A score to predict the occurrence of very late stent thrombosis in patients treated by percutaneous coronary intervention for acute coronary syndrome

<b>Study population</b> From January 1, 2014 to June 1, 2015, a total of 6,038 consecutive ACS patients who were admitted to Jilin University 1^st hospital for PCI treatment and met the basic inclusion and exclusion criteria were enrolled . The primary endpoint was definite stent thrombosis. We exclude patients who died prior to discharge (n=236), did not agree to take part in the follow-up interview (n=413), or were lost to follow-up after discharge (n=204). The median length of follow-up was 1,502 days. The external validation cohort included 2,438 consecutive patients admitted to the first affiliated hospital of Shantou University for PCI from January 1, 2014 to January 1, 2015 with the same inclusion and exclusion criteria. We exclude patients who died prior to discharge (n=88), did not agree to take part in the follow-up interview (n=186), or were lost to follow-up after discharge (n=106). The median length of follow-up was 1422 days. Ethics committee approval was obtained for all investigational sites, and the study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All patients gave written informed consent. <b>Definition of VLST</b> VLST was defined according to the 2007 definition of Academic Research Consortium (ARC) stent thrombosis criteria: stent thrombosis that occured more than one year after coronary stent implantation and was clearly confirmed by coronary angiography (CAG). <b>Statistical Analysis</b> Data are summarized as number (percentages) for categorical variables. Continuous variables are expressed as mean±SD. Categorical data were compared using the Chi-square test or Fisher exact tests while quantitative data were compared using the Mann–Whitney U test. All tests were 2-sided at the 0.05 significance level. The derivation cohort was used to identify predictors of occurrence of VLST and to establish a risk-scoring system which was verified in the validation cohort. The significant variables (p&lt;0.05) in univariable cox regression analysis and independent risk factors reported in previous literature were included in the multivariate cox regression analysis, and the optimal predictive variables of VLST were obtained by backward stepwise method. Some variables, such as leukocyte count (there is no sufficient evidence to completely exclude the possibility of infection and other factors that leading to its increase) are not included in the final model. Procedural variables such as stent diameter, length, type, and post-dilation were based on the operator's consideration during PCI. Multicollinearity between the variables in the final model was assessed by calculation of the variance inflation factor. These corrected coefficients of significant predictors in the final model were then divided by the lowest coefficient value and rounded to the nearest integer to assign a weight to each predictor. Total score of each patient was calculated by adding these weights together. An objective assessment of calibration was obtained by performing the Hosmer–Lemeshow goodness-of-fit test and by plotting observed vs. predicted incidence rate across deciles of risk score. The predictive performance of the risk model was assessed by the c-statistic and was cross-validated (leave one out method) in the development cohort. Clinical usefulness was evaluated using decision curve analysis. Statistical analysis was performed with the use of Statistical Package for Social Sciences version 23 (SPSS, Chicago, IL, USA) and R version 3.5.0 (R Foundation for Statistical Computing, Vienna, Austria) using the packages rms.

**研究人群** 2014年1月1日至2015年6月1日，纳入吉林大学第一医院收治的6038例连续急性冠状动脉综合征（Acute Coronary Syndrome, ACS）患者，所有患者均接受经皮冠状动脉介入治疗（Percutaneous Coronary Intervention, PCI）且符合基本纳入排除标准。本研究的主要终点为明确的支架血栓形成。排除标准如下：出院前死亡者（n=236）、不同意参与随访访谈者（n=413），以及出院后失访者（n=204）。本研究的中位随访时间为1502天。外部验证队列纳入2014年1月1日至2015年1月1日汕头大学第一附属医院收治的2438例连续PCI治疗患者，其纳入排除标准与前述队列一致。同样排除出院前死亡者（n=88）、不同意参与随访访谈者（n=186）及出院后失访者（n=106），该队列的中位随访时间为1422天。本研究所有研究中心均获得伦理委员会批准，研究实施符合1964年《赫尔辛基宣言》及其后续修订版的伦理标准，所有患者均签署书面知情同意书。

**极晚期支架血栓形成（Very Late Stent Thrombosis, VLST）的定义** VLST参照2007年学术研究联合会（Academic Research Consortium, ARC）制定的支架血栓判定标准定义：冠状动脉支架植入术后1年以上发生，且经冠状动脉造影（Coronary Angiography, CAG）明确证实的支架血栓。

**统计学分析** 分类变量以例数（百分比）进行总结，连续变量以均值±标准差（mean±SD）表示。分类数据比较采用卡方检验或Fisher确切概率法，定量数据比较采用Mann-Whitney U检验。所有检验均为双侧检验，检验水准设定为0.05。本研究使用推导队列识别极晚期支架血栓发生的预测因素，并建立风险评分系统，该系统在验证队列中得到验证。将单因素Cox回归分析中P<0.05的变量及既往文献报道的独立危险因素纳入多因素Cox回归分析，采用向后逐步法筛选得到VLST的最优预测变量。部分变量未纳入最终模型，例如白细胞计数：尚无充分证据可完全排除感染及其他导致其升高的相关因素。手术相关变量（如支架直径、长度、类型及后扩张操作）由术者在PCI术中自行决定。通过计算方差膨胀因子评估最终模型中变量间的多重共线性。将最终模型中显著预测因子的校正系数除以最小系数值，并四舍五入至最接近的整数，为每个预测因子赋予相应权重。通过对各权重求和计算每位患者的总评分。采用Hosmer-Lemeshow拟合优度检验及按风险评分十分位数分组的观察值与预测发生率绘图，对模型的校准度进行客观评估。采用C统计量评估该风险模型的预测性能，并在开发队列中采用留一法进行交叉验证。采用决策曲线分析评估模型的临床实用性。本研究统计学分析采用SPSS 23.0版本（SPSS，美国伊利诺伊州芝加哥市）及R 3.5.0版本（奥地利维也纳R统计计算基金会），并使用rms数据包。