Efficacy of Extended Dual Antiplatelet Therapy After Coronary Artery Bypass Grafting in Patients With High Inflammatory Risk

Woo Jin Jang; Ki Hong Choi; Chang Hoon Kim; Joo-Yong Hahn; Seung-Hyuk Choi; Hyeon-Cheol Gwon; Kiick Sung; Wook Sung Kim; Dong Seop Jeong; Young Bin Song

doi:10.1253/circj.CJ-24-0989

Abstract

Background: This study evaluated the efficacy of dual antiplatelet therapy (DAPT) on the long-term prognosis of coronary artery bypass grafting (CABG) patients with high inflammatory risk.

Methods and Results: We analyzed 2,409 patients who underwent isolated CABG between January 2001 and December 2017 and had baseline high-sensitivity C-reactive protein (hs-CRP) levels >2.0 mg/L. Patients were divided into 2 groups: those on DAPT for ≥12 months (n=545) and those on single antiplatelet therapy (SAPT; n=1,864). The primary outcome was all-cause death or myocardial infarction (MI) after CABG. Propensity score (PS) matching was used to minimize confounding factors and selection bias. During follow-up, the ≥12-month DAPT group had a significantly lower risk of the primary outcome than the SAPT group (7.5% vs. 13.3%; hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.24–0.72; P=0.002). After PS matching, the incidence of the primary outcome remained lower in the DAPT group (HR 0.36; 95% CI 0.19–0.71; P=0.003). The benefit of prolonged DAPT was consistent across subgroups.

Conclusions: In CABG patients with high inflammatory risk, prolonged DAPT (≥12 months) was associated with significantly lower rates of all-cause death or MI compared with SAPT.

Inflammation plays a significant role in the development of atherosclerosis and thrombosis, with biomarker surrogates like high-sensitivity C-reactive protein (hs-CRP) providing valuable prognostic insights for secondary prevention among patients with coronary artery disease.¹^–³ Dual antiplatelet therapy (DAPT), comprising aspirin and a P2Y₁₂ receptor antagonist, is currently recommended for patients who have undergone coronary bypass grafting (CABG).⁴^,⁵ Despite these recommendations, adherence to DAPT after CABG varies widely in real-world clinical practice, with less than half of cardiac surgeons prescribing DAPT following CABG, even in cases of acute coronary syndrome.⁶ The decision to prescribe DAPT in CABG patients is complicated by the risk of perioperative bleeding, discrepancies in guideline recommendations, and unclear benefits regarding the reduction of thrombotic events or the improvement of graft longevity.⁶^–⁸

Numerous experimental and clinical research underscores the pivotal influence of inflammation in the development of atherosclerotic thrombosis, with a particular focus on inflammatory markers like hs-CRP in the context of extensive coronary artery disease.⁹^,¹⁰ Several studies have demonstrated a strong association between elevated serum hs-CRP levels and cardiovascular mortality in patients with coronary artery disease.¹¹^,¹² This association extends even to studies involving apparently healthy men, in whom elevated hs-CRP levels have been linked to a higher risk of future cardiovascular events.¹³ The detection of elevated hs-CRP levels, indicative of an inflammatory risk, may be associated with adverse cardiovascular outcomes, suggesting that more intensive antiplatelet therapy could be beneficial for patients undergoing CABG.¹⁴^,¹⁵ However, there is currently no evidence demonstrating the prognostic effect of aspirin and additional postoperative P2Y₁₂ inhibitors, nor the benefit of prolonged DAPT after CABG, for reducing cardiovascular events in patients at risk of vascular inflammation.¹⁶^,¹⁷ The aim of the present study was to elucidate the protective effects of DAPT for ≥12 months after CABG in patients with high serum hs-CRP levels.

Methods

Study Population and Data Collection

This retrospective single-center observational study involved patients with coronary artery disease who underwent CABG. Between January 2001 and December 2017, 6,691 consecutive patients with coronary artery disease who underwent CABG were enrolled from an institutional registry of Samsung Medical Center in Seoul, Korea (Clinicaltrials.gov ID: NCT03870815). For the present study, patients were excluded if they were aged <18 years (n=14), did not have angiography or surgery data available (n=64), died in hospital (n=82), were not prescribed any antiplatelet agent (n=28), were prescribed anticoagulants (n=620), underwent combined valve surgery (n=103), did not have baseline hs-CRP data available (n=639), and had hs-CRP levels ≤2.0 mg/L (n=2,734; Figure 1). For the purposes of the present study, subjects were divided into 2 groups, namely those who used DAPT for ≥12 months and those using single antiplatelet therapy (SAPT), with the use of DAPT or SAPT determined by prescriptions until discharge after CABG.

