The Association Between SYNTAX Score and Long-term Outcomes in Patients With Unstable Angina Pectoris: a Single-center Retrospective Study

Background: SYNTAX Score affects clinical outcomes in early studies, whether SYNTAX Score could predict long-term outcomes in patients with unstable angina pectoris (UAP) in the era of new generation drug-eluting stent was unclear, and differences by SYNTAX Score in long-term outcomes between the medical therapy and percutaneous coronary intervention (PCI) in UAP patients were not well known. Methods (cid:0) In this single-center retrospective study, a total of 2,364 patients with UAP from January 2014 to June 2017 at Beijing Friendship Hospital were enrolled. The primary endpoint was a composite of major adverse cardiovascular events (MACE) , including all-cause death, cardiac death, nonfatal myocardial infarction (MI) and stroke after at least 2 year from discharge. Results (cid:0) In this study, 1,695 patients had low SYNTAX score (<22) , 432 patients had medium SYNTAX score (22-32), and 237 patients had high SYNTAX score ( ≥ 33), and 1,018 received medical therapy, 1,346 patients underwent PCI. Long-term MACE occurred in 95 patients during 3.38 ± 0.99 years follow up. Cox multivariate regression analysis showed advanced age, diabetes mellitus, heart failure, chronic kidney disease (CKD) and high SYNTAX score were independent predictors for MACE in the medical therapy group (P < 0.05), while, heart failure and CKD were predictors of MACE in PCI group. Compared to medical therapy group, PCI group showed lower MACE and cardiac death in patients with high SYNTAX score ( ≥ 33) (7.4% vs. 16.7%, P = 0.048; 3.7% vs 14.6%, P = 0.004), but no reduction in patients with low- and medium SYNTAX score. Conclusions (cid:0) High SYNTAX score could predict long-term MACE for UAP patients with medical therapy, but not for patients undergoing PCI. Compared to medical therapy, PCI could signicantly reduced long-term MACE and cardiac death for patients with high SYNTAX score.


Introduction
In recent decades, coronary heart disease (CHD) remains a major cause of mortality in worldwide, especially in developing countries.
The Synergy between Percutaneous Coronary Intervention with TAXus and Cardiac Surgery (SYNTAX) score was a tool to measure the complexity of coronary lesions, and has been recommended for the risk strati cation and treatment decision making for untreated left main trunk or three-vessel coronary heart disease (CHD). Previous studies con rmed that higher SYNTAX score was related to the worse short-term and long-term prognosis of patients with CHD [1][2] . However, in the era of new generation drug-eluting and advanced medicine treatment, whether SYNTAX Score could predict long-term MACE in CHD patients undergoing medical therapy or PCI is unclear.
Moreover, although coronary revascularization can improve the prognosis of medium and high risk patients with unstable angina pectoris (UAP) in early studies [3][4][5][6][7] , most risk scoring systems, such as GRACE and TIMI score, include clinical indicators, not considering characteristic of coronary artery disease. Using SYNTAX score to assess differences in long-term outcomes between medical therapy and PCI have seldom been found. So, we investigated the long-term outcomes in patients with UAP who underwent medical therapy or PCI.

Population
The present research was a single-center, retrospective, observational study. Data came from UAP patients database of Cardiovascular Center Beijing Friendship Hospital Database Bank (CBDBANK), which includes UAP patients treated from January 2014 to June 2017 in the Department of Cardiology, Beijing Friendship Hospital. All eligible patients were more than 18 years old, and had symptoms of angina as well as at least a ≥ 50% luminal stenosis in vessels ≥ 1.5 mm con rmed by coronary angiography.
UAP was diagnosed according to the criteria of the European Society of Cardiology guidelines [8] . Patients were excluded if they had previous percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) which could affect the accuracy of SYNTAX score. Severe anemia, coronary artery bridge, coronary artery spasm, malignant tumor and incomplete information were also exclusion criteria.
The treatment strategy was decided by physician according to coronary angiography, and coronary ow reserve fraction (FFR) or optical coherence tomography (OCT) or intravascular ultrasound (IVUS) were performed in borderline coronary lesions to decide the treatment. All patients were given secondary prevention medicine during hospitalization and after discharge, and were followed up by telephone regularly. According to the nal treatment method, patients were divided into two groups: the medical therapy group or the PCI group. This research was performed according to guidelines set by the Helsinki Declaration and was approved by the ethics commission of the institutional review board of Beijing Friendship Hospital.

