Should routine dual antiplatelet therapy be recommended after elective coronary artery bypass surgery: insights from the DACAB-FE trial

Single anti-platelet therapy with aspirin is routinely utilized following coronary artery bypass graft (CABG) surgery to reduce major adverse cardiovascular events (MACE) and to maintain graft patency (1-3). While the benefits of dual anti-platelet therapy (DAPT) in patients following acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI) are well established (4), the role of DAPT in patients undergoing non-urgent CABG is less clear. Prior smaller studies comparing aspirin monotherapy against DAPT (aspirin and clopidogrel) in reducing rates of coronary vein graft occlusion have returned conflicting results (5,6). Clopidogrel has since been superseded by more potent P2Y12 inhibitors, such as ticagrelor and prasugrel in the management of ACS (7,8), hence the question of whether these agents can improve clinical outcomes and graft patency rates post CABG as monotherapy or in combination with aspirin is naturally raised. In a subgroup analysis of the PLATO trial (7), 1,261 patients with ACS who underwent CABG post-randomization to either aspirin and ticagrelor or aspirin and clopidogrel were assessed at 12 months for clinical outcomes (9). Although this was a retrospective analysis of a non-randomized subgroup, the results demonstrated a significant reduction in the primary composite endpoint [cardiovascular death, myocardial infarction (MI) and stroke] in the ticagrelor-treated arm (9). Additionally, with evidence to suggest the safety and efficacy of ticagrelor monotherapy following an abbreviated period of DAPT in patients undergoing PCI (10,11) there has also been emerging interest in this antithrombotic strategy in the post-CABG population. Few studies have since examined the role of DAPT (involving newer agents) vs. ticagrelor or aspirin monotherapy post non-urgent CABG and reflecting the paucity of high-quality evidence supporting improvement in clinical outcomes, guidelines have refrained from making a firm recommendation for or against the routine use of DAPT in this setting.

Larger scale, contemporary trials examining the impact of DAPT in improving venous graft patency rates also demonstrate differing results. The DACAB (different antiplatelet therapy strategy after coronary artery bypass graft surgery) (12) prospective, multicenter, open label, evaluator blind, randomized controlled trial published in 2018 compared the saphenous vein graft (SVG) patency rates of 500 patients at 12 months across 6 centers in China with differing antiplatelet strategies. Patients undergoing elective CABG (63% of enrolled patients with unstable angina, 34% with stable angina and remaining with non-ST-elevation MI) were randomized 1:1:1 to aspirin monotherapy (100 mg once daily), ticagrelor monotherapy (90 mg twice daily) or DAPT with aspirin and ticagrelor. At 12 months, the primary outcome of SVG patency assessed by computed tomography (CT) coronary angiography or invasive coronary angiography differed between the DAPT and aspirin monotherapy arm (88.7% vs. 76.5%) with this result of an absolute difference of 12.2% reaching statistical significance [95% confidence interval (CI): 5.2–19.2%, P<0.001]. No differences were noted in vein graft patency rates when comparing aspirin and ticagrelor monotherapy. Rates of minor bleeding were higher in the DAPT-treated group (48 events, 28.6%) compared with the ticagrelor (19 events, 11.4%) and aspirin (13 events, 7.8%) monotherapy groups. With an underpowered sample size, no differences in rates of major bleeding and the secondary outcome of MACE were demonstrated between groups.

The POPular CABG (Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) trial (13) similarly sought to evaluate the efficacy of ticagrelor in addition to standard aspirin therapy in improving SVG patency rates. This trial enrolled 499 patients undergoing CABG (31% for ACS) from six sites in the Netherlands, with participants randomized 1:1 to either ticagrelor (90 mg twice daily) or placebo in addition to routine aspirin monotherapy (80–100 mg daily). The primary outcome was rates of SVG occlusion at 12 months assessed by CT coronary angiography. In contrast to the findings of the DACAB trial which favored a DAPT strategy, this similarly sized study showed no difference in the primary outcome at 12 months, with SVG occlusion occurring in 9.6% in the DAPT arm and 10.1% in the placebo (aspirin monotherapy) arm. These findings were consistent across subgroups including patients with chronic and acute coronary syndromes. Rates of SVG failure (defined as occlusion, need for revascularization or MI in territory supplied by the graft) were also not significantly different between groups. Similar to the DACAB trial, minor bleeding was higher in the ticagrelor arm and major bleeding was low overall.