Figure 1.

Study flowchart. CABG, coronary artery bypass grafting; hs-CRP, high-sensitivity C-reactive protein.

The research coordinators prospectively collected baseline characteristics, angiographic data, surgical procedural data, and outcome data from the registry. Additional information was obtained from medical records and telephone interviews, if necessary. The hs-CRP tests were performed during intensive care unit hospitalization or emergency department visits. Mortality data for patients lost to follow-up were confirmed using the National Death Records. All events were adjudicated by a cardiology expert blinded to the study.

The study protocol was approved by the Institutional Review Board of Samsung Medical Center on February 26, 2019, and the requirement for informed consent from individual patients was waived (Approval no. 2019-02-086-001). This study was conducted in accordance with the principles of the Declaration of Helsinki. The data were assessed for research purposes on May 13, 2024.

Surgical Techniques

CABG was performed according to relevant standard guidelines.⁷ Off-pump coronary artery bypass grafting (OPCAB) using the bilateral internal thoracic artery is the preferred technique at Samsung Medical Center. In fact, 88.5% of patients in this registry (n=5,119) were treated with OPCAB. All surgeries were performed using a standard median sternotomy. The bilateral internal thoracic arteries were prepared using skeletonization techniques with sharp dissection, clipping, and branch ligation. The saphenous vein was harvested from the patient’s upper or lower leg using split incisions. Heparinized saline was used to dilate the diameter of the saphenous vein graft (SVG). The in situ right gastroepiploic artery was prepared in a pedicled manner. The right internal mammary artery (RIMA) was anastomosed to the left side of the left internal mammary artery (LIMA) using a continuous running suture to construct a Y-composite graft. With few exceptions, the LIMA was anastomosed to the left anterior descending artery and its branches, and the RIMA was sequentially anastomosed to the left circumflex artery. If proximal right coronary artery stenosis was >80%, the RIMA was initially selected as a graft. If the length of the harvested RIMA was insufficient to reach the right coronary artery anastomosis, the right gastroepiploic artery was used. If the proximal right coronary artery stenosis was <80%, aortocoronary bypass was performed using the SVG. A Transonic Flowmeter (Transonic Systems, Ithaca, NY, USA) was used to evaluate the quality of anastomosis according to the transit time flow rate. Perioperative treatment strategies, including the use of cardiopulmonary bypass, number of grafts used, determination of anastomosis site, and the use of concomitant medications after CABG,¹⁸ were left to the discretion of the operator.

Study Outcomes and Definitions

The primary outcome of the present study was the occurrence of all-cause death or myocardial infarction (MI) after CABG during follow-up. Secondary outcomes included all-cause death, cardiovascular death, MI, stroke, and Bleeding Academic Research Consortium (BARC) Type 3–5 events. Graft patency, if necessary, was assessed using coronary computed tomography angiography or invasive coronary angiography at the discretion of the operator. All deaths were considered to be of cardiac origin unless a definite non-cardiac cause could be established. MI was defined as an elevated cardiac troponin level or myocardial band fraction of creatine kinase greater than the upper reference limit, with concomitant ischemic symptoms or electrocardiography findings indicative of ischemia. Procedure-related MI was not included in the definition. Stroke was defined as any non-convulsive focal or global neurological deficit of abrupt onset, caused by ischemia or hemorrhage within the brain. Bleeding events were evaluated using the BARC criteria. Grafts were evaluated according to the Fitzgibbon A, B, and O classifications and interpreted by an independent cardiology expert who was blinded to the treatment strategy.

Statistical Analysis

Continuous variables were compared using Student’s t-test or the Wilcoxon rank-sum test where applicable and are presented as the mean±SD or as the median with interquartile range (IQR). Categorical data were compared between groups using Fisher’s exact test or the Chi-squared test, as appropriate, and are presented as numbers and relative frequencies. Cumulative event rates were estimated using the Kaplan-Meier method, and treatment effects were assessed by stratified log-rank statistics. Patients were censored at 5 years (1,825 days) or when events occurred.

