Study population
The CBDBANK (Cardiovascular Centre Beijing Friendship Hospital Database Bank) consecutively enrolled patients diagnosed with ACS in the Department of Cardiology of Beijing Friendship Hospital. Patients with ACS (ST-segment elevation myocardial infarction [STEMI], non-ST-segment elevation myocardial infarction [NSTEMI], and unstable angina [UA]) were diagnosed based on relevant guidelines[19, 20]. A total of 8,022 patients were diagnosed with ACS and underwent PCI from January 2013 to January 2021. Of the 8,022 patients, 2,706 patients were excluded according to the exclusion criteria, which were (1) lack of GA, FPG, or follow-up data; (2) severe liver dysfunction (alanine ≥ 5 times the upper reference limits), severe renal insufficiency (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73m2), or kidney replacement treatment; (3) severe acute infection or malignancy; (3) previous coronary artery bypass grafting (CABG), cardiogenic shock (defined as systolic blood pressure [SBP] < 90 mmHg for ≥ 30 min or catecholamines to maintain SBP > 90 mmHg, clinical pulmonary congestion and impaired end-organ perfusion [altered mental status, cold/clammy skin and extremities, urine output < 30 ml/h, or lactate > 2.0 mmol/L], or a class IV rating according to the Killip classification), or heart failure (left ventricular ejection fraction [LVEF] < 30%). Finally, 5,316 patients were included in this study (Fig. 1). The study was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University, and was in accordance with the Declaration of Helsinki.
Treatment And Procedure
The coronary angiography and PCI operation were implemented according to relevant guidelines[21]. All patients received a 300 mg loading dose of aspirin, a 300 to 600 mg loading dose of clopidogrel (or 180 mg of ticagrelor), and 70–100 IU/kg unfractionated heparin. PCI was performed using 6 or 7 Fr guiding catheters via radial or femoral artery approach according to the standard techniques by experienced cardiologists. Patients were treated with predilatation and new-generation drug-eluting stents whenever possible. Standard medication after PCI was continued before discharge, including the maintenance dose of aspirin (100 mg/day), clopidogrel (75 mg/day) or ticagrelor (180 mg/day), statin, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), and beta-blockers.
Assessment Of Stress Hyperglycemia
Overnight fasting venous blood samples were drawn from patients and immediately transferred to the central laboratory (Beijing Friendship Hospital) for testing GA and FPG using standard laboratory techniques. The GA levels were represented as a percentage of GA concentration in total albumin. Stress hyperglycemia was defined by the glucose/GA ratio [16], which was calculated by using the following equation: glucose/GA ratio = FPG (mmol/L)/GA (%). The patients were divided into 4 by quartiles of glucose/GA ratio (Q1 < 0.334, Q2 = 0.334–0.384, Q3 = 0.385–0.442, Q4 > 0.442) for further analyses.
Follow-up And Outcome
Relevant information regarding cardiovascular events during hospitalization was confirmed based on their medical records. Clinical follow-up was performed at 1, 6, and 12 months, and every year after discharge by telephone interview or outpatient follow-up. The primary endpoint was all-cause mortality during hospitalization and over the follow-up period. Cardiovascular (CV) mortality was a secondary outcome. CV death was defined as death caused by stroke, AMI, heart failure, or documented sudden cardiac death.
Covariates
Baseline characteristics including demographic information (age, gender), medical history, lifestyles (smoking and drinking status [none, ever, current], body mass index [BMI]), laboratory results, and in-hospital therapy were collected from hospital records. Medical history included diabetes, hypertension, dyslipidemia, previous coronary heart disease, and chronic kidney diseases were identified according to the self-reported history of diagnosis. Criteria for diabetes include: (1) previously diagnosed diabetes under treatment of antidiabetic medication; (2) the typical symptoms of diabetes with an FPG ≥ 7.0 mmol/L, and/or random blood glucose ≥ 11.1 mmol/L, and/or 2-h blood glucose after oral glucose tolerance test ≥ 11.1 mmol/L. Hypertension was defined as SBP ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg three times on different days, and/or under antihypertensive treatments.
Overnight fasting blood samples were obtained and tested for total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride, high-density lipoprotein cholesterol (HDL-C), hemoglobin, albumin, high-sensitivity C-reactive protein (hs-CRP), cardiac troponin I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and creatinine in the central laboratory by standard methods. Dyslipidemia was defined as TC > 5.18 mmol/L (200 mg/dL), LDL-C > 3.37 mmol/L (130 mg/dL), triglyceride > 1.72 mmol/L (150 mg/dL), HDL-C < 1.0 mmol/L (40 mg/dL), and/or previous use of lipid-lowering agents. The eGFR was calculated using the MDRD (The Modification of Diet in Renal Disease) formula: eGFR (mL/min/1.73 m2) = 175 × (Scr)−1.154 × (Age)−0.203 × (0.742 if female) × (1.212 if African American) [22]. Echocardiograms were performed by expert cardiologists or certified sonographers, and the LVEF was assessed using the Simpsons method. Medications were obtained directly from the medical records, including aspirin, clopidogrel or ticagrelor, β-blocker, ACEI or ARB, and statins.
Statistical analysis
Continual variables were presented as means and standard deviation (SD) or median (interquartile interval), and were compared by one-way ANOVA or Kruskal-Wallis H test. Categorical variables were reported as frequency (percentage), and compared by chi-square or Fisher exact test.
Person-years were calculated from baseline to the date of death or loss to follow-up, or the end of follow-up (31 March 2021), whichever came first. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for glucose/GA ratio quartiles and mortality. We used three models that were progressively adjusted for confounders known to influence the prognosis of ACS. Model 1 was adjusted for age, gender, and BMI. Model 2 included Model 1 variables plus smoking status, diabetes, hypertension, dyslipidemia, previous myocardial infarction, previous PCI, previous stroke, and AMI. Model 3 included Model 2 variables plus left main coronary artery or three‑vessel disease, eGFR, SBP, heart rate, LVEF < 50%, hs-CRP, albumin, hemoglobin, ACEI/ARB at discharge, and β-blocker at discharge. Adjusted survival curves were performed based on the multivariable Cox regression (Model 3) for describing all-cause and CV mortality according to the glucose/GA ratio categories [23]. We additionally utilized restricted cubic splines based on Cox models to depict detailed descriptions of the dose-response curves between glucose/GA ratio and all-cause mortality as well as CV mortality [24]. The restricted cubic splines were fitted with 4 knots placed at the 5th, 35th, 65th, and 95th percentiles across the range of glucose/GA ratio. The Wald tests were used to evaluate the statistical significance (at the 0.05 level) of the overall association and for the nonlinearity of the risk curves. To explore the joint effects of diabetes and glucose/GA ratio in predicting event rates, we determined the incidence rate within each subgroup defined by glucose/GA ratio categories and diabetes status (with or without). Lastly, subgroup analyses were conducted to evaluate the association between glucose/GA ratio and mortality according to diabetes status.
Analysis was performed using Stata software, version 17.0 (StataCorp LP, College Station, TX, USA), and R software, version 4.1.2 (R Foundation for Statistical Computing). A 2-sided P-value < 0.05 was considered to be statistically significant.