Both trials have a number of limitations. The use of a blinded imaging endpoint in DACAB does overcome some of the open-label design limitations but can result in increased drop out if participants perceive they are receiving an inferior treatment. That being said, retention in the trial at 12 months was similar across arms. Limitations of the POPular CABG trial included limited study sites (majority enrolled from two sites) and high rates of sequential SVGs which are less commonly used in contemporary practice and may be more difficult to assess with CT coronary angiography. Both trials were underpowered to detect differences in clinical outcomes and major bleeding. The findings from these trials are also clearly conflicting, which may reflect the different technical factors related to the CABG procedure itself and enrolled populations (particularly with respect to race and ethnicity). The primary outcome in the DACAB trial was SVG patency (defined as <50% occlusion) differing from the primary outcome of POPular CABG of total 100% SVG occlusion, which may partially explain the significantly higher event rates in the aspirin monotherapy arm of DACAB. Comparing like with like, the post-hoc analysis of the DACAB cohort revealed total SVG occlusion rates in 19.4% of the aspirin monotherapy arm which remained significantly higher than rates observed in the DAPT arm 10.1% (P=0.006), suggesting the DAPT strategy remained superior. However, the 19.4% rate of total SVG occlusion at 12 months with aspirin monotherapy in DACAB remains significantly higher than rates observed in POPular CABG (10.1%) and the 10–15% occlusion rate at 12 months reported in the literature (14). The reasons for higher rates of SVG stenosis/occlusion in the DACAB trial are speculative with hypotheses including differences in study populations with a higher risk population in DACAB (higher rates of cardiovascular risk factors and ACS indications for surgery) and surgical characteristics including significantly lower rates of on-pump cardiopulmonary bypass (24.2% compared with 94.5%) and internal mammary artery use in DACAB.

A 2022 meta-analysis published by Sandner and co-authors (15) pooled data from the DACAB and POPular CABG trials alongside two smaller randomized control trials to examine the efficacy and safety of DAPT (with ticagrelor) compared with aspirin in improving SVG patency rates in patients undergoing non-urgent CABG. In this analysis, with harmonized graft-failure and bleeding definitions across all trials, the primary outcome of incidence of SVG failure (defined as >50% occlusion) with a median treatment of 365 days occurred in 11.2% in the ticagrelor DAPT arm compared with 20.0% in the aspirin monotherapy arm [difference 95% CI: −13.5% to −3.9%, odds ratio (OR) 0.51, 95% CI: 0.35–0.74, P<0.001]. Similarly, when assessed per patient, SVG failure occurred in 13.2% of patients treated with DAPT and 23% of patients treated with aspirin (difference 95% CI: −14.9% to −4.4%, OR 0.51, 95% CI: 0.35–0.74, P<0.001). However, there were significantly higher rates of clinically significant bleeding events with DAPT (22.1%) than with aspirin (8.7%) (difference 95% CI: 8.6% to 18.0%, OR 2.98, 95% CI: 1.99–4.47, P<0.001), findings which were similarly reflected in a 2018 meta-analysis by Cardoso and co-authors which examined over 20,000 patients (DAPT mostly with clopidogrel vs. aspirin) undergoing CABG for both acute and stable ischaemic heart disease (16). Whilst associated with significantly lower risk of net adverse events (graft failure and/or clinically significant bleeding) than aspirin alone, this notably did not translate to differences in clinical endpoints including composite or individual major adverse cardiac or cerebrovascular events (15). Hence, although evidence exists to support the role of ticagrelor DAPT in this stable cohort of patients undergoing CABG in improving the surrogate outcome of SVG patency rates, no robust randomized trial evidence has thus far demonstrated an improvement in clinical outcomes as a result.