After stratifying patients who underwent CABG, clinical outcomes were compared between the ≥12-month DAPT and SAPT groups using a Cox proportional hazard regression model to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Proportional hazards assumptions of the HR for women compared with men in the Cox proportional hazards models were graphically inspected in the “log minus log” plot and were also confirmed with the Schoenfeld residual test. Adjusted HRs and 95% CIs for clinical outcomes according to sex were obtained by the final Cox regression model that included age, body mass index, hypertension, diabetes, current smoking, heart failure, previous history of MI, the use of antiplatelet medication, the use of β-blockers, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, the use of statins, multivessel disease, left main involvement, OPCAB, combined valvular surgery, number of anastomoses, the use of the LIMA, the use of the RIMA, the use of bilateral internal thoracic arteries, and the use of an SVG.

Propensity-score matched analysis was also performed to reduce selection bias. The covariate balance after propensity score (PS) matching was assessed by calculating absolute standardized mean differences. Standardized mean differences after PS matching were within ±10% across all matched covariates with variance ratios near 1.0, suggesting the achievement of balance between the DAPT and SAPT groups. Stratified Cox proportional hazard models were used to compare the outcomes of the matched groups. All probability values were 2-sided, and P<0.05 was considered statistically significant. Statistical analyses were performed using R Statistical Software version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline Characteristics

In all, 2,409 CABG patients with a baseline serum hs-CRP >2.0 mg/L were included in the present study. The median hs-CRP level of the study population was 6.7 mg/L (IQR 3.5–17.6 mg/L). The mean age and body mass index of the cohort were 63.6±9.8 years and 24.7±3.2, respectively. Among the overall study population, 458 patients (19.0% of the study population) were treated with DAPT for ≥12 months after CABG, whereas 1,951 (81.0%) received SAPT after the index procedure. The group treated with DAPT for ≥12 months after CABG was younger, had a higher body mass index, and a higher frequency of men than the group treated with SAPT after CABG. In the ≥12-month DAPT group, the incidence of dyslipidemia, current smoking, and a previous history of PCI or MI was significantly higher than in the SAPT group. In addition, patients in the ≥12-month DAPT group were more likely to present with stable ischemic heart disease than those who received SAPT. Left ventricular ejection fraction was lower and estimated glomerular filtration rate was higher in the ≥12-month DAPT than SAPT group (Table 1).

Table 1.

Baseline Clinical Characteristics

	Overall population				PS-matched population
	≥12-month DAPT (n=545)	SAPT (n=1,864)	P value	SMD	≥12-month DAPT (n=507)	SAPT (n=507)	P value	SMD
Age (years)	62.7±9.9	63.8±9.7	0.018	11.44	63.0±9.8	63.3±10.1	0.601	3.28
Male sex	420 (77.1)	1,354 (72.6)	0.039	10.21	390 (76.9)	385 (75.9)	0.767	2.32
Body mass index (kg/m²)	25.0±3.1	24.6±3.2	0.009	12.86	24.9±3.1	24.8±3.2	0.630	3.02
Cardiovascular risk factors
Hypertension	357 (65.5)	1,171 (62.8)	0.253	5.59	333 (65.7)	328 (64.7)	0.792	2.07
Diabetes	262 (48.1)	829 (44.5)	0.138	7.22	240 (47.3)	244 (48.1)	0.850	1.58
Chronic kidney disease	48 (8.8)	162 (8.7)	0.932	0.41	44 (8.7)	39 (7.7)	0.647	3.60
Dyslipidemia	191 (35.0)	495 (26.6)	<0.001	18.47	172 (33.9)	163 (32.1)	0.593	3.77
Current smoking	216 (39.6)	651 (34.9)	0.044	9.74	198 (39.1)	199 (39.3)	1.000	0.40
Previous history of PCI	123 (22.6)	280 (15.0)	<0.001	19.46	104 (20.5)	95 (18.7)	0.527	4.47
Previous history of MI	73 (13.4)	192 (10.3)	0.042	9.59	60 (11.8)	59 (11.6)	1.000	0.61
Previous history of stroke	82 (15.0)	269 (14.4)	0.721	1.73	81 (16.0)	88 (17.4)	0.613	3.70
Previous history of PAD	53 (9.7)	167 (9.0)	0.585	2.63	51 (10.1)	51 (10.1)	1.000	0.00
Previous history of bleeding	5 (0.9)	9 (0.5)	0.240	5.28	5 (1.0)	6 (1.2)		1.90
Clinical presentation, initial				4.20				9.05
Stable ischemic heart disease	224 (41.1)	677 (36.3)	0.025		206 (40.6)	173 (34.1)	0.087
Unstable angina	172 (31.6)	704 (37.8)	0.025		162 (32.0)	187 (36.9)	0.087
Acute MI	149 (27.3)	483 (25.9)			139 (27.4)	147 (29.0)
LVEF before CABG (%)	52.2±14.3	54.1±13.6	0.009	12.95	52.8±14.1	52.7±13.8	0.862	1.09
LVEF <50%	195 (35.8)	619 (33.2)	0.264
eGFR (mL/min/1.73 m²)	72.8±31.4	69.1±29.5	0.011	12.25	72.5±31.1	73.0±33.0	0.821	1.42
eGFR <60 mL/min/1.73 m²	184 (33.8)	708 (38.0)	0.073
Medical treatment
Previous aspirin	393 (72.1)	1,193 (64.0)	<0.001	17.46	364 (71.8)	359 (70.8)	0.781	2.18
Previous P2Y₁₂ inhibitor^A	277 (50.8)	702 (37.7)	<0.001	26.73	250 (49.3)	247 (48.7)	0.900	1.18
Previous DAPT	266 (48.8)	678 (36.4)	<0.001	25.34	243 (47.9)	237 (46.7)	0.753	2.37
At discharge
Aspirin	545 (100.0)	1,851 (99.3)	0.051
P2Y₁₂ inhibitor^A	545 (100.0)	828 (44.4)	<0.001
β-blockers	454 (83.3)	1,304 (70.0)	<0.001	32.09	417 (82.2)	433 (85.4)	0.201	8.58
ACE inhibitors/ARBs	180 (33.0)	726 (38.9)	0.012	12.35	170 (33.5)	163 (32.1)	0.688	2.94
Statins	405 (74.3)	1,464 (78.5)	0.037	9.97	377 (74.4)	373 (73.6)	0.830	1.80
Laboratory data, initial
White blood cell count (/mm³)	7.71±2.20	7.34±2.30	0.001	16.53	7.7±2.2	7.7±2.5	0.754	1.97
Hemoglobin (g/dL)	12.9±1.9	12.7±1.9	0.014	11.92	12.9±1.9	12.9±1.9	0.832	1.34
Creatinine (mg/dL)	1.4±2.0	1.3±1.4	0.210	6.73	1.4±1.9	1.3±1.5	0.518	4.08
HDL (mg/dL)	40.8±9.9	41.1±10.7	0.606	2.50	40.8±9.3	41.5±10.0	0.252	7.20
LDL (mg/dL)	104.5±38.4	107.6±39.2	0.128	7.56	105.4±36.8	105.2±35.2	0.942	0.46