Data Collection
The following data were retrospectively collected from the CBDBANK: (1) demographic factors and cardiovascular risk factors, including sex, age, family history of CHD, smoking, hypertension, diabetes mellitus, dyslipidemia, stroke, peripheral arterial disease (PAD), heart failure; (2) laboratory data at admission including hemoglobin, and fasting plasma glucose (FPG), serum lipids, serum creatinine, BMI, and left ventricular ejection fraction (LVEF). (3) calculation of SYNTAX score: using the SYNTAX score calculator (available at http://www.syntaxscore.com), two experienced interventional cardiologists retrospectively calculated the SYNTAX score according to the diagnostic angiograms obtained prior to PCI. The total score was calculated by adding up all individual scores for each separate lesion with a stenosis diameter ≥50% in a vessel ≥1.5 mm in diameter by visual assessment. SYNTAX score were categorized as low SYNTAX score (≤22), medium SYNTAX score (23-32) and high SYNTAX score (≥33).

Study de nitions
Hypertension was de ned as having a previous diagnosis of hypertension or diagnosed in-hospitalization. Diabetes mellitus was having a previous diagnosis of diabetes mellitus or diagnosed in-hospitalization. Dyslipidemia was de ned as having a history of hyperlipidemia, or the total cholesterol (TC) ≥5.2 mmol/L, or low-density lipoprotein cholesterol (LDL-C) ≥3.4 mmol/L, or triglyceride(TG)≥1.7 mmol/L, or high density lipoprotein cholesterol (HDL-C) <1.0 mmol/L on admission. Hyperuricemia was serum uric acid concentration >420 µmol/L in males and >360 µmol/L in females [9] . Patients who used to smoke or currently smoke were considered to be smokers. Family history of CHD was any immediate family member (parents, siblings) having CHD. Stroke was having a ≥24h ischemic or hemorrhagic cerebrovascular event con rmed by a neurologist. Peripheral arterial disease was was de ned as having a previous diagnosis of peripheral arterial disease (including carotid artery, subclavian artery, lower extremity arterial disease). Heart failure (HF) was having a previous diagnosis of HF or left ventricular ejection fraction (LVEF) <50% on admission. Chronic kidney disease (CKD) was de ned as an eGFR <60 ml/min/1.73 m2. The estimated glomerular ltration rate (eGFR) was calculated based on the Chronic Kidney Disease Epidemiology Collaboration creatinine equation [10] . Body mass index (BMI) was determined by dividing the patients' weight in kilograms by the square of the patients' height in meters.

The endpoint
The primary endpoint was a composite of MACE, which included all-cause death, cardiac death, nonfatal myocardial infarction (MI) and stroke after at least 2 year from discharge. The secondary endpoint was all-cause death and cardiac death. Predictors of longterm MACE were also analyzed, and comparisons between medical therapy and the PCI at each SYNTAX score risk strati cation were performed.

Statistical analysis
Continuous data, expressed by mean ± SD, and comparisons between between 2 groups were analyzed using the unpaired Student's t test or Wilcoxon test, and comparisons of continuous variables among multiple groups were analyzed using 1-way analysis of variance. Categorical data, expressed by numbers and percentages, were compared using the chi-square test, or Fisher's exact test in cases with cell values <5. Kaplan-Meier method was adopted to estimate long -term outcomes among multiple groups and compared by the log-rank test. Cox proportional hazards regression used to identify MACE predictors, and all variables with a P < 0.1 in the univariate analysis were used to carry out the multivariate analysis. A two-side P < 0.05 was considered to be statistically signi cant. SPSS version 17.0 (SPSS, Chicago, IL,USA) was applied to conduct all analyses.

