**4.2 Antiplatelet therapy after CABG in setting of CCS**

Stable ischemic heart disease (SIHD) refers to patients with known or suspected ischemic heart disease, including those with new-onset chest pain and those who have undergone PCI or CABG, and this term is used in 2014 ACC/AHA/ AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease [80]. However, the disease is chronic, most often progressive and serious, even in clinically apparently silent periods. The new 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes (CCS) emphasize that the dynamic nature of the CAD process results in various clinical presentations, which can be conveniently categorized as either ACS or CCS [81]. Latest guidelines note limited evidence on the role of DAPT after CABG in SIHD [1, 71]. 2016 ACC/AHA DAPT guideline update provides a class IIb recommendation for 12 months of DAPT to improve SVG patency [71]. The 2017 ESC focused update guideline suggests insufficient evidence to generally recommend DAPT postoperatively to reduce vein graft occlusion in stable patients who underwent CABG, unless concomitant or prior indication overrides [1]. Several studies have provided conflicting results on the effects of DAPT on the SVG patency. Graft patency was assessed with invasive coronary angiography or computerized tomography (CT). In Clopidogrel After Surgery for Coronary Artery disease (CASCADE) randomized trial, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia (assessed with coronary angiography and intravascular ultrasound, IVUS) compared with ASA monotherapy [82]. Graft patency was not significantly improved

**55**

(HAS-BLED).

**CABG**

, HAS-BLED5

65–74 years, and sex category.

ABC4

*Antiplatelet Therapy after Coronary Artery Bypass Graft Surgery, Inconsistency of Clinical…*

in ROOBY trial [83] and a trial that randomized 100 patients after CABG [84]. In secondary analysis of CASCADE, the superiority of DAPT over ASA monotherapy in reducing the incidence of new occlusions within native coronary arteries after CABG was demonstrated [85]. Contradictorily, in Prevention of Coronary Artery Bypass Occlusion After Off-Pump Procedure (CRYSSA) trial, DAPT with ASA and clopidogrel was associated with significantly lower SVG occlusion rates than ASA monotherapy [86], and similar was shown in a previous RCT but with no significant differences in MACCE [87]. Observational studies in the cardiac surgery literature have suggested that clopidogrel may improve postoperative outcomes [88] and also demonstrated that the addition of clopidogrel to ASA was associated with a trend toward improved SVG patency 6 months after surgery [89], and it noted that postoperative clopidogrel was associated with less symptom recurrence and fewer adverse cardiac events [90]. Meta-analysis of DAPT with clopidogrel and ASA over monotherapy with ASA established that DAPT reduces the risk of SVG occlusion [91, 92] and was associated with a smaller incidence of early mortality but also linked with major bleeding episodes in the early postoperative period [92]. There is lack of studies that compare the effect of ticagrelor or prasugrel in addition to ASA on SVG patency. Effect of ticagrelor plus aspirin, ticagrelor alone, or aspirin alone on SVG patency 1 year after elective CABG was assessed in RCT and demonstrated that DAPT with ticagrelor and aspirin significantly improved graft patency, but there was no significant improvement with ticagrelor alone or aspirin alone, no statistically significant difference in event rates of MACCE, and no major bleeding in DAPT group [93]. And most recently, the Ticagrelor Compared with Aspirin for Prevention of Vascular Events in Patients Undergoing Coronary Artery Bypass Grafting (TiCAB) trial randomized patients in either ticagrelor twice daily or aspirin once daily group (study did not evaluate DAPT), and the primary outcome of MACE at 12 months did not differ significantly between two groups [94]. In latest meta-analyses data were also contradictory. One meta-analysis showed that DAPT appears to be associated with a reduction in graft occlusion and major adverse cardiac events in all-cause mortality, without significantly increasing major bleeding [95]. Improved graft patency with DAPT compared with aspirin was also shown in a meta-analysis of RCTs only [96]. Combined meta-analysis among patients undergoing CABG suggested association of DAPT with lover cardiovascular mortality in observational studies, but such findings were not replicated in RCTs [97].

**4.3 Triple therapy (aspirin, P2Y12 inhibitor, and OAC) in patients after PCI or** 

Addition of DAPT to oral anticoagulant (OAC) therapy increases bleeding complications for two- to threefolds [98, 99]. Therefore, patients who need triple therapy (comorbidity such as atrial fibrillation, thrombus in left ventricle, deep venous thrombosis, mechanical heart valve) are at high risk of bleeding. Assessing ischemic and bleeding risks using validated risk predictors (e.g., CHA2DS2-VASc3

avoid bleeding complications. Triple therapy in patients undergoing PCI should last as short as possible (1 month if concerns about bleeding risks are prevailing and up

<sup>3</sup> CHA2DS2-VASc indicates congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age

<sup>5</sup> Hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol

<sup>4</sup> Age, biomarkers (GDF-15, cTnT-hs, hemoglobin), and clinical history (ABC).

