INTRODUCTION

Antiplatelet therapy is an essential component of primary and secondary prevention of coronary artery disease. Aspirin is the cornerstone of antiplatelet therapy and is recommended after coronary artery bypass graft (CABG) surgery in current myocardial revascularization guidelines to reduce the occurrence of adverse cardiovascular events and CABG graft occlusion [1]. Dual antiplatelet therapy (DAPT), consisting of an oral platelet P2Y12 receptor inhibitor in addition to aspirin, enhances platelet inhibition and further reduces the risk of adverse cardiovascular events when thrombotic risk is high, such as after percutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) events. However, DAPT also leads to increased bleeding risk. As both ischemic events and bleeding events are associated with mortality [2,3], the ischemic benefit of DAPT must be weighed against the risk of bleeding.

There is limited evidence for the use of DAPT after CABG, as no dedicated randomized clinical trials (RCTs) sufficiently powered for clinical outcomes exist. When deciding whether to use DAPT after CABG, the clinical indication for which the patient is undergoing CABG surgery, that is, following an ACS event or stable ischemic heart disease (SIHD), and the pathophysiology of graft failure should be considered. 

Box 1:

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CLINICAL INDICATION FOR DUAL ANTIPLATELET THERAPY AFTER CORONARY ARTERY BYPASS GRAFT SURGERY

Subgroup analyses of the pivotal trials of P2Y12 inhibitors in ACS patients have consistently shown a benefit in patients subsequently undergoing CABG [4–6]. In a subgroup of patients undergoing CABG in the Platelet Inhibition and Patient Outcomes (PLATO) trial (n = 1261), ticagrelor (on a background of low-dose aspirin) was more effective than clopidogrel in reducing all-cause death [9.7 versus 4.7%, hazard ratio, 0.49; 95% confidence interval (CI), 0.32–0.77; P < .01] and cardiovascular death (7.9 versus 4.1%; hazard ratio, 0.52; 95% CI 0.32– 0.85; P < 0.01) at 12 months [5]. There was no significant difference in any bleeding outcomes between groups. In a subset of patients undergoing CABG (n = 346) in the TRITON TIMI 38 study (that randomized patients to aspirin and either clopidogrel or prasugrel) all-cause mortality was significantly reduced with prasugrel compared with clopidogrel [2.31 versus 8.67%; odds ratio (OR), 0.26; 95% CI 0.08–0.85; P = 0.025], however, a significantly higher chest tube blood loss was observed with prasugrel [6]. In patients undergoing CABG as part of the management strategy for ACS, a 6–12-month course of DAPT is currently recommended, depending on the patient's ischemic versus bleeding risk [7]. Ticagrelor and prasugrel are preferred over clopidogrel if the patient is not at high risk of bleeding.

Recent large observational studies have yielded discrepant results for the benefit of DAPT in patients undergoing CABG after an ACS event. In a single-center study from Korea including 5782 patients (ACS, n = 3199; SIHD, n = 2583) use of DAPT (95% clopidogrel, 5% ticagrelor) was associated with a lower adjusted risk of cardiovascular death or MI at 5 years than was single antiplatelet therapy (99% aspirin, 1% clopidogrel) among patients with ACS (4.0 versus 7.8%; hazard ratio, 0.521; 95% CI 0.339–0.799; P = 0.003), but not among those with SIHD (4 versus 4%; hazard ratio, 0.991; 95% CI 0.604–1.626; P = 0.971) [8▪]. In a report from the SWEDEHEART Registry of 6558 patients with ACS, no significant difference in the risk of major adverse cardiac events was found at 12 months between patients treated with aspirin and ticagrelor and those treated with aspirin alone (adjusted hazard ratio 0.84; 95% CI 0.85–1.21; P = 0.34), while the risk for major bleeding was higher in patients on DAPT (adjusted hazard ratio 1.90; 96% CI, 1.16–3.13; P = 0.011) [9▪].

The TACSI trial (NCT03560310), a prospective, multicenter, open-label registry-based randomized trial is currently testing the hypothesis that 1-year treatment with DAPT consisting of ticagrelor and aspirin is superior to aspirin alone after isolated CABG in patients with ACS [10].