Difference in baseline characteristics among SYNTAX score groups
In this study, the mean SYNTAX score was 17.53 ± 10.61 (range: 2-66), and 1,695 (71.7%) patients had low SYNTAX score, 432 (18.3%) patients had a medium SYNTAX score and 237 (10%) patients had a high SYNTAX score. The baseline characteristics according to SYNTAX score risk strati cation were presented in Table 1. The mean age, and prevalence of smoking, diabetes, previous MI, heart failure, and the mean level of FPG, LDL-C and Hs-CRP were signi cantly higher in patients with medium-and high-SYNTAX score than those with low SYNTAX score (all P < 0.05). There were no differences in hypertension, family history of CHD, prior stroke, peripheral arterial disease, atrial brillation, and the mean level of BMI, TG, TC and serum uric acid among patients with low-medium-and high-SYNTAX score (all P < 0.05). No differences in baseline clinical characteristics were existed between patients with medium SYNTAX score and those with high SYNTAX score, apart from more male patients in high SYNTAX score (P > 0.05, Table 1).

PCI versus medical therapy in baseline characteristics
Compared to patients in medical therapy group, patients in PCI group had more cardiovascular risk factors and comorbidities: the frequencies of male patients, smoking, diabetes, previous myocardial infarction, and the level of FPG, triglyceride, total cholesterol, LDL-C, and serum uric acid were notably higher (all P < 0.05). In contrast, the mean age, atrial brillation and the level of HDL-C in the PCI group were lower than in medical therapy group (all P < 0.05). There were no differences in hypertension, family history of CHD, prior stroke, peripheral arterial disease, heart failure, CKD, the mean level of BMI between PCI group and medical therapy group (all P > 0.05, Table 2). The PCI group had higher incidence of medium-and high-SYNTAX score compared to medical therapy group ( 26.1% vs 8.0%; 14.0% vs 4.7%, P < 0.05, Table 2).
Comparisons of long-term MACE by SYNTAX score and treatment In medical therapy group, the incidence of long-term MACE in patients with low-, medium-and high-SYNTAX score were 2.8%, 2.5%, 16.7%, and the all-cause mortality was 2.0%, 2.5%, 14.6%, and the cardiac mortality was 0.8%, 1.2%, 14.6%, respectively (Table 4).
Kaplan-Meier analysis showed that long-term MACE, all-cause mortality and cardiac mortality in patients with high SYNTAX score was higher than those of low-and medium-SYNTAX score in medical therapy group (all P <0.01, Figure 2 A-C).
In PCI group, the incidence of long-term MACE in low-, medium-and high-SYNTAX score were 4.0%, 4.0%, 7.4%, and the all-cause mortality was 2.6%, 2.6% , 6.9% and the cardiac mortality was 1.6%, 1.1%, 3.7%, respectively. Kaplan-Meier analysis showed the allcause mortality in patients with high SYNTAX score was higher than those of low-and medium-SYNTAX score (P < 0.05, Figure 3 B), while, no differences in long-term MACE and cardiac death were discovered among patients with low-, medium-and high-SYNTAX score in PCI group (P > 0.05, Figure 3 A, C).
The overall MACE showed no difference between medical therapy group and PCI group (P > 0.05). According to SYNTAX score risk strati cation, there were no difference in long-term MACE, all-cause mortality, cardiac death, nonfatal MI and stroke between medical therapy group and PCI group with low-and medium-SYNTAX score (P > 0.05). However, in patients with high SYNTAX score, patients in medical therapy group showed higher MACE and cardiac death than patients in PCI group (P < 0.05) , whereas no differences in all-cause mortality, nonfatal MI and stroke were detected between medical therapy group and PCI group (P > 0.05, Table 4).