) with a focus on modifiable risk factors is one of the strategies to

,

*DOI: http://dx.doi.org/10.5772/intechopen.90446*

*Antiplatelet Therapy after Coronary Artery Bypass Graft Surgery, Inconsistency of Clinical… DOI: http://dx.doi.org/10.5772/intechopen.90446*

in ROOBY trial [83] and a trial that randomized 100 patients after CABG [84]. In secondary analysis of CASCADE, the superiority of DAPT over ASA monotherapy in reducing the incidence of new occlusions within native coronary arteries after CABG was demonstrated [85]. Contradictorily, in Prevention of Coronary Artery Bypass Occlusion After Off-Pump Procedure (CRYSSA) trial, DAPT with ASA and clopidogrel was associated with significantly lower SVG occlusion rates than ASA monotherapy [86], and similar was shown in a previous RCT but with no significant differences in MACCE [87]. Observational studies in the cardiac surgery literature have suggested that clopidogrel may improve postoperative outcomes [88] and also demonstrated that the addition of clopidogrel to ASA was associated with a trend toward improved SVG patency 6 months after surgery [89], and it noted that postoperative clopidogrel was associated with less symptom recurrence and fewer adverse cardiac events [90]. Meta-analysis of DAPT with clopidogrel and ASA over monotherapy with ASA established that DAPT reduces the risk of SVG occlusion [91, 92] and was associated with a smaller incidence of early mortality but also linked with major bleeding episodes in the early postoperative period [92]. There is lack of studies that compare the effect of ticagrelor or prasugrel in addition to ASA on SVG patency. Effect of ticagrelor plus aspirin, ticagrelor alone, or aspirin alone on SVG patency 1 year after elective CABG was assessed in RCT and demonstrated that DAPT with ticagrelor and aspirin significantly improved graft patency, but there was no significant improvement with ticagrelor alone or aspirin alone, no statistically significant difference in event rates of MACCE, and no major bleeding in DAPT group [93]. And most recently, the Ticagrelor Compared with Aspirin for Prevention of Vascular Events in Patients Undergoing Coronary Artery Bypass Grafting (TiCAB) trial randomized patients in either ticagrelor twice daily or aspirin once daily group (study did not evaluate DAPT), and the primary outcome of MACE at 12 months did not differ significantly between two groups [94]. In latest meta-analyses data were also contradictory. One meta-analysis showed that DAPT appears to be associated with a reduction in graft occlusion and major adverse cardiac events in all-cause mortality, without significantly increasing major bleeding [95]. Improved graft patency with DAPT compared with aspirin was also shown in a meta-analysis of RCTs only [96]. Combined meta-analysis among patients undergoing CABG suggested association of DAPT with lover cardiovascular mortality in observational studies, but such findings were not replicated in RCTs [97].

#### **4.3 Triple therapy (aspirin, P2Y12 inhibitor, and OAC) in patients after PCI or CABG**

Addition of DAPT to oral anticoagulant (OAC) therapy increases bleeding complications for two- to threefolds [98, 99]. Therefore, patients who need triple therapy (comorbidity such as atrial fibrillation, thrombus in left ventricle, deep venous thrombosis, mechanical heart valve) are at high risk of bleeding. Assessing ischemic and bleeding risks using validated risk predictors (e.g., CHA2DS2-VASc3 , ABC4 , HAS-BLED5 ) with a focus on modifiable risk factors is one of the strategies to avoid bleeding complications. Triple therapy in patients undergoing PCI should last as short as possible (1 month if concerns about bleeding risks are prevailing and up

*The Current Perspectives on Coronary Artery Bypass Grafting*

and ticagrelor for patients with ACS after CABG [79].