PEGASUS and THEMIS, the two largest RCTs in patients with SIHD, have shown a benefit of longer duration (≥12 months) treatment with ticagrelor on a background of low-dose aspirin over aspirin alone in patients with a history of myocardial infarction [11] and those with type II diabetes mellitus [12], albeit at an increased risk of bleeding. In patients with a history of SIHD and type II diabetes mellitus (including 30% of patients with prior CABG) ticagrelor reduced the risk of cardiovascular death, MI or stroke by 10% at 3 years (hazard ratio 0.90; 95% CI 0.81–0.99; P = 0.038) mainly because of reduction in spontaneous MI [12]. The incidence of TIMI major bleeding was higher with ticagrelor (2.2 versus 1%; hazard ratio, 2.32; 95% CI 1.82–2.94; P < 0.001), as was the incidence of intracranial hemorrhage (0.7 versus 0.5%; hazard ratio, 1.71; 95% CI 1.18–2.48; P = 0.005). Among patients receiving ticagrelor, the median exposure was 7.7 months to the 90 mg dose and 32.1. months to the 60 mg dose [12].

However, there is no clear evidence for a benefit of DAPT after CABG in patients with SIHD, who represent the majority of patients undergoing CABG [13]. Meta-analyses of smaller RCTs and observational studies have not shown a significant benefit of DAPT on mortality or ischemic outcomes after CABG in patients with SIHD [14,15]. Verma et al.[14] reported no significant difference in all-cause mortality between DAPT with clopidogrel and aspirin after CABG in patients with SIHD [relative risk (RR), 0.56; 95% CI 0.18–1.67; P = 0.29). Cardoso et al.[15] in a meta-analysis of 22 studies (11 RCTs, 11 observational; n = 20 315) comparing DAPT (clopidogrel, 20 studies; ticagrelor, 2 studies) to aspirin reported that DAPT was associated with lower cardiovascular mortality (OR 0.67; 95% CI 0.49–0.93; P = 0.02) and a trend towards lower all-cause mortality (OR 0.78; 95% CI 0.59–1.03; P = 0.08); however, this benefit was not seen in sub-analyses of RCTs or in patients with SIHD. In addition, the risk of major bleeding events was significantly increased with DAPT (eight RCTs; OR 1.31; 95% CI 1.02–1.68; P = 0.03).

DUAL ANTIPLATELET THERAPY AND SAPHENOUS VEIN GRAFT FAILURE

Maintaining graft patency is the intuitive mechanism behind the long-term benefits of CABG, and graft failure is associated with adverse cardiac events and even death [16]. Saphenous vein grafts (SVG) are the most frequently used conduit in CABG and are used in more than 90% of CABG procedures [17]. However, a substantial proportion of SVG (approximately 20%) [18▪] fail within the first year after surgery.

Study-level meta-analyses including mainly studies that compared DAPT with clopidogrel versus aspirin alone have reported that addition of clopidogrel is associated not only with significantly reduced SVG failure rates [15,19,20] but also with an increased risk of bleeding events [15,19]. The benefit of DAPT with clopidogrel in reducing SVG graft failure was particularly evident among patients undergoing off-pump CABG [19] and has informed guidelines on the use of DAPT with clopidogrel after off-pump CABG [21].

RCTs investigating the effect of DAPT with the more potent P2Y12 inhibitor ticagrelor compared with aspirin on SVG failure yielded conflicting results [22,23]. In addition, the individual trials lacked statistical power for bleeding outcomes. A recent individual patient data meta-analysis has addressed the question of the efficacy and safety of DAPT with ticagrelor for SVG failure (Fig. 1) [24▪▪]. Graft failure and bleeding events were re-adjudicated to assure comparability between the included trials. DAPT with ticagrelor was associated with a significantly lower incidence of SVG failure (11.2%) per graft than was aspirin [20%; difference, −8.7% (95% CI −13.5 to −3.9%); OR, 0.51 (95% CI 0.35–0.74); P < 0.001] and was associated with a significantly lower incidence of SVG failure per patient [13.2 versus 23%, difference, −9.7% (95% CI −14.9 to −4.4%); OR, 0.51 (95% CI 0.35–0.74); P < 0.001]. These results were consistent in all prespecified subgroups, including patients with SIHD (56% of included patients). There was also a significant reduction of the composite of SVG failure and cardiovascular death (13.9% ticagrelor DAPT versus 23.4% aspirin; OR 0.52, 95% CI 0.36–0.76; P < 0.001). However, the benefit on SVG failure was accompanied by a significantly increased risk of clinically actionable bleeding events [defined as Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding]: 22.1% ticagrelor DAPT versus 8.7% aspirin (OR 2.98, 95% CI 1.99–4.47; P < 0.001). Notably, the median treatment duration with DAPT was 12 months. The findings underscore that a patient's individual risk of graft failure, ischemic events, and bleeding needs to be weighed carefully when deciding whether to add a P2Y12 inhibitor to aspirin after CABG surgery.

