Re-evaluating antiplatelet therapy post-coronary artery bypass grafting: insights from the DACAB trial’s five-year follow-up

Antiplatelet therapy is the cornerstone of postoperative management following coronary artery bypass grafting (CABG). Its primary purpose is to prevent thrombotic complications and improve graft patency, thereby reducing the risk of major adverse cardiovascular events (MACEs) such as myocardial infarction, stroke, and death. Despite its established role, there remains no consensus on the optimal antiplatelet regimen post-CABG (1,2). Findings from randomised and observational studies suggest that dual antiplatelet therapy is more effective than aspirin monotherapy in preventing saphenous vein graft failure (3). Current clinical guidelines recommend dual antiplatelet therapy only in selected patients at high ischaemic risk after CABG (1,2). This lack of standardisation can lead to inconsistent treatment practices and varied patient outcomes.

Antiplatelet therapy’s critical role in preventing graft occlusion and subsequent cardiovascular events post-CABG cannot be overstated. However, the absence of consensus on optimal therapy highlights the complexity of balancing efficacy with safety, particularly given the risk of bleeding associated with dual antiplatelet therapy. Zhu et al. presented the results of a 5-year follow-up study from the Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial, which investigated the long-term effects of different antiplatelet strategies in patients who had undergone elective CABG (4).

The DACAB trial, a multicentre randomised controlled study conducted across six tertiary hospitals in China, included 500 patients randomised into three groups to receive either dual antiplatelet therapy (ticagrelor 90 mg twice daily plus aspirin 100 mg once daily), ticagrelor monotherapy (90 mg twice daily), or aspirin monotherapy (100 mg once daily) for one year after surgery. After the first year, antiplatelet therapy was prescribed according to the standard of care by treating physicians. The trial’s rigorous design, with a high level of adherence to the assigned treatments and comprehensive follow-up, provided robust data on the comparative efficacy and safety of these strategies over 5 years.

The primary outcome of the trial was the incidence of MACE, which encompassed all-cause death, myocardial infarction, stroke, and coronary revascularisation. The results demonstrated a significant reduction in the risk of MACE with dual antiplatelet therapy compared to both aspirin monotherapy and ticagrelor monotherapy. Specifically, the 5-year incidence of MACE was 22.6% in the dual therapy group, significantly lower than the 29.9% observed in the aspirin monotherapy group (P=0.04) and the 32.9% in the ticagrelor monotherapy group (P=0.05). These findings were consistent across various sensitivity analyses, underscoring the robustness of the results (4).

The safety profile of the therapies was also evaluated in this study, showing specific major bleeding incidences as follows: 4.9% in the dual therapy group, 2.5% in the ticagrelor monotherapy group, and 4.3% in the aspirin monotherapy group. Although the incidence was highest in the dual therapy group, the differences were not statistically significant.

The findings of the DACAB trial align with and expand upon previous studies examining antiplatelet therapy post-CABG. For instance, the CASCADE trial, which involved 113 patients randomised to receive either aspirin monotherapy or aspirin plus clopidogrel, demonstrated a trend towards improved graft patency and reduced cardiovascular events in the dual therapy group. However, the study was not powered to detect significant differences in clinical outcomes, and the follow-up period was relatively short at one year (5). The DACAB trial, with its 5-year follow-up and larger sample size, provides more robust evidence supporting the long-term benefits of dual antiplatelet therapy.

Similarly, the TiCAB trial, which compared ticagrelor to aspirin in 200 post-CABG patients, found no significant difference in MACE at one year (6). However, the trial was underpowered, and the follow-up period was insufficient to capture long-term outcomes. The DACAB trial’s findings address these limitations, offering more comprehensive evidence of the benefits of dual antiplatelet therapy over a longer duration.

Other studies have also explored the efficacy of different antiplatelet regimens post-CABG, with varying results. A meta-analysis by Deo et al. [2013] reviewed data from multiple randomised and observational studies, concluding that dual antiplatelet therapy was associated with a lower risk of graft occlusion but an increased risk of bleeding (3). This underscores the importance of balancing the benefits and risks of therapy, particularly in patients at high risk of bleeding.

The implications of the DACAB trial are substantial, particularly in the context of current clinical guidelines, which often reserve dual antiplatelet therapy for high-risk patients (1,2). High-risk patients are typically defined by criteria such as a history of acute coronary syndrome, multiple saphenous vein grafts, and other cardiovascular risk factors. The demonstrated long-term benefits of dual therapy in the DACAB trial suggest that broader application of this strategy could improve outcomes for a larger population of post-CABG patients. This is particularly relevant given the ongoing debate and lack of consensus regarding the optimal antiplatelet regimen following CABG (1,2). Although the DACAB trial did not show a statistically significant difference in major bleeding among the groups, the significant reduction in MACEs with dual antiplatelet therapy suggests that extending dual therapy to a broader patient cohort could be beneficial, provided there is careful patient selection and monitoring for bleeding risks.

The findings prompt several critical questions for clinical practice. Should dual antiplatelet therapy become the standard for all post-CABG patients, or should its use remain limited to those at high ischaemic risk? How can clinicians balance the increased bleeding risk associated with dual therapy against its benefits in reducing thrombotic events? These questions highlight the need for a personalised approach to therapy, taking into account individual patient risk factors, comorbidities, and preferences.

