The DACAB trial was a prospective, multicenter, randomized trial. Briefly summarized, 500 patients from six Chinese tertiary hospitals were randomized to ticagrelor 90 mg twice daily plus aspirin 100 mg once daily, ticagrelor alone 90 mg twice daily, or aspirin alone 100 mg once daily for 1-year open-label antiplatelet therapy after CABG between July 2014 and November 2015. The primary outcome was 1-year vein graft patency at the graft level. The trial design and eligibility criteria have been published previously (18). In this secondary analysis, patients who had LDL-C and Lp(a) measured at baseline and LDL-C repeatedly measured during the follow-up period were pooled. Thus, 459 patients in the DACAB trial formed the present analysis. This study was approved by the independent institutional review board of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

Baseline LDL-C and Lp(a) were obtained when patients were admitted to the participating hospitals. Repeated measurements of LDL-C were required at 1, 3, 6, and every 12 months after CABG. The average value of these LDL-C levels during the follow-up was used to represent the postoperative LDL-C level. The patients were stratified into LDL-C <1.8, 1.8–<2.6, and ≥2.6 mmol/L subgroups. We adopted the sequential thresholds from the 2016 European Guidelines on cardiovascular prevention in consideration of the study period (19). Lp(a) was evaluated by an immunoturbidimetric method according to the manufacturer's instructions with a normal value of <30 mg/dL; thus, the patients were classified into Lp(a) <30 and ≥30 mg/dL subgroups. We did not repeat Lp(a) measurement for the reason that Lp(a) was considered genetically determined by LPA gene and the concentration remained relatively stable and was refractory to lifestyle and drugs including statins (20).

The primary outcome was 4-point MACE, composed of all-cause death, myocardial infarction (MI), stroke, and repeated revascularization (MACE-4). Secondary outcomes included MACE-3 and MACE-5. MACE-3 was composed of cardiovascular death (CV death), MI, and stroke. MACE-5 was composed of all-cause death, MI, stroke, repeated revascularization, and rehospitalization for unstable angina. All-cause death included cardiovascular and non-cardiovascular death. CV death was referred to any death caused by cardiovascular cause and any death that had no identified reason. MI was composed of ST-segment elevation MI (STEMI) or non-STEMI (NSTEMI). Stroke was defined as new focal neurological deficit lasting >24 h and adjudicated by a neurologist based on image records. Patients were contacted at 1, 3, 6, and every 12 months after surgery. All end point events were adjudicated and reviewed by the independent adjudication committee. Antiplatelet therapy was prescribed according to the randomization for the first year, and then other secondary prevention medications were prescribed based on recommendation from the latest guidelines. Information about the use of secondary prevention medication was updated every 3 months during the first year after CABG.

Continuous variables were expressed as mean with standard deviation (SD) or median with interquartile range (IQR). Categorical variables were presented as frequencies with percentages. Continuous variables were compared by using Student's t-test or one-way ANOVA and categorical variables were examined by using Fisher's exact test or Chi-squared test. The results of time-to-event analyses were carried out by using the Kaplan–Meier estimates, and the log-rank test was used to calculate the statistical difference. Cox proportional hazards model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). These models were adjusted for traditional cardiovascular risk factors and statistically significant variables in the subgroup comparisons. All analyses were performed by using SAS version 9.4 (SAS Institute Inc.). All statistical tests were two-sided and P values <0.05 were considered statistically significant.

