DACAB trial supports long-term use of ticagrelor and aspirin dual therapy after coronary artery bypass grafting

The 2021 American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Guideline for Coronary Artery Revascularization reported the use of antiplatelet therapy in patients following coronary artery bypass graft (CABG) as a class I recommendation (1). While aspirin monotherapy has remained the mainstay of antiplatelet therapy for many decades, randomized trials provided little evidence of its efficacy when combined with newer anti-platelet agents like ticagrelor. Despite the widespread use of low-dose aspirin therapy after CABG, maintaining saphenous vein graft (SVG) patency continues to be a challenge with almost 8–25% developing restenosis at 1 year (2). Additionally, more than 1/2 of all saphenous vein conduits demonstrate significant occlusion 10 years after surgery (2).

In routine practice, healthcare providers have used dual antiplatelet therapy (DAPT) by combining aspirin with clopidogrel, an irreversible inhibitor of the platelet P2Y12 adenosine diphosphate receptor. This combination provides a synergistic antithrombotic effect, however, at the expense of an increased bleeding risk compared to monotherapy with aspirin (3). The bleeding risks are particularly amplified in the elderly and more comorbid patients that surgeons are now operating on more frequently (4). A prior meta-analysis reported that DAPT improved early graft patency rates in patients only for off pump CABG and not for those undergoing conventional on-pump surgery (5). Thus, in summary, the use of aspirin and clopidogrel as DAPT may not be beneficial for all patients and may be harmful for a few. Hence, the results of this trial, that DAPT with ticagrelor is useful and safe in the long-term, are very important given the possible bleeding risk with clopidogrel.

Ticagrelor, approved by the Food and Drug Administration for use in 2011, is also a P2Y12 receptor inhibitor. However, unlike clopidogrel, its action is reversible, and its half-life is shorter. Hence, it theoretically has a lower risk of bleeding and the drug action can be reversed if needed. In addition, clopidogrel’s effectiveness is dependent upon a gene-based conversion to its active form; this adds heterogeneity to its efficacy, which is not the case with ticagrelor (6). Ticagrelor is already recommended for use after acute myocardial infarction (MI), or non-ST elevation MI. However, the Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) follow-up study is among the first to report long-term clinical outcome of ticagrelor-added DAPT after CABG.

Briefly, the DACAB study compared 1-year SVG patency rates after elective CABG and randomized 1:1:1 to receive aspirin 100 mg daily monotherapy, ticagrelor 90 mg daily monotherapy, or aspirin 100 mg + ticagrelor 90 mg daily combination therapy (7).

This follow-up study evaluated the occurrence of major adverse cardiovascular events (MACE) (all-cause death + MI + stroke + coronary artery revascularization) over a 5-year period. In this updated intent-to-treat analysis, investigators observed 148 MACE events across a median follow-up time of 61.1 months (8). While events were lower in the ticagrelor + aspirin arm (39 events), they were comparable in the ticagrelor monotherapy (54 events) and aspirin monotherapy (55 events) arms. Therefore, the relative risk for MACE was lower with ticagrelor + aspirin therapy versus aspirin alone (22.6% vs. 29.9%; hazard ratio 0.65, 95% confidence interval: 0.43 to 0.99; P=0.04) and versus ticagrelor monotherapy (22.6% vs. 32.9%; hazard ratio 0.66, 95% confidence interval: 0.44 to 1.00; P=0.05). More importantly, bleeding rates were not higher with ticagrelor + aspirin. Their primary results were also supported by an additional sensitivity landmark analysis after selecting only patients that were event free at 1-year post-surgery.

However, despite being trial follow-up data, the study does have some limitations. Firstly, analyses have not been statistically adjusted for the ongoing use of other preventive strategies lipid-lowering therapy, blood pressure lowering or additional antithrombotic therapy. Secondly, as this is a follow-up study, crossover of patients between arms may have occurred in the interim period. Additionally, repeat SVG patency was not evaluated along with clinical outcome, hence, while MACE is attributed to vein graft failure, this fact has not been conclusively demonstrated. Such testing was actually performed in a similar 2-year study published recently (9). Lastly, while antiplatelet therapy is physiologically very important to maintain early SVG patency, preventing atherosclerosis is biologically more important to maintain long-term patency (10). However, despite these limitations, the study provides important evidence that DAPT with ticagrelor is safe and maybe even beneficial long term post-CABG (11).

The ideal duration of DAPT following CABG has been a persistent question which is still undecided. Prior studies have utilized a wide range of therapy duration, anywhere from 1 to 15 months (11,12). A 2018 meta-analysis reported that longer duration (≥6 months) DAPT was associated with lower incidence of stroke, but was not found to be associated with improved all-cause mortality, cardiovascular death, or major bleeding (12). We believe that, given the biological mechanism of SVG patency, 6–8 weeks of DAPT followed by aspirin monotherapy may be a safe, beneficial regime in most patients.

In the coming years, we can look forward to more complete information concerning the ideal duration of DAPT following CABG. For example, the Timing of Platelet Inhibition after Coronary Artery Bypass Grafting (TOP-CABG) trial being conducted among 2,300 patients across 16 centers in China is comparing de-escalated DAPT (ticagrelor + aspirin for first three months post-CABG and aspirin + ticagrelor placebo for next nine months) and DAPT (ticagrelor + aspirin for 1 year after CABG) (13). Given the increasing risk profile and age of patients undergoing CABG in the recent years, it is even more important to weigh both MACE and bleeding risk individually (5). While not routinely used, calculating bleeding rates using risk scores may also be useful for deciding therapy (14).

In conclusion, the follow-up DACAB trial reported that MACE risk was lower after elective CABG in patients receiving combined aspirin and ticagrelor. Based on patient profile, these results demonstrate that longer duration DAPT may be safe and confer additional cardiovascular benefit in selected patients.

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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