Unless indicated otherwise, data are presented as the mean±SD or n (%). ^AP2Y₁₂ inhibitors included clopidogrel, ticagrelor, and prasugrel. ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; CABG, coronary artery bypass grafting surgery; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; PS, propensity score; SAPT, single antiplatelet therapy; SMD, standardized mean difference.

Surgical characteristics are presented in Table 2. The proportions of multivessel disease and 3-vessel disease were higher in the ≥12-month DAPT than SAPT group. Compared with the SAPT group, the ≥12-month DAPT group was treated more frequently using LIMA and SVG for surgical conduit but less frequently with other arterial grafts. The number of anastomosis sites was greater in the ≥12-month DAPT than SAPT group (Table 2).

Table 2.

Characteristics of Surgical Treatment

	Overall population				PS-matched population
	≥12-month DAPT (n=545)	SAPT (n=1,864)	P value	SMD	≥12-month DAPT (n=507)	SAPT (n=507)	P value	SMD
Coronary anatomy
Left main involvement	94 (17.2)	361 (19.4)	0.266	5.48	92 (18.1)	108 (21.3)	0.236	7.93
Multivessel disease	523 (96.0)	1,736 (93.1)	0.016	12.58	486 (95.9)	487 (96.1)	1.000	1.00
3-vessel disease	413 (75.8)	1,333 (71.5)	0.050	9.69	380 (75.0)	387 (76.3)	0.661	3.21
2-vessel disease	110 (20.2)	403 (21.6)	0.471	3.53	106 (20.9)	100 (19.7)	0.696	2.94
Procedural characteristics
Urgent/emergency CABG	38 (7.0)	105 (5.6)	0.244	5.52	33 (6.5)	38 (7.5)	0.623	3.86
Off-pump CABG	473 (86.8)	1,617 (86.7)	0.981	0.12	445 (87.8)	451 (89.0)	0.624	3.69
CPB	72 (13.2)	247 (13.3)	0.981	0.12	62 (12.2)	56 (11.0)	0.624	3.69
MCS
Preoperative	10 (1.8)	26 (1.4)	0.228	3.50	8 (1.6)	4 (0.8)	0.384	7.40
Intraoperative	4 (0.7)	21 (1.1)	0.177	4.11	4 (0.8)	4 (0.8)	1.000	0.00
Postoperative	5 (0.9)	21 (1.1)	0.250	2.08	5 (1.0)	4 (0.8)	1.000	2.10
Conduit used
Left internal mammary artery	524 (96.1)	1,825 (97.9)	0.020	10.49	495 (97.6)	497 (98.0)	0.829	2.71
Right internal mammary artery	482 (88.4)	1,610 (86.4)	0.209	6.23	453 (89.3)	461 (90.9)	0.461	5.29
Bilateral mammary arteries	470 (86.2)	1,585 (85.0)	0.484	3.44	445 (87.8)	455 (89.7)	0.371	6.25
Other arterial grafts^A	56 (10.3)	334 (17.9)	<0.001	22.23	56 (11.0)	52 (10.3)	0.760	2.56
Saphenous vein graft	156 (28.6)	302 (16.2)	<0.001	30.26	123 (24.3)	126 (24.9)	0.884	1.37
No. conduits	2.2±0.6	2.2±0.6	0.066	9.03	2.22±0.54	2.24±0.55	0.604	3.26
No. anastomosis sites	4.2±1.3	3.9±1.3	<0.001	26.58	4.1±1.3	4.2±1.3	0.679	2.60

