Single antiplatelet therapy
Early placebo-controlled studies published in the eighties tested warfarin, indobufen, aspirin at different doses and the combination of high-dose aspirin and dipyridamole, with mixed results [
14‐
23]. In the largest of these studies (
n = 555) all the aspirin-based regimens improved graft patency at 60 days from surgery [
19]. These results were consistent in a smaller trial (
n = 231) where an aspirin dose of 324 mg daily, given within one hour after CABG, resulted in a significant reduction in SVG occlusion at 1 week that was sustained at one year [
18]. Following these studies, aspirin became a pillar of secondary prevention in this setting [
24,
25]. However, the response to aspirin can be highly variable among CABG patients [
26,
27]. Therefore, alternative antiplatelet agents, including the P2Y
12 receptor inhibitors clopidogrel and ticagrelor, have been investigated (Table
1).
Table 1
Randomized trials comparing monotherapy regimens after CABG
David JL et al., 1999 | 62 | Clopidogrel (C) 50 mg/die or 75 mg/die or 100 mg/die | Ticlopidine (T) 250 mg/bid | 28 days | Ex-vivo platelet aggregation: Day 9: inhibition in the T group but not in the C groups (p < 0.01); Day 28: equally significant inhibition in the T, C100 and C75 groups (p < 0.001) and at a less extent in the C50 group (p < 0.01) | BT was significantly prolonged versus baseline in the T, C100 and C75 (p < 0.001). The prolongation was significant but at a less extent in the C50 group (p < 0.05) |
Lim E. et al., 2004 | 54 | Clopidogrel (C) 75 mg/die | ASA (A) 100 mg or 325 mg | 5 days | Mean percentage aggregations with collagen: 56% for A and 99% for C; mean difference between the two arms was 42% (95% CI, 27 − 56%) in favor of A | NA |
TiCAB, 2019 | 1,859 | Ticagrelor (T) 90 mg/bid | ASA (A) 100 mg/die | 12 months | Composite of cardiovascular death, MI, repeat revascularization, and stroke: HR 1.19; 95% CI 0.87 to 1.62; p = 0.28 | BARC ≥ 4 for periprocedural and hospital stay-related bleedings and BARC ≥ 3 for post-discharge bleedings: HR 1.17; 95% CI 0.71 to 1.92; p = 0.53 |
TARGET, 2022 | 250 | Ticagrelor (T) 90 mg/bid | ASA (A) 81 mg/bid | 12 months | SVG occlusion: 13.2% vs. 17.4%; p = 0.30 | Freedom from major adverse cardiovascular events; p = 0.60 |
Dual antiplatelet therapy
Randomized clinical trials of DAPT for the prevention of graft occlusion are summarized below and in Table
2.
Table 2
Randomized clinical trials of dual versus single antiplatelet strategies after CABG
Gao G. et al., 2010 | 249 | 704 | SVGs (68%), LIMA, RA | ASA 100 mg plus clopidogrel 75 mg | ASA 100 mg | 3 months | CTA | 6.5 vs. 10.3 (p = 0.07) | 8.4 vs. 14.3 (p = 0.04) |
Mujanovic E. et al., 2009 | 20 | 56 | SVGs (64%), LIMA | ASA 100 mg plus clopidogrel 75 mg | ASA 100 mg | 3 months | Coronary angiography | 6.9 vs. 29.6 (p = 0.04) | 10.5 vs. 47.1 (p = 0.02) |
CRYSSA, 2012 | 300 | 960 | SVGs (57%), LIMA, RIMA, RA | ASA 100 mg plus clopidogrel 75 mg | ASA 100 mg | 12 months | CTA | 4.84 vs. 8.35 (p = 0.03) | 7.4 vs. 13.1 (p = 0.04) |
