trial. Am Heart J 2023;259:1-8. [Crossref] [PubMed]