Unless indicated otherwise, data are presented as the mean±SD or n (%). ^AOther arterial grafts included the radial artery and right gastroepiploic artery. CPB, cardiopulmonary bypass; MCS, mechanical circulatory support. Other abbreviations as in Table 1.

Clinical Outcomes

The mean follow-up duration was 1,501 days (4.2 years). In the study cohort, patients receiving DAPT for ≥12 months after CABG had a significantly lower incidence and risk of all-cause death or MI than those receiving SAPT during follow-up (7.5% vs. 13.3%, respectively; HR 0.45; 95% CI 0.29–0.70; P<0.001). The risks of all-cause death (HR 0.34; 95% CI 0.20–0.56; P<0.001) and cardiac death (HR 0.33; 95% CI 0.16–0.69; P=0.003) were significantly lower in the ≥12-month DAPT than SAPT group (Figure 2). There were no significant differences between the ≥12-month DAPT and SAPT groups in the risk of MI (HR 2.13; 95% CI 0.82–5.54; P=0.119), stroke (HR 1.19; 95% CI 0.67–2.13; P=0.552), or BARC Type 3–5 bleeding (HR 0.86; 95% CI 0.45–1.64; P=0.642). Competing risk analysis and multiple sensitivity analyses, including multivariate Cox proportional hazard models and PS-matched analyses, consistently showed similar results for patients treated with DAPT for ≥12 months and those treated with SAPT after CABG (Table 3; Figure 2).

Figure 2.

Kaplan-Meier curves comparing 5-year risk of all-cause death or myocardial infarction (MI). (A) Overall population. (B) Propensity score (PS)-matched population. CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy.

Table 3.

Comparison of 5-Year Risk of Clinical Outcomes

	≥12-month DAPT (n=545)	SAPT (n=1,864)	Univariable analysis		Multivariable analysis^A		PS-matched analysis
	≥12-month DAPT (n=545)	SAPT (n=1,864)	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
All-cause death or MI	24 (7.5)	127 (13.3)	0.45 (0.29–0.70)	<0.001	0.42 (0.24–0.72)	0.002	0.36 (0.19–0.71)	0.003
All-cause death	17 (5.7)	119 (12.5)	0.34 (0.20–0.56)	<0.001	0.30 (0.25–0.55)	<0.001	0.20 (0.08–0.45)	<0.001
Cardiovascular death	8 (2.8)	58 (6.5)	0.33 (0.16–0.69)	0.003	0.39 (0.16–0.98)	0.045	0.13 (0.03–0.62)	0.011
MI	8 (2.1)	9 (0.9)	2.13 (0.82–5.54)	0.119	5.36 (0.63–45.32)	0.124	1.77 (0.37–8.51)	0.477
Stroke	17 (4.9)	36 (3.4)	1.19 (0.67–2.13)	0.552	1.41 (0.61–3.26)	0.417	1.06 (0.48–2.32)	0.891
BARC Type 3–5 bleeding	12 (2.4)	40 (3.2)	0.86 (0.45–1.64)	0.642	1.07 (0.49–2.37)	0.861	0.64 (0.35–1.16)	0.141

