Effect factors of the death in heart failure with mildly reduced ejection fraction and establishment of predictive model
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摘要: 目的 探讨射血分数轻度降低的心力衰竭(HFmrEF)全因死亡的影响因素，通过长期随访数据构建列线图模型，用于预测患者1年、2年、3年期的全因死亡率。方法 顺序入选2014年4月—2019年3月山西省3所三级甲等医院诊治的慢性心力衰竭且射血分数为41%~49%的患者1 148例进行随访，以全因死亡为终点事件，随访截止日期为2022年4月1日。将所有研究对象按7：3比例随机分为训练集和验证集，训练集用于模型的构建，验证集用于模型性能的评估。利用Cox回归分析患者全因死亡的影响因素，R 4.3.1用于构建列线图预测模型。采用一致性指数(C-index)、受试者工作特征曲线下面积(AUC)和校正曲线评价模型的区分度和预测性能，通过临床决策曲线(DCA)评估模型的临床潜在应用价值。根据ROC曲线确定的最佳截断阈值对患者进行死亡风险分层，并采用Kaplan-Meier曲线比较高风险组和低风险组患者之间的生存差异。结果 多因素Cox回归分析显示，住院费用全自付(HR=4.722，95%CI：2.544~8.765)、入院NYHA心功能Ⅳ级(HR=2.982，95%CI：1.507~5.898)、N末端脑钠肽前体(对数值)[lg(NT-proBNP)]水平升高(HR=2.360，95%CI：1.414~3.938)、合并心房颤动(HR=2.321，95%CI：1.419~3.797)增加患者全因死亡风险；高估算肾小球滤过率(eGFR)水平(HR=0.984，95%CI：0.973~0.995)、服用血管紧张素转换酶抑制剂/血管紧张素Ⅱ受体拮抗剂(ACEI/ARB)药物(HR=0.320，95%CI：0.191~0.535)及接受经皮冠状动脉介入治疗/冠状动脉旁路移植术(PCI/CABG)治疗(HR=0.503，95%CI：0.264~0.958)降低患者全因死亡风险。依此构建的列线图模型经测试集验证，C-index为0.839，1年、2年、3年生存期预测模型的AUC分别为0.864、0.860、0.857。校正曲线和DCA曲线结果显示，模型预测效果和实际生存情况拟合度较好，具有较好的临床适用性。风险分层能够有效区分高、低危患者的预后。结论 基于医保类型、NYHA心功能分级、NT-proBNP、eGFR、心房颤动、ACEI/ARB类药物及PCI/CABG治疗7个因素构建的列线图预测模型有助于高风险HFmrEF患者早期识别与治疗决策指导。
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关键词:
- 射血分数轻度降低的心力衰竭 /
- 全因死亡 /
- 影响因素 /
- 列线图 /
- 预测模型
Abstract: Objective To explore the effect factors of the death of heart failure with mildly reduced ejection fraction(HFmrEF), and to construct a nomogram model based on long-term follow-up data to predict the all-cause mortality of patients at 1 year, 2 years and 3 years.Methods A total of 1148 patients with chronic heart failure and ejection fraction of 41%-49% who were diagnosed and treated in three tertiary-level A hospitals in Shanxi Province from April 2014 to March 2019 were sequentially enrolled for follow-up, with all-cause death as the endpoint event, and the deadline for follow-up was April 1, 2022. All study subjects were randomly divided into a training set and a validation set in a 7: 3 ratio; the training set was used for model construction, and the validation set was used for model performance evaluation. Cox regression was used to analyze the factors influencing all-cause mortality in patients, and R 4.3. 1 was used to construct the column-line graph prediction model. The consistency index(C-index), the area under the working curve(AUC) of subjects, and calibration curves were used to evaluate the discriminatory and predictive performance of the model, and the clinical potential application value of the model was assessed by the clinical decision curve(DCA). Based on the optimal cut-off threshold determined by the ROC curve, the patients were stratified by death risk, and the Kaplan-Meier curves were used to compare the survival differences between the patients in the high-risk and low-risk groups.Results Multifactorial Cox regression analysis showed that self-paying(HR=4.722, 95%CI: 2.544 to 8.765), admission the New York Heart Association