Baseline features and population studied
Selected patients (204 patients) were diagnosed with SCAD for the first time (mean age, 72 years; male, 69%). The CRP and Alb concentrations of all patients were assessed at admission between October 2014 and October 2017. We divided patients into three equal groups according to the CAR. Eight patients without CAR noted were excluded from the study. Of the 196 remaining patients enrolled in the study, 66 patients were placed into the high-level CAR group, 65 patients were placed in the low-level CAR group, and 65 were placed in the middle-level CAR group. Table 1 summarizes the baseline clinical characteristics of the cohort. We found that in the group with the highest CAR, participants were generally older and had higher CRP concentrations but lower levels of eGFR, LVEF, HbAlc, and HDL-Chol. Moreover, there were no significant differences in medication history, coronary artery disease types, or concomitant diseases among these diverse groups. All participants were followed up for an average of 793.75 ± 430.26 days. During the follow-up period, 18 people died. Among them, 6 died of cardiovascular causes, 3 had a non-fatal myocardial infarction, and 11 had stroke events. Additionally, in order to assess the power of our study, we conducted post-hoc power analysis. Using GPower version 3.1.9.7, we showed that a sample size of 196 respondents yielded a power of 100%, an effect size (f) of 44.295, and a significance level of 0.05 (two-sided).
Table 1
Baseline Characteristics of participants (N = 196)
Variables | CAR | P-value |
| Low(n = 65) | Middle(n = 65) | High(n = 66) | |
Age (years) | 69.46 ± 9.92 | 74.03 ± 9.80 | 75.02 ± 9.88 | 0.003 |
Sex, male, n (%) | 48 (73.85%) | 45 (69.23%) | 43 (65.15%) | 0.558 |
BMI (kg/m2) | 23.40 ± 3.69 | 23.68 ± 3.88 | 23.61 ± 4.15 | 0.722 |
Past smoker, n (%) | 37 (56.92%) | 32 (49.23%) | 28 (42.42%) | 0.252 |
Hb(g/dL) | 14.23 ± 1.65 | 13.74 ± 2.30 | 12.73 ± 1.80 | < 0.001 |
ALB (g/dL) | 4.19 ± 0.34 | 3.94 ± 0.52 | 3.63 ± 0.56 | < 0.001 |
CRP (mg/dL) | 0.03 ± 0.01 | 0.12 ± 0.05 | 1.19 ± 1.60 | < 0.001 |
CAR, x100 | 0.24 ± 0.10 | 0.91 ± 0.34 | 9.93 ± 13.99 | < 0.001 |
eGFR(mL/min/1.73 m2) | 66.65 ± 22.43 | 59.37 ± 25.21 | 56.50 ± 25.92 | 0.013 |
AST (U/L) | 24.54 ± 10.15 | 23.78 ± 8.58 | 25.67 ± 13.82 | 0.859 |
ALT (U/L) | 22.09 ± 13.00 | 19.89 ± 9.99 | 20.56 ± 13.76 | 0.533 |
T-Chol (mg/dL) | 189.64 ± 33.65 | 189.28 ± 31.70 | 175.64 ± 40.46 | 0.066 |
HDL-Chol (mg/dL) | 53.84 ± 11.73 | 50.00 ± 14.68 | 46.06 ± 12.28 | 0.004 |
TG (mg/dL) | 130.03 ± 91.86 | 134.55 ± 84.80 | 131.98 ± 88.03 | 0.938 |
LDL-Chol (mg/dL) | 112.35 ± 24.95 | 110.12 ± 25.88 | 107.24 ± 33.36 | 0.597 |
HBA1c (%) | 6.26 ± 0.80 | 6.30 ± 0.92 | 6.24 ± 0.89 | 0.872 |
SBP (mmHg) | 137.12 ± 14.93 | 134.89 ± 21.80 | 137.27 ± 23.89 | 0.864 |
DBP (mmHg) | 78.38 ± 10.75 | 74.82 ± 14.32 | 79.24 ± 14.70 | 0.137 |