Sun J.C.J. et al., 2010 | 100 | 395 | SVGs (58%), LIMA, RIMA, RA | ASA 81 mg plus clopidogrel 75 mg | ASA 81 mg plus placebo | 1 months | CTA | 5.0 vs. 7.1 (p = 0.43) | 6.5 vs. 6.8 (p = 0.92) |
CASCADE, 2010 | 113 | NA | SVGs and arterial grafts | ASA 162 mg plus clopidogrel 75 mg | ASA 162 mg plus placebo | 12 months | Coronary angiography with IVUS | 4.8 vs. 4.5 (p = 0 0.90) | 5.7 vs. 6.8 (p = 0.69) |
TEG-CABG, 2017 | 165 | 355 | SVGs (58%), LIMA, RIMA, RA | ASA 75 mg plus clopidogrel 75 mg | ASA 75 mg | 3 months | CTA | 25.7 vs. 22.4 (p = 0.84)* | 11.9 vs. 6.7 (p = 0.29) |
TAP-CABG, 2016 | 70 | 207 | SVGs (48%) LIMA, RA | ASA 81 mg plus ticagrelor 90 mg bid | ASA 81 mg plus placebo | 3 months | CTA | 10.3 vs. 18.3 (p = 0.11) | 10.0 vs. 22.0 (p = 0.12) |
DACAB, 2018 | 500 | 1891 | SVGs (77%), LIMA, RA | Ticagrelor 90 mg bid or ASA 100 mg plus ticagrelor 90 mg bid | ASA 100 mg | 12 months | CTA or coronary angiography | NA | 17.2 vs. 23.5 (p = 0.10) 11.3 vs. 23.5 (p < 0.001) |
POPULAR-CABG, 2020 | 499 | 1847 | SVGs (58%), LIMA, RIMA, RA | ASA (100 or 80 mg) plus ticagrelor 90 mg bid | ASA (100 or 80 mg) plus placebo | 12 months | CTA | NA | 9.6 vs. 10.1 (p = 0.64) |
Danek B.A. et al., 2020 | 84 | NA | SVGs | ASA 100 mg plus prasugrel 10 mg/die | ASA 100 mg plus placebo | 12 months | Coronary angiography with OCT, IVUS and NIRS | NA | p = 0.06 |
Tang Y. et al., 2021 | 147 | 480 | SVGs (70%), LIMA | ASA 100 mg plus ticagrelor 90 mg bid | ASA 100 mg plus clopidogrel 75 mg | 12 months | CTA | 6.7 vs. 7.5 (p = 0.73) | 9.0 vs. 10.1 (p = 0.75) |
Bai C. et al., 2022 | 152 | 540 | SVGs (75%) and LIMA | Indobufen 100 mg bid plus clopidogrel 75 mg | ASA 100 mg plus clopidogrel 75 mg | 12 months | CTA or coronary angiography | 4.9 vs. 7.4 (p = 0.22) | 5.5 vs. 8.7 (p = 0.21) |
No trials of DAPT with clopidogrel and aspirin exist that were powered for hard clinical endpoints. Data from observational studies and post-hoc analyses of randomized trials designed for other purposes are available, but likely fraught by confounding bias. If anything, these studies were consistent in showing no benefit on mortality with clopidogrel in addition to aspirin. In the 2,072 patients with acute coronary syndromes (ACS) who received CABG in the CURE trial, DAPT reduced the risk of cardiovascular death, myocardial infarction, or stroke by 11%, but increased the risk of hemorrhagic complications by 30% [
43]. Conversely, in a large retrospective registry from China (
n = 18,069), CABG patients with DAPT had a lower incidence of all-cause death, stroke, myocardial infarction, or repeat revascularization at six months and had no differences in bleeding events [
44]. In a sub-analysis of the ROOBY trial, DAPT increased early death (i.e., within 30 days) and did not improve the risk of death at long-term [
45]. Additionally, in a study including aspirin-resistant patients, DAPT did not result in reduced death at six months [
46]. These results were consistent with a post hoc analysis of the FREEDOM trial, where no differences in death, adverse ischemic events and bleeding was observed at five years among patients with type II diabetes mellitus undergoing CABG [
47].