class Ⅳ(HR=2.982, 95%CI: 1.507 to 5.898), elevated of N-terminal brain natriuretic peptide precursor(Logarithmic value) [lg(NT-proBNP)]levels(HR=2.360 with 95%CI: 1.414 to 3.938), and combined atrial fibrillation(HR=2.321, 95%CI: 1.419 to 3.797) increased the risk of all-cause mortality in patients; high estimated glomerular filtration rate(eGFR) levels(HR=0.984, 95%CI: 0.973 to 0.995), and the use of angiotensin-converting enzyme inhibitors or angiotensin receptor antagonist(ACEI/ARB) medications(HR=0.320, 95%CI: 0.191~0.535) and receiving percutaneous coronary intervention or coronary artery bypass grafting(PCI/CABG) treatments(HR=0.503, 95%CI: 0.264~0.958) reduced the risk of all-cause mortality in patients. The C-index of the column-line graph model constructed accordingly was 0.839, and the AUCs of the 1-, 2-, and 3-year survival prediction models were 0.864, 0.860, and 0.857, respectively, and the calibration curves suggested that the model prediction effect was basically in line with the actual survival situation, and the DCA curves indicated that the model had good clinical applicability. Risk stratification can effectively distinguish the prognosis of high-and low-risk patients.Conclusion Based on these 7 factors(medical insurance type, NYHA classification, NT-proBNP, eGFR, atrial fibrillation, ACEI/ARB drugs, and PCI/CABG treatment), the nomogram is helpful for the early identification and treatment decision-making guidance of high-risk HFmrEF patients. -
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图 1 HFmrEF患者预后生存预测列线图
Figure 1. Nomogram of prognostic survival prediction in patients with HFmrEF
图 4 HFmrEF预测模型的临床决策曲线
Figure 4. Clinical decision curves of the HFmrEF prediction model
图 5 根据模型预测风险分层的Kaplan-Meier曲线
Figure 5. Kaplan-Meier curves for predicting risk stratification based on the model
表 1 两组患者基线资料的比较
Table 1. basic data between two groups
例(%), M(P25, P75) 项目 存活组(1 037例) 死亡组(111例) χ2/Z P值 一般资料 年龄/岁 67(59，76) 76(69，81) -7.526 < 0.001 男性 747(72.03) 68(61.26) 5.651 0.017 职业 12.413 < 0.001 体力劳动 369(35.58) 21(18.92) 非体力劳动 668(64.42) 90(81.08) 医保类型 13.954 < 0.001 城镇医保 636(61.33) 70(63.06) 新型农村合作医保 298(28.74) 19(17.12) 全自费 103(9.93) 22(19.82) 吸烟史 11.851 < 0.001 未吸烟 385(37.13) 23(20.72) 戒烟 148(14.27) 21(18.92) 吸烟 504(48.60) 67(60.36) 饮酒史 270(26.04) 18(16.22) 5.145 0.023 NYHA心功能分级 63.941 < 0.001 Ⅱ 453(43.68) 22(19.82) Ⅲ 394(38.00) 33(29.73) Ⅳ 190(18.32) 56(50.45) 心率/(次/min) 73(66，81) 73(68，80) -0.493 0.622 收缩压/mmHg△ 130(116，140) 130(112，149) -0.798 0.425 舒张压/mmHg 80(70，85) 78(68，85) -0.822 0.411 体重指数/(kg/m2) 24.28(22.23，26.93) 23.59(20.93，25.59) -2.982 0.073 合并症 糖尿病 337(32.50) 41(36.94) 0.895 0.344 高血压 601(57.96) 77(69.37) 5.402 0.020 心脏瓣膜病 83(8.00) 15(13.51) 3.898 0.048 冠状动脉粥样硬化性心脏病 831(80.14) 87(78.38) 0.193 0.660 COPD 180(17.36) 33(29.73) 10.156 < 0.001 脑卒中 210(20.26) 47(42.34) 28.164 < 0.001 肾功能不全 105(10.13) 25(22.52) 15.346 < 0.001 房颤 229(22.08) 56(50.45) 43.235 < 0.001 实验室指标 lg(NT-proBNP)/(pg/mL) 3.03(2.67，3.43) 