LVEF (%) | 65.63 ± 6.58 | 63.18 ± 9.92 | 60.80 ± 11.84 | 0.013 |
Basic Disease |
OCI, n (%) | 8 (12.31%) | 12 (18.46%) | 13 (19.70%) | 0.482 |
PAD, n (%) | 14(21.54%) | 16 (24.62%) | 20 (30.30%) | 0.505 |
AF, n (%) | 7 (10.77%) | 9 (13.85%) | 10 (15.15%) | 0.750 |
HT, n (%) | 50 (76.92%) | 47 (72.31%) | 49 (74.24%) | 0.832 |
DLP, n (%) | 36 (55.38%) | 29 (44.62%) | 31 (46.97%) | 0.434 |
DM, n (%) | 28 (43.08%) | 22 (33.85%) | 20 (30.30%) | 0.290 |
Lesional characteristics |
Multivessel lesions, n (%) | 17 (26.15%) | 18 (27.69%) | 16 (24.24%) | 0.903 |
Bifurcation lesions, n (%) | 39 (60.00%) | 28 (43.08%) | 30 (45.45%) | 0.112 |
LMT, n (%) | 3 (4.62%) | 6 (9.23%) | 4 (6.06%) | 0.557 |
Ostial lesions, n (%) | 10 (15.38%) | 10 (15.38%) | 8 (12.12%) | 0.827 |
Calcified lesions, n (%) | 4 (6.15%) | 13 (20.00%) | 11 (16.67%) | 0.062 |
CTO, n (%) | 7 (10.77%) | 2 (3.08%) | 3 (4.55%) | 0.151 |
Stent type | 0.028 |
BMS, n (%) | 7 (10.77%) | 0 (0.00%) | 4 (6.06%) | |
DES, n (%) | 58 (89.23%) | 65 (100.00%) | 62 (93.94%) | |
Medication |
Aspirin, n (%) | 65 (100.00%) | 64 (98.46%) | 65 (98.48%) | 0.606 |
Thienopiridines, n(%) | 63 (96.92%) | 65 (100.00%) | 65 (98.48%) | 0.360 |
Warfarin, n (%) | 3 (4.62%) | 1 (1.54%) | 1 (1.52%) | 0.434 |
DOAC, n (%) | 5 (7.69%) | 7 (10.77%) | 9 (13.64%) | 0.546 |
Ezetimibe, n (%) | 2 (3.08%) | 0 (0.00%) | 1 (1.52%) | 0.360 |
PPI, n (%) | 39 (60.00%) | 41 (63.08%) | 48 (72.73%) | 0.279 |
Stains, n (%) | 40 (61.54%) | 33 (50.77%) | 30 (45.45%) | 0.172 |
ACEI, n (%) | 7 (10.77%) | 5 (7.69%) | 7 (10.61%) | 0.800 |
ARB, n (%) | 25 (38.46%) | 25 (38.46%) | 36 (54.55%) | 0.100 |
Beta-blockers, n (%) | 12 (18.46%) | 23 (35.38%) | 17 (25.76%) | 0.090 |
MRA, n (%) | 1 (1.54%) | 6 (9.23%) | 4 (6.06%) | 0.160 |
Values are n(%) or mean ± SD. Abbreviations: BMI = body mass index, Hb = hemoglobin, Alb = serum albumin, CRP = C-reactive protein, CAR = CRP/Alb, eGFR = estimated glomerular filtration Ra, ALT = alanine aminotransferase, AST = aspartate transaminase, T-Chol = total cholesterol, TG = Triglyceride, HDL-Chol = high-density lipoprotein cholesterol, LDL-Chol = low density lipoprotein cholesterol, HbA1C = hemoglobin A1c, SBP = Systolic blood pressure, DBP = Diastolic blood pressure, LVEF = left ventricular ejection fraction, OCI = old cerebral infarction, PAD = peripheral artery disease, AF = Atrial fibrillation, HT = hypertension, DLP = Dyslipidemia, DM = diabetes mellitus, DOAC = direct oral anticoagulants, PPI = proton pump inhibitor, ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin-receptor blocker, MRA = mineralocorticoid receptor antagonist, BMS = bare metal stent, DES = drug-eluting stent, LMT = left main trunk lesions, CTO = chronic total occlusion. |
The association between CAR and the poor prognosis of SCAD