These patients were stratified into three groups according to the baseline LDL-C levels. Clinical characteristics among the three groups were compared. Patients with increased baseline LDL-C were tended to be younger, more associated with on-pump CABG and less prescribed with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at discharge. Increased baseline LDL-C levels were associated with lower prevalence of previous MI and hypertension (Table 1). There was no loss to follow-up. MACE-4 was observed in 133 (29.0%) patients, including 41 cases (30.4%) in the LDL-C <1.8 mmol/L group, 59 (29.1%) in the LDL-C 1.8–<2.6 mmol/L group, and 33 (27.3%) in the LDL-C ≥2.6 mmol/L group. Compared with the baseline LDL-C <1.8 mmol/L group, the risk of MACE-4 was not statistically different in the LDL-C 1.8–<2.6 mmol/L (HR = 0.90, 95% CI, 0.61–1.35; P = 0.620) and ≥2.6 mmol/L groups (HR = 0.86, 95% CI, 0.54–1.36; P = 0.521) (Figure 1). After adjusted for multiple covariates including age, gender, comorbidities, baseline Lp(a), secondary prevention medication, on-pump surgery, and the use of internal mammary artery (IMA), compared with patients with baseline LDL-C <1.8 mmol/L, the HR for MACE-4 occurrence was 0.82 (95% CI, 0.51–1.33; P = 0.613) for patients with LDL-C 1.8–<2.6 and 0.90 (95% CI, 0.60–1.35; P = 0.426) for patients with LDL-C ≥2.6 mmol/L.

The results of MACE-3 and MACE-5 yielded similar trends (Figure 1). Compared with the baseline LDL-C <1.8 mmol/L group, the adjusted HR for MACE-3 was 0.82 (95% CI, 0.51–1.33) and 0.80 (95% CI, 0.46–1.37) for the LDL-C 1.8–<2.6 and ≥2.6 mmol/L groups, respectively, and the adjusted HR for MACE-5 was 0.86 (95% CI, 0.58–1.28) and 0.78 (95% CI, 0.49–1.25; all P > 0.05), respectively.

According to the follow-up protocol, repeated measurement of LDL-C levels at 1, 3, 6, and every 12 months after CABG was accomplished. The average LDL-C value of each patient was calculated and the patients were stratified into three groups by referring to the same thresholds. The attainment of LDL-C target <1.8 mmol/L following CABG was accomplished in 129 (28.1%) patients, 186 (40.5%) achieved LDL-C 1.8–<2.6 mmol/L, and 144 (31.4%) remained with LDL-C ≥2.6 mmol/L. Most characteristics were comparable, except that patients with increased postoperative LDL-C were younger, lower male gender, and more associated with on-pump CABG (Table 1). MACE-4 was reported in 18 (14.0%) patients with LDL-C <1.8 mmol/L, 49 (26.3%) with LDL-C 1.8–<2.6 mmol/L, and 66 (45.8%) with LDL-C ≥2.6 mmol/L. Compared with the postoperative LDL-C <1.8 mmol/L group, the risk of MACE-4 was higher for patients with LDL-C 1.8–<2.6 and ≥2.6 mmol/L. The crude HRs were 1.96 (95% CI, 1.14–3.86; P = 0.015) and 3.86 (95% CI, 2.29–6.50; P < 0.001) (Figure 2). After adjusted for age, gender, comorbidities, baseline LDL-C, Lp(a), secondary prevention medication, on-pump surgery, and use of IMA, the HRs for MACE-4 occurrence were 1.92 (95% CI, 1.12–3.29; P = 0.019) and 3.90 (95% CI, 2.29–6.64; P < 0.001) for LDL-C 1.8–<2.6 and ≥2.6 mmol/L groups, when compared with the LDL-C <1.8 mmol/L group. Postoperative LDL-C ≥2.6 mmol/L was mainly associated with increased risk of MI and stroke (all P < 0.05), but not in all-cause death and repeated .revascularization (all P > 0.05) compared with LDL-C <1.8 mmol/L (Figure 2).

The results of MACE-3 and MACE-5 were similar (Figure 3). Compared with patients with postoperative LDL-C <1.8 mmol/L, the adjusted HR for MACE-3 was 1.86 (95% CI, 1.00–3.45; P = 0.048) and 3.61 (95% CI, 1.98–6.58; P < 0.001) for patients with LDL-C 1.8–<2.6 and LDL-C ≥2.6 mmol/L; the adjusted HR for MACE-5 was 1.85 (95% CI, 1.09–3.14; P = 0.023) and 3.65 (95% CI, 2.17–6.14; P < 0.001), respectively.

