Antiplatelet therapy after coronary artery bypass surgery: the results from the randomized DACAB trial

We read with great interest the scientific work by Zhu and coworkers, which reports the 5-year results of the Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Grafting (DACAB) randomized trial (1). The investigators have randomized 500 elective coronary artery bypass grafting (CABG) patients enrolled between July 2014 and November 2015 from six centers in China. One hundred and sixty-eight patients received dual antiplatelet therapy (DAPT) consisting of 90 mg of ticagrelor twice daily plus aspirin 100 mg once daily, 166 patients ticagrelor monotherapy 90 mg twice daily, and 166 patients aspirin monotherapy 100 mg once daily within 24 hours post-CABG. Primary outcomes were major adverse cardiovascular events (MACEs), including a composite of all-cause death, myocardial infarction, stroke, and coronary revascularization.

The follow-up at 5 years was completed for 477 (95.4%) out of 500 patients. One hundred and forty-eight patients experienced MACE: of them 39 out of 159 in the DAPT group of patients (24.5%), 54 out of 157 in the ticagrelor group (34.4%), and 55 out of 161 in the aspirin group (34.2%). The risk of MACE at 5 years was significantly lower with the use of DAPT in comparison with aspirin therapy alone [22.6% vs. 29.9%; hazard ratio (HR) 0.65, 95% confidence interval (CI): 0.43–0.99; P<0.05] and with ticagrelor therapy alone (22.6% vs. 32.9%; HR 0.66, 95% CI: 0.44–1.00; P=0.05). These results were consistent in all the statistical analyses performed.

The presented study includes and it is an extension of previously published study by Zhao and co-investigators regarding the results of vein grafts patency at 1 year of follow-up after the start of the trial. Saphenous vein graft patency rate at 1 year of follow-up was 88.7% (432 out of 487 vein grafts) in patients taking ticagrelor plus aspirin vs. 82.8% (404 out of 488 vein grafts) in those taking on ticagrelor, and vs. 76.5% (371 out of 485 vein grafts) in those taking on aspirin (2). The difference between ticagrelor plus aspirin vs. aspirin alone was statistically significant (12.2%; P<0.001), whereas the difference between ticagrelor alone vs. aspirin alone was not statistically significant (6.3%; P=0.10). Consequently, the conclusions of the initial study were that among patients undergoing elective CABG, dual antiplatelet aggregation therapy based on ticagrelor and aspirin significantly increased vein graft patency after 1 year versus aspirin alone. On the contrary, there was no significant difference between ticagrelor alone and aspirin alone.

Including the initial findings, the present study of the DACAB trial indicates that the treatment with ticagrelor in the context of DAPT for 1 year after CABG in patients operated on electively reduces the risk of MACE at 5 years in comparison with aspirin or ticagrelor monotherapy (1).

For the first time, DACAB trial has the merit of having evaluated the effectiveness of DAPT based on ticagrelor on a population of elective patients undergoing CABG, the safety of administering ticagrelor twice daily starting from the first postoperative day after surgery during the first year of follow-up. Furthermore, the evaluation of the patency of venous grafts and the assessment of MACE and primary end-points were precisely investigated up to 5 years of follow-up, including the rates of major and minor bleedings. In Tables 1,2, some of the main results of the study trial we have highlighted and summarized, have been reported.

As known, DAPT with acetylsalicylic acid and P2Y₁₂ platelet receptor inhibitors represents the standard of care in the treatment of acute coronary syndromes: acetylsalicylic acid plus clopidogrel are currently administered to prevent serious cardiovascular adverse events, i.e., myocardial infarction, recurrence of angina. Approved for its use in European Union in 2010 and in United States in 2011, ticagrelor in as antiplatelet drug that inhibits the adenosine diphosphate ADP P2Y₁₂ platelet receptor (3). Unlike clopidogrel, which irreversibly blocks the platelet adhesive action, ticagrelor performs a reversible block, thus allowing a more rapid recovery of platelet function after its suspension. For this reason, European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) Guidelines recommend suspension at least 5 days for clopidogrel and 3 days for ticagrelor prior to surgical myocardial revascularization (3). Furthermore, ESC Guidelines underline that there is a limited evidence suggesting that the use of DAPT in patients with stable coronary artery disease mitigates the risk of vein (but not arterial) grafts occlusion. Moreover, unlike for acute coronary syndromes, there is currently no evidence of a survival benefit or a reduction on thromboembolic events with DAPT in patients with stable coronary artery disease undergoing CABG.

Agrawal et al. (4), in a recent meta-analysis performed on 38 studies including 77,447 CABG patients, have shown that DAPT compared with single therapy was associated with significantly lower all-cause mortality [odds ratio (OR) 0.65; P=0.002], cardiovascular mortality (OR 0.53; P=0.008), and MACCE (OR 0.68; P=0.01). However, DAPT was associated with higher rates of major (OR 1.30; P=0.007) and minor bleeding (OR 1.87; P=0.001) complications. DAPT-ticagrelor/prasugrel compared with DAPT-clopidogrel was associated with significantly lower all-cause (OR 0.43; P≤0.0001) and cardiovascular mortality (OR 0.44; P=0.008). These benefits were particularly evident in patients affected by acute coronary syndromes undergoing CABG.