Unless indicated otherwise, data are presented as n (%). The cumulative incidence of events is presented as Kaplan-Meier estimates. ^AAdjusted variables included age, sex, body mass index, dyslipidemia, current smoking, previous history of MI, previous history of PCI, initial clinical presentation, eGFR, previous use of aspirin, previous use of P2Y₁₂ inhibitor, the use of a P2Y₁₂ inhibitor, β-blocker, and/or ACE inhibitor or ARB at discharge, the number of anastomosis, the use of the left internal mammary artery, the use of another arterial graft, and the use of a saphenous vein graft. BARC, Bleeding Academic Research Consortium; CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Prognostic Effects of 12-Month DAPT According to Type of Surgical Conduit (Arterial Only vs. Combination Arterial/SVG)

Among the total study population, graft patency was evaluated in 1,138 (47.2%) patients during the follow-up period, using coronary computed tomography angiography (n=672) or invasive coronary angiography (n=466). In patients undergoing CABG with arterial grafts only, the incidence of graft failure was numerically lower in the ≥12-month DAPT than SAPT group, but the difference was not statistically significant (Figure 3). In patients undergoing CABG using arterial grafts and SVG, there was a similar rate of graft failure between the ≥12-month DAPT and SAPT groups. There was no significant interaction between the use of DAPT for ≥12 months and the type of graft vessels used for the risk of all-cause death or MI (P for interaction=0.492). In patients treated with arterial grafts only, ≥12-month DAPT was associated with a significantly lower incidence and risk of all-cause death or MI at 5 years than SAPT (7.0% vs. 13.6%, respectively; HR 0.45; 95% CI 0.24–0.84; P=0.013). In patients treated with CABG using arterial grafts and SVG, there was also a significant difference in all-cause death or MI at 5 years between the ≥12-month DAPT and SAPT groups (8.7% vs. 17.0%, respectively; HR 0.42; 95% CI 0.19–0.95; P=0.036; Table 4).

Figure 3.

Study flowchart: subgroup analysis according to the type of surgical conduits used. DAPT, dual antiplatelet therapy; hs-CRP, high-sensitivity C-reactive protein; SAPT, single antiplatelet therapy.

Table 4.

Comparison of 5-Year Risk of Clinical Outcomes According to the Type of Surgical Conduits Used

	DAPT ≥12 months	SAPT	Univariate analysis			Multivariate analysis^A
	DAPT ≥12 months	SAPT	HR	95% CI	P value	HR	95% CI	P value
Arterial grafts only (n=1,951)	389	1,562
All-cause death or MI	16 (7.0)	100 (13.6)	0.46	0.27–0.78	0.004	0.45	0.24–0.84	0.013
All-cause death	12 (5.8)	92 (11.7)	0.38	0.21–0.69	0.001	0.34	0.17–0.69	0.003
Cardiovascular death	5 (2.6)	45 (6.1)	0.32	0.13–0.82	0.017	0.32	0.11–0.94	0.039
MI	4 (1.2)	8 (1.0)	1.44	0.43–4.78	0.554	3.07	0.34–8.08	0.321
Stroke	14 (5.8)	28 (3.3)	1.50	0.79–2.85	0.217	2.42	0.86–6.85	0.095
BARC Type 3–5 bleeding	5 (1.5)	31 (3.0)	0.53	0.21–1.38	0.194	0.78	0.26–2.36	0.653
Arterial graft and SVG (n=458)	156	302
All-cause death or MI	8 (8.7)	27 (17.0)	0.37	0.17–0.81	0.013	0.42	0.19–0.95	0.036
All-cause death	5 (5.4)	27 (17.0)	0.23	0.09–0.59	0.002	0.27	0.10–0.73	0.009
Cardiovascular death	3 (3.1)	13 (9.0)	0.29	0.08–1.00	0.050	0.45	0.12–1.64	0.226
MI	4 (4.1)	1 (0.4)	5.12	0.57–45.99	0.145	5.41	0.55–52.69	0.146
Stroke	3 (3.0)	8 (3.9)	0.55	0.14–2.07	0.374	0.72	0.18–2.92	0.648
BARC Type 3–5 bleeding	7 (4.7)	9 (3.9)	1.32	0.49–3.56	0.584	2.32	0.79–6.79	0.125

Unless indicated otherwise, data are presented as n (%). The cumulative incidence of events is presented as Kaplan-Meier estimates. ^AAdjusted variables included age, sex, dyslipidemia, previous history of PCI, eGFR <60 mL/min/1.73 m², previous use of aspirin, the use of a P2Y₁₂ inhibitor and/or ACE inhibitor or ARB at discharge, the use of the left internal mammary artery, and the use of an other artery graft. ^BAdjusted variables included age, body mass index, dyslipidemia, previous history of PCI, clinical presentation, previous use of P2Y₁₂ inhibitor, the use of a β-blocker at discharge, and off-pump coronary artery bypass grafting. Abbreviations as in Tables 1,3.