FIGURE 1:

Individual patient data meta-analysis of randomized clinical trials comparing dual antiplatelet therapy with ticagrelor versus aspirin after coronary artery bypass surgery. CABG surgery, coronary artery bypass graft surgery; DAPT, dual antiplatelet therapy.

THE CONCEPT OF SHORTER DURATION DUAL ANTIPLATELET THERAPY AFTER CORONARY ARTERY BYPASS GRAFT SURGERY

Given the known relationship between longer duration (≥12 months) DAPT after CABG and the risk of bleeding, the use of DAPT in patients with SIHD should be guided by the pathophysiology of SVG failure (Fig. 2). Platelet-mediated thrombosis is the predominant mechanism of early SVG failure and occurs secondary to endothelial injury sustained during surgery. The risk of thrombotic SVG occlusion is highest in the first month after surgery, which provides a biological rationale for the use of DAPT for a limited time early after surgery with de-escalation of DAPT to aspirin or P2Y12 inhibitor monotherapy thereafter to reduce the risk of bleeding associated with longer duration DAPT.

FIGURE 2: Pathophysiology of saphenous vein graft failure and biological rationale for shorter duration dual antiplatelet therapy. Dual antiplatelet therapy may be beneficial to prevent early graft failure, whereas aspirin or P2Y12 inhibitor monotherapy may be used to prevent late graft failure. Reproduced from Gaudino et al. [32].

Only few RCTs have investigated the effect of shorter duration DAPT on SVG failure (Table 1) and are limited by small sample sizes. In addition, the majority of the studies used clopidogrel in addition to aspirin, a P2Y12 inhibitor with less potent and less predictable platelet inhibition compared with ticagrelor. Clopidogrel is known to exhibit interindividual response variability [25], with about one-third of patients having inadequate platelet inhibitory effects. Importantly, these patients, who continue to have high platelet reactivity despite use of clopidogrel, are at increased risk of thrombotic events [26]. All studies testing shorter duration DAPT after CABG de-escalated DAPT to aspirin. Drawing on reports after PCI showing preserved ischemic efficacy with a reduction in bleeding events [27▪], an alternative option may be de-escalation to P2Y12 inhibitor monotherapy after shorter duration DAPT, however, solid data on the efficacy and safety of P2Y12 inhibitor monotherapy in CABG patients is lacking. The concept of shorter duration DAPT after CABG requires testing in an appropriately powered RCT, preferably using DAPT with ticagrelor, and subsequent de-escalation of DAPT to aspirin consistent with current guideline recommendations.

Table 1 - Randomized clinical trials comparing graft patency in patients treated with shorter duration dual antiplatelet therapy or aspirin after coronary artery bypass graft surgery Study (first author, year) Experimental arm Control arm Duration of DAPT Number of patients Type of graft studied Main findings Mujanovic, 2009 Clopidogrel + Aspirin Aspirin 3 months 20 SVG, LITA Addition of clopidogrel to aspirin increased graft patency versus aspirin after off-pump CABG (93.1 versus 70.4%, P = 0.037), but no effect on LITA patency was seen. Gao, 2010 Clopidogrel + Aspirin Aspirin 3 months 249 SVG Clopidogrel + aspirin versus aspirin was associated with increased SVG patency (91.6 versus 85.7%; P = 0.043). Sun, 2010 Clopidogrel + Aspirin Placebo + Aspirin 1 months 99 SVG, arterial Graft occlusion was not significantly different between groups (clopidogrel + aspirin 5% versus aspirin 7.1%, P = 0.43), and did not differ by type of graft. Saw, 2016 Ticagrelor + Aspirin Placebo + Aspirin 3 months 70 SVG, arterial Graft occlusion was not significantly different between groups (ticagrelor versus placebo, 10.3 versus 18.3%; P = 0.112). Graft occlusion or stenosis ≥50% was lower in the ticagrelor versus placebo group (11.5 versus 26.7%, P = 0.007). Rafiq, 2017 Clopidogrel + Aspirin Aspirin 3 months 165 SVG, arterial No between-group differences were found in the incidence of graft stenosis or occlusion in hypercoagulable patients.