In the same way of evidence, Sandner et al. (5) in a review focused on the optimal anti-aggregation strategy of patients undergoing CABG based on five randomized trials, essentially recommends DAPT after acute coronary artery syndrome events, but aspirin alone should be remain the cornerstone of antithrombotic therapy in stable ischemic patients. Likely, shorter duration DAPT, i.e., for 1 year, based on pathophysiology of the failure of the vein grafts, may be a good therapeutic option, that anyway requires adequate analysis in powered randomized trials. Anyway, the authors underlined that the benefit of DAPT must be weighed against the increase risk of bleeding events. On the contrary, Willemsen and the Investigators of the POPular CABG Trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) trial (6), showed no differences at 1 year in the vein graft failure rate (12.9% vs. 13%) between ticagrelor and aspirin (80–100 mg daily). The authors underlined that in patients undergoing CABG for acute coronary syndrome only, ticagrelor is likely to provide antithrombotic benefits independently from the saphenous vein graft patency, thus confirming what has already been reported in the Guidelines.

And in fact, the efficacy of the ticagrelor in comparison with clopidogrel was already been showed by the PLATO study trial on the reduction of the rates of cardiovascular events, myocardial infarction and stroke at 12 months of follow-up in 18,624 patients affected by acute coronary syndrome (9.8% vs. 11.7%, P<0.001) (7).

As well as the perioperative risk of major bleeding in patients undergoing CABG with DAPT-ticagrelor or DAPT-clopidogrel is undoubtedly not negligible. In a recently published study (8), we have retrospectively evaluated the risk of bleeding and mortality in patients with acute coronary syndromes undergoing CABG, for whom or it was not possible to suspend DAPT within 24 hours prior surgery (48 patients, group C), or that it was possible to suspend it within 48–72 hours (126 patients, group B) before CABG, or more than 72 hours (159 patients, group A). Operative mortality was 1.87% in group A, 0.79% in group B, absent in group C. The incidence of mediastinal re-exploration for bleeding was 1.25%, 1.59%, 8.33% (P=0.01). Multivariable analysis showed that ongoing ticagrelor intake on in group C (P<0.05) and group C “per se” (P<0.05) were predictors of significantly increased risk of postoperative bleeding, but not of increased risk of mortality. Obviously, the limited number of patients examined during our study must be taken into account. Indeed, Schoerghuber and co-workers, in a meta-analysis of 4,837 patients (seven studies) confirmed that preoperative guideline-conforming withdrawal of P2Y₁₂ receptor inhibitors is associated with a 50% lower BARC-4 (CABG-related bleeding) risk in patients undergoing on-pump CABG, but it is not associated with increased risk of operative mortality (9). On the contrary, in the DACAB study, the investigators started therapy with ticagrelor and aspirin after the first postoperative day, and it was seen that the risk of bleeding was very low, thus demonstrating the safety of its use in the postoperative period and during follow-up. Analyzing data collected of the DACABG study at 1 year of follow-up (2), perioperative bleeding requiring reoperation was observed only in one patient (0.6%), and no any patient experienced chest tube output >2 liters within a 24-h period or fatal bleeding. The rate of major bleeding (intracranial in only one patient) at 1 year of follow-up was 1.2% (2/168). Of note, this rate was 3% at the gastro-intestinal tract, and the rate of minimal or minor bleedings, i.e., of the skin or of the nose, raised up to 23%. Bleeding leading temporary interruption of treatment occurred in 15 cases (8.9%). In conclusion, the DACAB trial demonstrates that the association of ticagrelor with acetylsalicylic acid (aspirin) is further protective against adverse cardiac events in the medium-term, and therefore represents an additional therapeutic strategy available for patients electively undergoing CABG. Obviously, antiplatelet therapy is only one aspect of preventing late vein graft occlusion. There are other important aspects that can determine the patency or the failure of the vein graft, such as the saphenous vein harvesting technique, the distal and proximal anastomosis technique, the target coronary vessel, as well as the orientation and the sufficient length of the vein graft. From the data discussed and reported in literature and in our opinion, the essential aspect to debate remains how to balance the risk of bleeding related to DAPT intake with the benefit instead of the reduced thrombotic-ischemic risk. In acute coronary syndromes, due to their physiopathology, the risk-benefit ratio of DAPT seems clearly to be in favor of the benefit; in fact, even if the risk of bleeding is shown to be higher, very often DAPT therapy in the preoperative period is not interrupted, and is also continued after CABG. The DACAB trial has shown that DAPT intake in patients with stable chronic ischemia only, after having performed CABG, is safe and effective, at least for the medium-term follow-up, without showing a significantly increased risk of major bleeding. Further, long-term studies may confirm the excellent results obtained by the investigators, so as to be able to extend treatment with ticagrelor to larger populations of elective CABG patients. The study obviously has some limitations, such as having mainly studied the patency of venous grafts and not of arterial grafts, and the small sample of patients, so much so that the investigators themselves suggested basing the treatment decision on clinical and surgical characteristics of each individual patient. However, at the moment, given that the incidence of bleeding, although not high and not associated with major adverse events, such as that from the nose and the gastrointestinal tract as reported by the investigators, appears to be non-negligible, particular caution should be considered when administering ticagrelor in patients with respiratory problems and diseases of the gastrointestinal system.

Acknowledgments

Funding: None.

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