The beneficial effects of DAPT for ≥12 months were consistent across various patient or procedural characteristics, without significant interaction in patients undergoing CABG using arterial grafts or a combination of arterial grafts and SVG (Figure 4). However, in patients undergoing CABG using arterial grafts only, there was a significant interaction between antiplatelet treatment strategy (≥12-month DAPT vs. SAPT) and the type of CABG (OPCAB vs. CABG using cardiopulmonary bypass) for the risk of all-cause death or MI (P for interaction=0.003).

Figure 4.

Comparative unadjusted hazard ratios (HRs) of cardiovascular death or myocardial infarction (MI) at 5 years for different subgroups according to the type of graft vessel used: (A) arterial grafts only; (B) arterial grafts and saphenous vein grafts (SVG). CABG, coronary artery bypass grafting; CI, confidence interval; LV, left ventricular; PCI, percutaneous coronary intervention.

Discussion

We investigated the prognostic effect of ≥12-month DAPT after CABG on long-term clinical outcomes in patients with baseline serum hs-CRP >2.0 mg/L using a large, dedicated, recent, real-world CABG registry. Our main finding was that DAPT for ≥12 months after CABG can reduce the risk of all-cause death or MI in patients with a high inflammatory risk, as reflected by baseline serum hs-CRP, compared with SAPT, regardless of sex, comorbidity, or type of surgical grafts used. The association between DAPT for ≥12 months and long-term prognosis in CABG patients with serum hs-CRP >2.0 mg/L was maintained after PS-matched analysis and was consistent across various subgroups.

The management of inflammation for secondary prevention in patients undergoing CABG remains infrequent. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS)¹⁵ convincingly showed that among patients with prior MI and hs-CRP ≥2.0 mg/L, treatment with a monoclonal antibody targeting interleukin-1β was associated with fewer cardiovascular events. Although that study only dealt with patients undergoing invasive intervention for MI, the findings provide direct evidence that inflammation could potentially induce recurrence of cardiovascular events and therefore needs to be addressed. Antiplatelet therapy is a cornerstone of secondary prevention for acute or long-term cardiovascular events in patients with ischemic heart disease. The benefits of antiplatelet agents have mainly been attributed to their anti-inflammatory off-target effects, as well as their direct anti-aggregative effects.¹⁹ In particular, patients treated with CABG often experience potential inflammation and may benefit from potent and prolonged antiplatelet therapy after the index procedure for secondary cardiovascular prevention. Mangano et al. reported that early initiation of aspirin after CABG significantly reduced ischemic mortality compared with no antiplatelet therapy.²⁰ Previous randomized controlled trials have evaluated the effect of P2Y₁₂ inhibitors in addition to aspirin on SVG patency, yielding conflicting findings.²¹^,²² Background or residual inflammation can predict adverse clinical outcomes in patients undergoing CABG,²³ and may inform clinical decisions or indicate the usefulness of a particular treatment strategy after CABG by providing sufficient antiplatelet therapy to control inflammation, as well as long-term cardiovascular outcomes.

Current guidelines recommend that P2Y₁₂ inhibitors should be resumed after CABG to complete 12 months of DAPT in patients with acute coronary syndrome (Class IC recommendation). The effectiveness of DAPT after CABG has been discussed in several studies, but, to date, clinical evidence is lacking as to which patients would benefit and to what extent DAPT needs to be performed.⁴^,⁸^,²⁴ In the present study, we evaluated the prognostic impact of potent and prolonged DAPT after CABG on long-term clinical outcomes in patients with a high inflammatory risk, as evidenced by hs-CRP, using long-term follow-up data from a large, dedicated, real-world CABG registry. Our principal finding was that the use of DAPT for ≥12 months after CABG was associated with significantly lower all-cause death or MI compared with the use of SAPT in patients with baseline serum hs-CRP levels >2.0 mg/L. In addition, DAPT treatment had beneficial effects regardless of the type of surgical conduit used (arterial grafts vs. a combination of arterial grafts and SVG). Surgeons generally have concerns that the use of DAPT after CABG may increase the risk of perioperative bleeding complications; however, contrary to these concerns, we identified that there was no significant difference in postoperative BARC Type 3–5 bleeding risk between the ≥12-month DAPT and SAPT groups. PS analysis from a Danish administrative database demonstrated that in patients with acute MI, aspirin plus clopidogrel after CABG was associated with a significantly lower risk of death or MI than the use of aspirin alone over a mean follow-up of 466 days.²⁵ Although that study evaluated patients presenting with MI with a short-term follow-up,²⁵ their results corresponded well with our findings.