The univariate analysis results are reported in Table 2. Univariate analysis showed that age, BMI, Hb, LDL-Chol, CAR, PAD, and warfarin use were positively correlated with the poor prognosis of SCAD. Then the significant variables (P < 0.05) in univariate analysis and non-collinear variables (except collinear variables body weight and TC-Chol) were incorporated into the multivariate regression model. In this study, the Cox proportional hazard regression model was used to evaluate the association between CAR and the poor prognosis of SCAD. We evaluated the adjusted and unadjusted models separately (Table 3). In the crude model, there was a positive correlation between CAR and the poor prognosis of SCAD (HR = 1.03, 95% CI:1.01–1.06, P < 0.001), while the result of the minimum adjusting model (model I, adjusted for age, BMI, PAD) showed no significant changes compared to crude model (HR:1.03, 95% CI:1.01–1.05, P = 0.018). And after adjusting the full model (model II, adjusted for age, BMI, Hb, LDL-Chol, PAD, and warfarin), we could still see a positive correlation between them (HR = 1.03, 95% CI:1.01–1.06, P = 0.02). For the sensitivity analysis, we disposed of CAR as a categorical variable. In model II, we found that patients with a high CAR level increased the MACE risk by 2.76 times compared with a low CAR level (P for trend = 0.024). And in Kaplan–Meier analysis (Fig. 1), the long-term MACE-free survival rate of patients with high CAR levels decreased significantly (P = 0.015). Furthermore, the goodness of fit statistics of the two models were 235.158 and 216.411; respectively, the model II had the best model fit. And the C index for the two models were 0.751 and 0.79 (Table 4), which means that model I and model II predict each outcome fairly well.
Table 2
The results of univariate analysis.
Variables | HR (95%CI) | P-value |
Age | 1.06 (1.02,1.11) | 0.01 |
Sex(male) | 1.08 (0.49, 2.4) | 0.85 |
BMI | 0.83 (0.74,0.92) | < 0.01 |
Past smoker | 0.49 (0.22,1.08) | 0.08 |
Hb | 0.66 (0.55,0.79) | < 0.01 |
CAR, x100 | 1.03 (1.01,1.06) | < 0.01 |
eGFR | 0.99 (0.98,1.01) | 0.27 |
AST | 1.01 (0.98,1.04) | 0.59 |
ALT | 0.99 (0.95,1.02) | 0.49 |
HDL-Chol | 0.99 (0.96,1.02) | 0.53 |
TG | 1.00 (1.00,1.01) | 0.84 |
LDL-Chol | 0.98 (0.97,1.00) | 0.02 |
HBA1c | 1.20 (0.88,1.63) | 0.26 |
LVEF | 0.99 (0.95,1.02) | 0.47 |
OCI | 2.12 (0.93,4.81) | 0.07 |
PAD | 2.45 (1.16,5.16) | 0.02 |
AF | 2.06 (0.83,5.11) | 0.12 |
HT | 1.01 (0.43,2.38) | 0.98 |
DLP | 0.53 (0.25,1.16) | 0.11 |
DM | 0.65 (0.29,1.48) | 0.31 |
Aspirin | 0.15 (0.02,1.09) | 0.06 |
Thienopiridines | 0.63 (0.08,4.65) | 0.65 |
Warfarin | 4.60 (1.09,19.47) | 0.04 |
Stains | 0.68 (0.32,1.44) | 0.31 |
Multivessel lesions | 1.14 (0.50,2.58) | 0.76 |
Bifurcation lesions | 0.70 (0.33,1.49) | 0.36 |
Abbreviations: HR: Hazard ratio; CI: confidence intervals; other abbreviations as in Table 1. |
Table 3
Association between CAR and SCAD in different models.