In this study cohort, Lp(a) ranged from 1 to 138 mg/dL, with a median level of 17 mg/dL (interquartile range, 9–31 mg/dL). The distribution of Lp(a) was skewed and Lp(a) ≥30 mg/dL was identified in 131 (28.5%) patients (Figure 4). Most baseline characteristics between the two groups were comparable, except that patients with Lp(a) ≥30 mg/dL had a lower prevalence of hypertension (Table 2). MACE-4 was detected in 47 patients in the Lp(a) ≥30 mg/dL group and in 86 in the Lp(a) <30 mg/dL group. As shown by the Kaplan–Meier curves, compared with the Lp(a) <30 mg/dL group, patients with Lp(a) ≥30 mg/dL had a higher incidence of MACE-4 (35.9% vs. 26.2%; P = 0.024) with a crude HR of 1.50 (95% CI, 1.05–2.14; P = 0.025) (Figure 5). The adjusted HR (aHR) (adjusted for age, gender, comorbidities, baseline LDL-C, secondary prevention medication, on-pump surgery, and use of IMA) was 1.52 (95% CI, 1.06–2.18; P = 0.022) for MACE-4. The increased risk of MACE-4 was mainly due to the increased risk of MI in the Lp(a) ≥30 mg/dL group (22.1% vs. 13.4%, HR = 1.73, 95% CI, 1.09–2.77; P = 0.021). No significant difference was found concerning the risk of all-cause death (11.5% vs. 6.7%, HR = 1.77, 95% CI, 0.92–3.42; P = 0.087), stroke (5.3% vs. 6.1%, HR = 0.89, 95% CI, 0.38–2.10; P = 0.787), and repeated revascularization (4.6% vs. 5.5%, HR = 0.85, 95% CI, 0.34–2.15; P = 0.738) between the two groups (Figure 5).

Similarly, Lp(a) ≥30 mg/dL was associated with increased risk of MACE-3 (29.0% vs. 19.5%, aHR = 1.62, 95% CI, 1.08–2.44; P = 0.019) and MACE-5 (35.9% vs. 26.8%, aHR = 1.49, 95% CI, 1.04–2.14; P = 0.028) (Figure 6).

Information about statin use was updated every 3 months during the first year after CABG. A total of 437 (95.2%) patients were reported to be dispensed with statins constantly and 22 patients discontinued the use of statin. Baseline characteristics between the two groups were compared. Poor 1-year statin adherence was observed more in patients with increased postoperative LDL-C levels, receiving dual antiplatelet therapy, and less use of IMA (Supplementary Table S1). MACE-4 occurred in 10 (45.5%) patients with poor adherence and 123 (28.1%) patients with good adherence. The crude HR for MACE-4 was 2.03 (95% CI, 1.07–3.88; P = 0.031) (Supplementary Figure S1). Poor 1-year statin adherence was associated with increased MACE-4 events with an adjusted HR of 2.32 (95% CI, 1.19–4.52; P = 0.013). Increased risk of MACE-4 was mainly due to the increased risk of all-cause death (22.7% vs. 7.3%, HR = 3.92, 95% CI, 1.52–10.09; P = 0.005) (Supplementary Figure S2). Poor 1-year statin adherence was also related with enhanced risk of MACE-5 (50.0% vs. 28.4%, aHR = 2.62, 95% CI, 1.38–4.98; P = 0.003), but not with MACE-3 (31.8% vs. 21.7%, aHR = 2.04, 95% CI, 0.93–4.51; P = 0.077) (Supplementary Figure S1).

There were several limitations in our research that should be taken into account. First, due to prospective observational study essence, bias could not be avoided and additional confounding factors might not be detected and adjusted, but our research was based on a well-conducted randomized trial, and LDL-C and Lp(a) levels were prospectively collected. Second, we did not evaluate the long-term adherence of statins and did not investigate the utilization of ezetimibe or PCSK9 inhibitor during the follow-up, but statin monotherapy predominated as the mode of lipid management in this cohort and the first PCSK9 inhibitor was not approved by the Chinese CFDA until 2018. Third, Lp(a) was reported in mass concentration instead of particle concentration, which might lead to over- or underestimation of the true Lp(a) burden due to the size heterogeneity of the apo(a) component. Fourth, other lipid profiles including triglyceride levels were not collected and investigated in this current analysis. Fifth, this secondary analysis was based on the Chinese population; a cautious interpretation is warranted when the results were generalized to other ethnic groups.