Interestingly, in our subgroup analyses, we found no interaction between the efficacy of DAPT for ≥12 months and the type of CABG conduit used (arterial grafts only vs. arterial grafts and SVG). In addition, in patients undergoing OPCAB using arterial grafts only, ≥12-month DAPT reduced the 5-year risk of all-cause death or MI compared with SAPT. Previous studies have shown that using aspirin or clopidogrel alone after CABG yielded comparable results to DAPT in the context of surgical graft patency.²⁰ However, until now, the specific benefits of DAPT use have not been evaluated in CABG patients.²¹^,²² Our study assessed the association between ≥12-month DAPT use and long-term clinical outcomes in CABG patients with higher potential inflammation (high inflammatory risk reflected by baseline hs-CRP).

For patients with multivessel coronary disease who require CABG and have atherosclerotic risk, the prognostic implications of DAPT cannot be overlooked. While awaiting the results of other inflammation-targeted trials, it is conceivable that there may be paradigm shift in the treatment of atherosclerosis and cardiovascular disease.²⁶^,²⁷ We hope that our results can serve as a reminder of the usefulness of DAPT for ≥12 months in CABG patients with high inflammatory risk. Further well-designed randomized trials are warranted and need to be continuously monitored.

Study Limitations

This study has several limitations. First, this was a non-randomized retrospective observational study, which may have introduced confounding factors or selection bias that could significantly affect the results. The choice of surgical technique and the concomitant use of perioperative medications were at the discretion of individual operators, leading to variability. Although sensitivity analyses, including multivariable Cox regression and PS matching, were conducted to mitigate potential confounders, unmeasured variables remained unadjusted. In addition, the study included patients from a single center only, limiting the generalizability of the findings. Second, due to the retrospective nature of our registry, the reason for selecting specific antiplatelet therapies, initiating SAPT or DAPT, or making changes to postoperative medical treatment during the follow-up period could not be comprehensively identified for all study patients. In addition, factors and characteristics related to infections, connective tissue diseases, or non-specific inflammation were not adequately covered in the data, limiting our ability to ascertain their role in observed prognostic differences. Third, graft patency could not be evaluated in all subjects during the follow-up period due to the institution’s policy of not conducting routine follow-up coronary angiography or coronary computed tomography angiography after CABG. Fourth, the role of new potent P2Y₁₂ inhibitors (ticagrelor and prasugrel) could not be evaluated due to their low prescription rates in the study cohort. Fifth, time bias may have been introduced due to significant changes in the use of DAPT over the years of registry enrollment. However, no significant interaction was observed between the use of DAPT for ≥12 months and the year of enrollment with respect to all-cause death or MI during follow-up in both patient groups. Sixth, our registry included a higher number of patients with unstable angina compared with previous CABG registries, possibly due to enrollment occurring before the development of high-sensitivity troponins. Seventh, adherence to medical treatment was not considered in the present analysis, which could be a limitation. Eighth, the prevalence of unstable angina in our study population was higher than in other CABG registries,²⁸^,²⁹ potentially limiting the generalizability of the findings to populations with less severe disease. Finally, the high rates of complete arterial graft and OPCAB seen in the hospital and the low rates of periprocedural MI may have been influenced by racial differences or underestimation, further limiting the generalizability of our results.

Conclusions

In patients with baseline serum hs-CRP >2.0 mg/L, the use of DAPT for ≥12 months was associated with a significantly lower incidence of all-cause death or MI compared with SAPT after CABG. Although postoperative bleeding complications were more frequent in the ≥12-month DAPT than SAPT group, there was no significant difference in the long-term risk of BARC Type 3–5 bleeding, regardless of sex, comorbidity, or type of surgical conduit used. Based on our results, ≥12-month DAPT after CABG has the potential to improve long-term clinical outcomes in patients with a high inflammatory risk. Further investigation into the potential therapeutic implications of these findings should be considered, including considerations for individual patient risk profiles and strategies to mitigate bleeding complications associated with DAPT for ≥12 months.

Acknowledgments

None.

Sources of Funding

This study did not receive any specific funding.

Disclosures

The authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Institutional Review Board of the Samsung Medical Center (Approval no. 2019-02-086-011).

Data Availability

The deidentified participant data will not be shared.

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