Variable | Crude Model | | Model I | | Model II |
HR (95%CI) | P | | HR (95%CI) | P | | HR (95%CI) | P |
CAR | 1.03 (1.01,1.06) | < 0.001 | | 1.03 (1.01,1.05) | 0.018 | | 1.03 (1.01,1.06) | 0.020 |
CAR(percentage) | | | | | | | | |
Low | Reference | | | Reference | | | Reference | |
Middle | 1.26 (0.39,4.14) | 0.700 | | 1.1 (0.33, 3.63) | 0.880 | | 0.93 (0.26,3.31) | 0.100 |
High | 3.32 (1.21,9.07) | < 0.001 | | 2.89 (1.04,8.02) | < 0.01 | | 2.76 (0.96,7.92) | 0.060 |
P for trend | | 0.011 | | | 0.021 | | | 0.024 |
Crude model: we did not adjust other Variables; Model I adjust for: age, BMI and PAD; Model II adjusts for age, BMI, Hb, LDL-Chol, PAD, and Warfarin; Abbreviations: HR: Hazard ratio; CI: confidence intervals; P = P-value. |
Table 4. Goodness-of-fit statistics and discrimination
of the two multivariable cox regression models.
Model diagnostic measure | Model I | Model II |
Goodness of fit | | |
-2log likelihood | 235.158 | 216.411 |
Discrimination | | |
C index | 0.751 | 0.79 |
C index: concordance index. |
Analysis of nonlinear relationships between CAR and the poor prognosis of SCAD
In this present research, CAR was a continuous variable; we also used the GAM to identify the nonlinear relationship between CAR and the poor prognosis of SCAD. Figure 2 represents a curvilinear relationship (adjusted for age, BMI, Hb, LDL-Chol, PAD, and warfarin) between the MACE risk of CAR and SCAD. The inflection point of CAR calculated by the two-piecewise linear regression model was 3.933 (log-likelihood ratio test P = 0.02). As we anticipated, there was a positive correlation between CAR on the left side of the inflection point (CAR ≤ 3.933) and poor prognosis of SCAD (HR:1.48, 95% CI:1.10–1.99, P = 0.009). On the right hand of the inflection point (CAR > 3.933), the positive correlation between the two tends to be saturated (HR:1.01, 95% CI:0.97–1.05, P = 0.64; Table 5).
Table 5
The result of the two-piecewise linear regression model.
| MACE (HR,95%CI) | P-value |
Fitting model by standard linear regression | 1.03 (1.01, 1.06) | 0.02 |
Fitting model by two-piecewise linear regression |
The inflection point of CAR | 3.933 | |
≤3.933 | 1.48 (1.10, 1.99) | 0.009 |
>3.933 | 1.01 (0.97, 1.05) | 0.64 |
P for log-likelihood ratio test | | 0.02 |
The model I and Modle II adjusted age, BMI, Hb, LDL-Chol, PAD, and Warfarin. Abbreviations: MACE: major adverse cardiovascular events; HR: Hazard ratio; CI: confidence intervals. |
We further explored other risks that could contribute to the association between CAR and MACE in patients with SCAD, and estimated the factors that might affect the results by using subgroup analysis. Here, we used age, BMI, Hb, LDL-Chol, and PAD as stratified variables; each stratification was adjusted according to all the stratification factors, except for the stratification factor itself. The Cox proportional hazard model was used to explore the robustness of the results of each subgroup, and the effects of these variables were observed (Table 6). Through the likelihood ratio test of the interaction between subgroups, we noted no statistical significance for any stratified variables (P for interaction > 0.05). These results further support the stable independent association between CAR and poor prognosis of SCAD.