**4.2 Antiplatelet therapy after CABG in setting of CCS**

Stable ischemic heart disease (SIHD) refers to patients with known or suspected ischemic heart disease, including those with new-onset chest pain and those who have undergone PCI or CABG, and this term is used in 2014 ACC/AHA/ AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease [80]. However, the disease is chronic, most often progressive and serious, even in clinically apparently silent periods. The new 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes (CCS) emphasize that the dynamic nature of the CAD process results in various clinical presentations, which can be conveniently categorized as either ACS or CCS [81]. Latest guidelines note limited evidence on the role of DAPT after CABG in SIHD [1, 71]. 2016 ACC/AHA DAPT guideline update provides a class IIb recommendation for 12 months of DAPT to improve SVG patency [71]. The 2017 ESC focused update guideline suggests insufficient evidence to generally recommend DAPT postoperatively to reduce vein graft occlusion in stable patients who underwent CABG, unless concomitant or prior indication overrides [1]. Several studies have provided conflicting results on the effects of DAPT on the SVG patency. Graft patency was assessed with invasive coronary angiography or computerized tomography (CT). In Clopidogrel After Surgery for Coronary Artery disease (CASCADE) randomized trial, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia (assessed with coronary angiography and intravascular ultrasound, IVUS) compared with ASA monotherapy [82]. Graft patency was not significantly improved

patients revascularized with CABG after MI, the benefit and efficacy of postoperative clopidogrel treatment in reducing risk of death or recurrent MI were confirmed [74]. The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized patients with ACS to DAPT with either ASA plus ticagrelor 90 mg twice daily or ASA plus clopidogrel 75 mg once daily [75]. The composite primary end point of death from vascular causes, MI, or stroke was significantly reduced in the ticagrelor group, and ticagrelor was associated with a higher rate of major bleeding (no statistical difference in overall major bleeding). In a subgroup of patients who underwent CABG, effect on the primary outcome at 1 year was again consistent but did not reach significance. Cardiovascular mortality and all-cause mortality were significantly lower with ticagrelor, and there was no significant statistical benefit of ticagrelor related to MI and stroke [75]. DAPT with clopidogrel and ticagrelor in patients with non ST-elevation acute coronary syndrome (NSTE-ACS) was evaluated 3 months after off-pump CABG (only arterial grafts were used) in retrospective observational study, and there was no significant difference in overall survival or composite outcome of MACCE or major bleeding [76]. Prasugrel was compared with clopidogrel in patients with acute coronary syndrome RCT (TRITON-TIMI 38) where DAPT with ASA plus clopidogrel 75 mg daily or ASA plus prasugrel 10 mg daily was used [77]. Although major bleeding complications were significantly higher with prasugrel, the primary composite outcome of MACCE was significantly lower in prasugrel group, and all-cause mortality within 30 days in a subgroup of patients undergoing CABG was significantly reduced [77]. Meta-analysis of nine RCT that confirms benefit of DAPT among the subset of patients after ACS who had undergone CABG suggests that higher-intensity (prasugrel or ticagrelor) than lower-intensity (clopidogrel) DAPT is associated with an approximate 50% lower all-cause mortality in such patients, but data are primarily based on post-randomization subset from a single RCT [78]. Latest review on DAPT and CABG with focus on ACS supports the use of DAPT with ASA

**54**

<sup>3</sup> CHA2DS2-VASc indicates congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65–74 years, and sex category.

<sup>4</sup> Age, biomarkers (GDF-15, cTnT-hs, hemoglobin), and clinical history (ABC).

<sup>5</sup> Hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol (HAS-BLED).

to 6 months if concerns about ischemic risks are prevailing), and then dual therapy is to be considered (OAC and clopidogrel) up to 12 months [1]. Non-vitamin K oral anticoagulant (NOAC) should be considered instead of vitamin K antagonist (VKA). International normalized ratio (INR) is suggested to be in the lower part of the recommended target range, and time in therapeutic range should be maximized (i.e., >65–70%) when VKA is used [1, 71]. Using low dose (≤100 mg) of ASA is recommended and also routine use of proton pump inhibitors (PPIs) [1, 71]. Clopidogrel is the P2Y12 inhibitor of choice in such regimen of therapy; the use of prasugrel and ticagrelor should be avoided [1]. In a study of 377 patients who underwent drug-eluting stent implantation and had an indication for oral anticoagulation, prasugrel was evaluated as alternative to clopidogrel, and results showed an increased risk of bleeding in patients needing triple therapy [100]. Recent meta-analysis demonstrated that the use of ticagrelor as part of dual or triple therapy is associated with significantly higher rates of clinically relevant hemorrhagic complications than clopidogrel [101]. Latest review article on this subject points out already known stronger antiplatelet effect of ticagrelor and prasugrel, yet they are not used because of the increased risk, whether real or perceived, which has not been confirmed with large RCT in patients with ACS and atrial fibrillation [102]. In patients eligible for CABG surgery, DAPT should be avoided on the top of OAC and is not suggested in which antiplatelet agent in addition to OAC should be used [1].