CABG, coronary artery bypass graft surgery; DAPT, dual antiplatelet therapy; LITA, left internal thoracic artery; SVG, saphenous vein graft.

P2Y12 INHIBITOR MONOTHERAPY AFTER CORONARY ARTERY BYPASS GRAFT SURGERY

Whether P2Y12 inhibitor monotherapy, as opposed to DAPT, would provide a better net clinical benefit after CABG may also be considered. The Ticagrelor in CABG (TiCAB) trial randomized 1859 patients to ticagrelor monotherapy or aspirin and reported no between-group differences in the incidence of the primary composite efficacy endpoint of cardiovascular death, MI, stroke, or repeat revascularization (ticagrelor: 9.7%, aspirin: 8.2%; hazard ratio 1.10, 95% CI 0.87–1.62; P = 0.28) or the secondary safety endpoint of major bleeding (ticagrelor: 3.7%, aspirin: 3.2%; hazard ratio 1.17, 95% CI 0.71–1.92; P = 0.53) at 1 year; this study did not include SVG failure as an outcome [28]. The Ticagrelor Antiplatelet Therapy to Reduce Graft Events and Thrombosis (TARGET) trial that randomized 250 patients after CABG to ticagrelor monotherapy or aspirin (81 mg twice daily) reported no difference between groups in the incidence of SVG occlusion at 1 year [29] (588 SVG total, 17.4 versus 13.2%, aspirin versus ticagrelor; P = 0.30) or at 2 years [30] (425 SVG total, 15.7 versus 13.2%, aspirin versus ticagrelor, P = 0.71). When pooling individual patient data from the TARGET trial and the ticagrelor monotherapy arm of the Different Antiplatelet Therapy Strategy After CCABG Surgery (DACAB) [22] trial, ticagrelor monotherapy was not associated with better efficacy than aspirin alone (although the point estimate favored ticagrelor monotherapy: OR, 0.86; 95% CI 0.58–1.27; P = 0.44 for SVG failure), and was not associated with increased bleeding risk (OR, 1.25; 95% CI 0.69–2.29; P = 0.46) [24▪▪].

A recent observational study from Korea compared clinical outcomes and graft patency rates in 227 matched pairs of off-pump CABG patients who, after 1 year on DAPT with clopidogrel and all grafts patent at 1-year graft imaging, were continued on either aspirin or clopidogrel monotherapy for an additional 4 years [31]. Survival (hazard ratio 1.05; 95% CI 0.55–2.01, P = 0.89) and the incidence of major adverse events (hazard ratio 1.01; 95% CI 0.60–1.73; P = 0.96), as well as the incidence of new graft occlusion (clopidogrel 3.2% versus aspirin 4.7%, P = 0.39) at 5-year follow-up did not differ significantly between the groups. However, a switch to a different antithrombotic strategy was required in 22.8% of patients in the aspirin group and 2.2% in the clopidogrel group (P < .001), limiting conclusions on the efficacy of clopidogrel versus aspirin monotherapy after CABG.

CONCLUSION

Current evidence supports the use of DAPT in patients undergoing CABG after an ACS event, and the use of aspirin for secondary prevention in patients with SIHD. DAPT with clopidogrel or ticagrelor for 1 year is associated with a reduced risk of SVG failure, but the benefit of DAPT must be weighed against an increased risk of bleeding events. Strategies of shorter duration DAPT or P2Y12 inhibitor monotherapy after CABG require further evaluation.

Acknowledgements

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Conflicts of interest

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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