The DACAB-FE (DACAB Follow-up Extension) trial by Zhu and co-authors (17), recently published in BMJ in 2024 reports 5-year clinical outcomes following on from the DACAB trial and provides initial insights into clinical outcomes with a DAPT strategy following elective CABG. All patients from the original DACAB trial were included in DACAB-FE with the primary outcome being MACE (death, MI, stroke, coronary revascularization) at 5 years. The incidence of MACE was significantly lower among patients originally treated with DAPT compared with those originally treated with aspirin alone [22.6% vs. 29.9%; hazard ratio (HR) 0.65, 95% CI: 0.43–0.99; P=0.04] and ticagrelor alone (22.6% vs. 32.9%; HR: 0.66, 95% CI: 0.44–1.00; P=0.05). The event curves separate early during randomized treatment assignment with no evidence of increasing difference between arms in the landmark analysis between years 2–5 where aspirin monotherapy was most commonly administered. Similarly, the rate of composite net adverse clinical events (MACE + major bleeding) appeared lower in the DAPT arm compared with aspirin monotherapy with results of borderline statistical significance (25% vs. 35%; HR 0.67, 95% CI: 0.45–1.00; P=0.05). Whilst underpowered to detect differences in the individual endpoints even at 5 years (no differences observed in mortality, major bleeding and coronary revascularization), the lower rates of MACE in the DAPT strategy compared with aspirin appeared to be driven by lower rates of ischemic stroke and MI. In comparing ticagrelor with aspirin monotherapy – no differences were demonstrated in the incidence of MACE at 5 years (HR 0.99, 95% CI: 0.68–1.44; P=0.97). The strengths of the trial include comparisons between three different antiplatelet strategies and high adherence to the randomized treatment during the first year and very high rates of complete follow-up data (95.4%) at 5 years. Linking biological plausibility, the rates of lower early graft patency appeared to correlate with subsequent clinical events, particularly in the aspirin monotherapy arm. The main limitation relates to endpoint ascertainment which was done remotely for the majority of participants in follow up—this may have led to an incomplete assessment of the safety and outcomes (particularly silent MI). Additionally, it is possible that differing surgical characteristics (lower rates of on-pump cardiopulmonary bypass and internal mammary graft use) may have affected clinical outcomes.

Should 12 months of DAPT now become the standard for non-ACS post-CABG patients? The recently updated European Society of Cardiology (ESC) guidelines for chronic coronary disease currently provide only a Class IIb level B recommendation for DAPT in selected patients at low risk for bleeding (18). The subsequently reported DACAB-FE is not definitive (or large) enough to have impacted the guidelines, but when paired with the data supporting higher rates of early graft patency, the case for DAPT is stronger. However, the signal toward bleeding remains important and, analogous to the PCI literature, becomes a competing priority for patients with coronary disease (19). Given that the majority of ischemic events in DACAB appeared within the first three months, perhaps the more pertinent question becomes duration of DAPT. It may be that an abbreviated period of DAPT could address early graft failure and ischemic risk yet mitigate bleeding, thereby achieving optimal net benefit. Such an approach is reflected in the PCI literature with shorter DAPT duration and de-escalation to P2Y12 monotherapy the increasingly favoured strategy (20). The currently enrolling ODIN study which will compare one-month DAPT with aspirin monotherapy among patients undergoing CABG, powered for both ischemic and bleeding endpoints, may help move the needle (21).

Acknowledgments

None.