3.51(3.25，3.81) -9.328 < 0.001 胱抑素C/(mg/L) 1.11(0.98，1.40) 1.30(1.08，1.79) -4.743 < 0.001 eGFR/[mL/min/(1.73m2)] 90.70(72.87，109.29) 67.17(51.43，84.91) -8.012 < 0.001 尿酸/(μmol/L) 370(314，435) 393(329，474) -2.070 0.038 血清总胆固醇/(mmol/L) 4.04(3.38，4.81) 4.04(3.36，4.79) -0.158 0.875 甘油三酯/(mmol/L) 1.41(1.04，1.85) 1.33(1.01，1.76) -1.184 0.236 HDL-C/(mmol/L) 0.99(0.84，1.14) 0.99(0.84，1.15) -0.282 0.778 LDL-C/(mmol/L) 2.43(1.93，3.05) 2.44(1.88，3.09) -0.115 0.908 红细胞分布宽度/% 13.94(13.40，14.70) 14.50(13.90，15.45) -5.122 < 0.001 血红蛋白/(g/L) 137(125，149) 132(118，142) -3.815 < 0.001 ALT/(U/L) 20.80(14.00，33.00) 18.00(12.00，25.00) -3.055 0.052 AST/(U/L) 27.00(21.00，41.00) 24.87(20.00，35.79) -1.839 0.066 白蛋白/(g/L) 43.00(40.00，46.00) 40.30(37.15，43.20) -5.147 < 0.001 血清总胆红素/(mmol/L) 14.70(11.20，19.36) 15.95(11.40，20.48) -1.046 0.295 血钾/(mmol/L) 4.07(3.82，4.34) 4.11(3.79，4.42) -0.694 0.487 血钠/(mmol/L) 139.00(138.00，141.00) 139.00(137.50，141.50) -0.078 0.938 心电图 QRS间期/ms 98(90，112) 98(90，115) -0.960 0.337 QTC间期/ms 440(418，468) 448(422，477) -1.721 0.085 心脏彩超 室间隔厚度/mm 9(8，11) 10(9，11) -1.801 0.072 左室舒张末期内径/mm 56(52，59) 55(51，59) -0.345 0.730 左室后壁厚度/mm 9(9，10) 9(8，11) -0.750 0.453 左室射血分数/% 45(43，47) 44(42，46) -1.424 0.155 治疗情况 抗血小板药物 957(92.29) 94(84.68) 7.488 0.006 硝酸酯类药物 705(67.98) 77(69.37) 0.089 0.766 β受体阻滞剂 246(23.72) 22(19.82) 0.853 0.356 ACEI/ARB 609(58.73) 27(24.32) 48.029 < 0.001 他汀类药物 961(92.67) 96(86.49) 5.255 0.022 利尿剂 833(80.33) 91(81.98) 0.175 0.676 正性肌力药物 120(11.57) 17(15.32) 1.337 0.248 PCI/CABG 376(36.26) 14(12.61) 24.993 < 0.001 注：△1 mmHg=0.133 kPa。COPD：慢性阻塞性肺疾病；HDL-C：高密度脂蛋白胆固醇；LDL-C：低密度脂蛋白胆固醇；ALT：丙氨酸氨基转移酶；AST：门冬氨酸氨基转移酶。 
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表 2 HFmrEF患者全因死亡影响因素的单因素和多因素Cox回归分析
Table 2. Univariate and multivariate Cox regression analysis of influencing factors of all-cause mortality in patients with HFmrEF
变量 单因素Cox回归分析 多因素Cox回归分析 HR 95%CI P HR 95%CI P 年龄 1.059 1.035~1.083 < 0.001 男性 0.649 0.442~0.953 0.027 职业：体力劳动 1.796 1.058~3.048 0.003 医保类型 城镇医保 参考值 参考值 新型农村医疗合作医保 0.672 0.374~1.208 0.184 1.519 0.690~3.345 0.299 全自费 2.137 1.200~3.714 0.008 4.722 2.544~8.765 < 0.001 吸烟史 未吸烟 参考值 戒烟 1.090 0.493~2.408 0.832 吸烟 1.167 0.980~2.835 0.059 饮酒史 0.551 0.291~1.043 0.067 NYHA心功能分级 Ⅱ 参考值 Ⅲ 1.716 0.911~3.230 0.094 1.569 0.816~3.015 0.177 Ⅳ 5.294 2.935~9.550 < 0.001 2.982 1.507~5.898 0.002 lg(NT-proBNP) 4.924 3.258~7.441 < 0.001 2.360 1.414~3.938 0.001 eGFR 0.976 0.968~0.985 < 0.001 0.984 0.973~0.995 0.006 胱抑素C 1.164 1.008~1.344 0.039 血红蛋白 0.985 0.975~0.995 0.002 红细胞分布宽度 1.089 1.015~1.167 0.017 白蛋白 0.958 0.932~0.985 0.003 高血压 1.313 0.313~2.118 0.265 心脏瓣膜病 1.571 0.755~3.270 0.227 房颤 3.609 2.300~5.663 < 0.001 2.321 1.419~3.797 0.001 COPD 2.526 1.729~3.690 < 0.001 脑卒中 2.015 1.337~3.038 0.001 肾功能不全 2.535 1.620~3.967 < 0.001 抗血小板药物 0.426 0.230~0.790 0.007 ACEI/ARB 0.304 0.187~0.497 < 0.001 0.320 0.191~0.535 < 0.001 他汀类药物 0.513 0.264~0.997 0.049 PCI/CABG 0.345 0.186~0.639 0.001 0.503 0.264~0.958 0.037
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