At variance with DACAB, the POPULAR-CABG trial (
n = 499) showed no significant difference in one-year SVG patency with aspirin and ticagrelor compared to aspirin alone [
50]. The different results of DACAB and POPULAR-CABG have two contributing explanations. Firstly, in DACAB, a higher proportion of patients underwent CABG for ACS than in POPULAR-CABG (i.e., two thirds versus one third). ACS is known as the population that benefits the most from a ticagrelor-based DAPT. Secondly, the use of cardiopulmonary bypass was markedly lower in DACAB (25%) than in POPULAR-CABG (95%). The impact of this difference on graft patency is unclear. Two recent meta-analyses suggested that the antiplatelet regimens that include ticagrelor are associated with improved clinical outcomes and increased graft patency [
51,
52]. However, the findings of these meta-analyses were mixed regarding the risk of clinically important bleeding. In view of the conflicting results of the available studies, the efficacy of DAPT with ticagrelor and aspirin in improving the patency of SVGs remains undefined.
The only available data comparing DAPT with prasugrel and aspirin and DAPT with clopidogrel and aspirin comes from a subset analysis of the TRITON-TIMI 38 trial, which included 346 patients with ACS undergoing CABG [
59]. Despite an increase in bleeding and surgical re-exploration, prasugrel-based DAPT was associated with a lower rate of death within 30 days after CABG. It is possible that the greater degree of platelet inhibition provided by prasugrel may have contributed to both the increased non-fatal bleeding and the reduced risk of fatal cardiac events and mortality. This evidence is mostly derived from sub-analyses of trials with non-stratified randomization, and therefore is not sufficient to draw definitive conclusions.
A recent Chinese trial (
n = 152) compared DAPT with indobufen and clopidogrel to DAPT with aspirin and clopidogrel and found similar patency rates of SVG and arterial grafts at 12 months [
60]. This trial also showed a similar rate of MACE between the two groups and a lower incidence of gastrointestinal adverse events in the indobufen group. Based on these findings, indobufen might be considered in DAPT combinations if aspirin is not an option.
Anticoagulant therapy
Early studies investigated the effectiveness of various anticoagulants in preventing graft occlusion after CABG.
In the landmark Post-CABG (Post-Coronary Artery Bypass Graft) trial, 1,351 patients on aspirin were randomized to low-dose warfarin (e.g., dual-pathway inhibition) or placebo [
63]. While no significant effect was observed on progression of SVG disease, there were a 35% reduction in mortality (
p = 0.008) and a 31% reduction of death or nonfatal myocardial infarction (
p = 0.003) with warfarin and aspirin at 7.5 years [
64]. The mechanism leading to such effects remained unexplained and play of chance cannot be ruled out. Indeed, only 11% of patients were on VKA during the extended follow-up.
In a prespecified substudy of the COMPASS trial, 1,448 patients were randomized within 4 to 14 days after CABG to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg daily [
68]. At an average of 1.13 years, compared to aspirin alone, rivaroxaban did not reduce the rate of both arterial and SVG failure either as a combination with aspirin or as monotherapy. Additionally, the two rivaroxaban-based strategies did not reduce the risk of a composite of cardiovascular death, stroke, or myocardial infarction and increased the risk of bleeding at 30 days after CABG. Notably, when compared to aspirin alone, the combination of rivaroxaban and aspirin did not increase the rate of graft patency in both patients treated with on-pump and off-pump techniques. Conversely, rivaroxaban monotherapy improved the rate of graft patency in patients undergoing off-pump CABG (odds ratio 0.37; 95% CI, 0.16 to 0.82;
p = 0.01), but not in those undergoing on-pump CABG. Overall, these results do not support the use of rivaroxaban, either alone or in a dual-pathway inhibition regimen, after CABG. Further studies are warranted to corroborate the promise of rivaroxaban in patients undergoing off-pump CABG.