Footnote

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-239/coif). J.A.M. reports grants from The Hospital Research Foundation, Diabetes Australia, Australian Government Medical Research Future Fund Targeted Translation Research Accelerator, University of Adelaide; payment from Abbott Medical Australia, and support from AstraZeneca, Pfizer. P.J.P. reports grants from The Hospital Research Foundation, National Health and Medical Research Council of Australia (NHMRC ID 1127159), AMGEN, and Biotronik; consulting fees from Amgen, Eli Lilly, Esperion, Novartis, and Novo Nordisk; speaker honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Schering-Plough, Pfizer, Novartis, Novo Nordisk and Sanofi; travel funding from AstraZeneca, Eli Lilly, Novartis, and Novo Nordisk; has participated in advisory boards for Novartis, AMGEN, Novo Nordisk, and Eli Lilly and Sanofi; has served as a board director for Australian Cardiovascular Alliance, CORCILLUM Systems, South Australian Postgraduate Medical Education Association. A.J.N. reports funding from AMGEN; consulting fees from Amgen, Eli Lilly, Boehringer Ingelheim, Novartis, and Novo Nordisk; speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Novo Nordisk and Sanofi; travel funding from AstraZeneca, Eli Lilly, Novartis, and Novo Nordisk; has participated in advisory boards for Novartis, AMGEN, Novo Nordisk, Eli Lilly, Sanofi, Vaxxinity, and CRISPR Therapeutics. The other author has no conflicts of interest to declare.

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References

1. Mangano DTMulticenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002;347:1309-17. [PubMed]
2. Gavaghan TP, Gebski V, Baron DW. Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study. Circulation 1991;83:1526-33. [PubMed]
3. Collaborative overview of randomised trials of antiplatelet therapy--II: Maintenance of vascular graft or arterial patency by antiplatelet therapy. Antiplatelet Trialists' Collaboration. BMJ 1994;308:159-68. [Crossref] [PubMed]
4. Rodriguez F, Harrington RA. Management of Antithrombotic Therapy after Acute Coronary Syndromes. N Engl J Med 2021;384:452-60. [Crossref] [PubMed]
5. Gao G, Zheng Z, Pi Y, et al. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial. J Am Coll Cardiol 2010;56:1639-43. [Crossref] [PubMed]
6. 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]
7. 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]
8. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15. [Crossref] [PubMed]
9. Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011;57:672-84. [Crossref] [PubMed]
10. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med 2019;381:2032-42. [Crossref] [PubMed]
11. Ge Z, Kan J, Gao X, et al. Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial. Lancet 2024;403:1866-78. [Crossref] [PubMed]
12. 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]
13. Willemsen LM, Janssen PWA, Peper J, et al. Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG): A Randomized, Double-Blind, Placebo-Controlled Trial. Circulation 2020;142:1799-807. [Crossref] [PubMed]
14. Goldman S, Zadina K, Moritz T, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol 2004;44:2149-56. [Crossref] [PubMed]
15. Sandner S, Redfors B, Angiolillo DJ, et al. Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Artery Bypass Graft Surgery: A Systematic Review and Meta-analysis. JAMA 2022;328:554-62. [Crossref] [PubMed]
16. Cardoso R, Knijnik L, Whelton SP, et al. Dual versus single antiplatelet therapy after coronary artery bypass graft surgery: An updated meta-analysis. Int J Cardiol 2018;269:80-8. [Crossref] [PubMed]
17. 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]
18. Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J 2024;45:3415-537. [Crossref] [PubMed]
19. Cao D, Chandiramani R, Chiarito M, et al. Evolution of antithrombotic therapy in patients undergoing percutaneous coronary intervention: a 40-year journey. Eur Heart J 2021;42:339-51. [Crossref] [PubMed]
20. Valgimigli M, Hong SJ, Gragnano F, et al. De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials. Lancet 2024;404:937-48. [Crossref] [PubMed]
21. Sandner S, Gaudino M, Redfors B, et al. One-month DAPT with ticagrelor and aspirin for patients undergoing coronary artery bypass grafting: rationale and design of the randomised, multicentre, double-blind, placebo-controlled ODIN trial. EuroIntervention 2024;20:e322-8. [Crossref] [PubMed]