Discussion
In this study, the main observation were these: (1) male, advanced age, smoking, diabetes, heart failure, CKD, FPG, LDL-C and Hs-CRP were positively correlated with SYNTAX score, (2) a high SYNTAX score was a predictors for long-term MACE in medical therapy group, not in PCI group, (3) compared to medical therapy group, PCI could decline signi cantly the long-term MACE in patients with high SYNTAX score, but not reduction in long-term MACE in patients with low-and medium-SYNTAX score.
A series of studies reported that aging, male, diabetes mellitus and impaired renal function were independent predictors for high SYNTAX score [11][12][13][14] . Karadeniz M showed that increased hs-CRP were one of the strong predictors of high SYNTAX score in ACS patients [15] . Minamisawa M reported high SYNTAX score was associated with heart failure [16] . In this study, we found the cardiovascular risk factors of patients with medium SYNTAX score are similar to those with high SYNTAX score, and male, advanced age, smoking, diabetes, heart failure, CKD, FPG, LDL-C and Hs-CRP were positively correlated with SYNTAX score, which were consistent with the above conclusion. Despite the pathogenesis between SYNTAX score and heart failure or CKD are not clear, this result suggested that high SYNTAX score may be related to systemic atherosclerosis. Therefore, intensive management of cardiovascular risk factors, especially for glucose, eGFR and Hs-CRP, was important to prevent coronary atherosclerosis.
Previous reports demonstrated that patients with high SYNTAX score had worse prognosis, moreover, studies using SYNTAX scores reported its capacity to predict adverse events for patients undergiong PCI and the prognostic value of the SYNTAX score in all cause mortality was also shown at different points in time up to ve years after PCI [17][18][19][20] . This study reached the same conclusion that MACE was higher in patients with high SYNTAX sore in both medical therapy group and PCI group. However, this study showed that a high SYNTAX score (≥ 33) was an independent predictor for long-term MACE in the medical therapy group, but not in PCI group.
This result maybe related to the advancement of coronary intervention technology and stent in recently years. In addition, advanced age, diabetes mellitus were independent predictors for long-term MACE in the medical therapy group, but not in PCI group, which indicated PCI could decline long-term MACE in high risk UAP patients. We also discovered that heart failure and CKD were independent predictors for long-term MACE in both medical therapy group and PCI group. Accordingly, intensive management should be made in patients with heart failure or CKD.
Compared to medical treatment, PCI could improve short-term and long-term prognosis of patients with CHD, and CABG was better than PCI in patients with high SYNTAX score [1][2] . Recently, BARI-2D Trial demonstrated, among patients with diabetes and stable ischemic heart disease, 5-year MACE were not lower after PCI than medical therapy in patients with a low-or mid/high-SYNTAX score (17.8% vs. 19.2%, P = 0.84; 35.6% vs. 26.5%, p= 0.12) [21] . Moreover, Su CS et al reported that there was no difference in inhospital and long-term mortalities between CABG and PCI in patients with multivessel CHD [22] . In thus study, we found that PCI showed an advantage in regard to long-term MACE and cardiac death in patients with a high SYTAX score, but not declining longterm MACE among either patients with a low-or medium-SYNTAX score. The result was inconsistent with the BARI-2D Trial, which may be that patients with stable coronary heart disease and type 2 diabetes mellitus were enrolled in the BARI-2D Trial, and it did not compare clinical outcomes in patients with a high SYNTAX score. This nding also suggested patients with high SYNTAX scores bene t more from coronary revascularization.

Conclusions
First, a high SYNTAX score was an predictor for long-term MACCE in medical therapy group, but not in PCI group. Second, PCI could reduce MACE and cardiac death signi cantly for patients with high SYNTAX score compared to medical therapy after at least 2-year Page 6/13 from discharge.

Study Limitations
In our study, there were several limitations. First, this was a single-center, retrospective, observational study, and the result was less convincing than randomized controlled trials. Second, UAP patients received medical therapy or PCI were enrolled and patients undergoing coronary artery bypass grafting were not enrolled, so our ndings may not be representative for these patients. Third, SYNTAX score are only risk strati cation of anatomic features of coronary lesions and do not consider the degree of coronary stenosis and clinical factors, so patients with the same SYNTAX score may have different degrees of coronary stenosis, and the prognosis may be different. Finally, we focused on hard cardiac events in this study, so revascularization was not assessed as an outcome. Future studies should be carried out to examine these.     Comparison of MACE among SYNTAX Score in medical therapy group