Furthermore, the individuality of responsiveness to antiplatelet therapy is an important consideration, as there is significant evidence suggesting substantial resistance to antiplatelets in some patients, which can affect the efficacy of the therapy (7). This phenomenon, often referred to as “antiplatelet resistance”, occurs when patients exhibit a diminished response to medications like aspirin or clopidogrel, potentially leading to higher rates of thrombotic events despite treatment. A systematic review and meta-analysis found that the overall prevalence of antiplatelet therapy resistance in patients who underwent CABG was 39% (8). This resistance was not merely a laboratory finding but had profound clinical implications; those with resistance had significantly higher risks of MACEs and postoperative myocardial infarction (8). Such findings underscore the need for personalised approaches in managing antiplatelet therapy, incorporating regular monitoring and possibly alternative therapeutic strategies for those identified as non-responders (7).

In practice, implementing the findings of the DACAB trial would require careful stratification of patients based on their risk profiles. High-risk patients, such as those with a history of myocardial infarction or those with multiple saphenous vein grafts, might derive the most benefit from dual antiplatelet therapy. Conversely, patients at high risk of bleeding, such as the elderly or those with gastrointestinal disorders, might be better suited to monotherapy.

Despite its strengths, the DACAB trial had limitations that should be considered. One notable limitation was the adjustment of antiplatelet therapy based on physician discretion after the first year, which could introduce variability in long-term outcomes. This reflects real-world practice but complicates the interpretation of the trial’s findings, as changes in therapy could affect the incidence of MACE and other outcomes.

Additionally, the coronavirus disease 2019 (COVID-19) pandemic necessitated remote follow-ups for many patients, potentially affecting the accuracy of event reporting, particularly for silent myocardial infarctions. While the trial’s design included measures to ensure accurate data collection, such as regular telephone follow-ups and electronic health record reviews, the impact of remote monitoring on the trial’s findings cannot be entirely ruled out.

Additional limitations of the DACAB trial include its relatively limited sample size, which may impact the generalizability of the findings. A longer follow-up period would also be necessary to assess the long-term safety and efficacy of dual antiplatelet therapy in CABG patients. Furthermore, the trial did not evaluate the influence of comorbidities or genetic factors, such as antiplatelet resistance, which may significantly affect treatment response and outcomes.

Future research should focus on determining the optimal duration of dual antiplatelet therapy post-CABG and exploring its efficacy in specific patient populations, such as those with diabetes or the elderly. These populations may have different risk profiles and responses to therapy, and understanding these differences could help tailor treatment strategies more effectively.

For instance, diabetes is a well-known risk factor for both thrombosis and bleeding, complicating the choice of antiplatelet therapy. Diabetic patients exhibit enhanced platelet reactivity and higher levels of inflammatory markers, contributing to a prothrombotic state (9). Hyperglycaemia, a hallmark of diabetes, can lead to glycation of platelet proteins, thereby increasing platelet adhesion and aggregation. Additionally, insulin resistance and endothelial dysfunction prevalent in diabetes further exacerbate thrombotic risk (10). Conversely, diabetes can also be associated with an increased risk of bleeding due to impaired platelet function and altered coagulation pathways, creating a dilemma when selecting antiplatelet regimens (11). Studies specifically examining the efficacy and safety of dual antiplatelet therapy in diabetic patients post-CABG could provide valuable insights, helping to balance the heightened risk of thrombotic events against the potential for increased bleeding.

Similarly, elderly patients often have higher risks of both ischemic and bleeding events, necessitating a careful balance in therapy. Aging is associated with a range of physiological changes that increase the risk of thrombosis, such as increased platelet reactivity, higher levels of procoagulant factors, and impaired endothelial function. These changes contribute to a heightened risk of ischemic events, including myocardial infarction and stroke. Additionally, elderly patients frequently have multiple comorbidities such as hypertension, atrial fibrillation, and diabetes, which further amplify their thrombotic risk (12).

Conversely, the elderly are also at an elevated risk of bleeding complications due to age-related changes in haemostasis, reduced renal function, and a higher likelihood of polypharmacy, which can include anticoagulants and other medications that affect bleeding risk (13). These dual risks make the management of antiplatelet therapy in elderly patients particularly challenging. Studies specifically targeting the elderly population post-CABG to evaluate the efficacy and safety of various antiplatelet regimens could provide critical insights, helping to refine treatment guidelines and improve patient outcomes.

Another area for future research is the role of platelet function testing in guiding antiplatelet therapy. Point-of-care platelet function tests can help identify patients who are non-responders to certain antiplatelet agents, allowing for more personalized treatment (14). Incorporating these tests into routine clinical practice could optimize therapy and improve outcomes. Further supporting this, a recent meta-analysis found that antiplatelet resistance is prevalent in nearly 39% of CABG patients, significantly increasing their risk of MACEs and postoperative myocardial infarction (8). This underscores the need for a tailored approach to antiplatelet therapy post-CABG, as resistance to standard therapies may hinder optimal outcomes.

The DACAB trial significantly enhances our understanding of antiplatelet therapy post-CABG, providing compelling evidence for the long-term benefits of dual antiplatelet therapy with ticagrelor and aspirin. The trial’s findings challenge the status quo, suggesting that dual antiplatelet therapy could be beneficial for a broader cohort of patients than currently recommended. Implementing these findings in clinical practice would require a shift towards more personalized, risk-based therapy, with careful monitoring and adjustment based on patient response.

As research continues to evolve, it is essential to remain adaptable and responsive to new evidence. The DACAB trial represents a significant step forward, but it is not the final word. Ongoing studies and real-world data will continue to refine our understanding of antiplatelet therapy post-CABG, ultimately leading to better patient outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-152/coif). The authors have no conflicts of interest to declare.

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