硝苯地平和美托洛尔对心脏病的治疗效果

doi:10.6040/j.issn.1671-7554.0.2024.1469

摘要/Abstract

摘要： 目的利用真实世界医疗数据,针对心脏病患者研究硝苯地平和美托洛尔药物在主要心血管事件、全因死亡和药源性肝损伤中的作用。方法基于齐鲁全生命周期电子研究型数据库(Cheeloo Lifespan Electronic Health Research Data-library,Cheeloo LEAD),选取2012年1月1日至2022年12月31日期间首次诊断为心脏病的患者作为研究对象,采用倾向性评分匹配的新使用者队列设计,开展真实世界研究。通过大规模L1正则化倾向性评分方法进行协变量匹配,实现拟随机化处理,采用Cox比例风险回归模型评估硝苯地平(暴露组)和美托洛尔(对照组)分别对主要心血管事件、全因死亡和药源性肝损伤的平均因果效应。结果男性心脏病患者更易出现主要心血管事件、全因死亡和药源性肝损伤。L1正则化倾向性评分匹配后,协变量标准化差异全部在0.2以下且绝大部分在0.1以下,暴露组和对照组的生存曲线无明显交叉。药源性肝损伤与全因死亡的发生率在组间比较中,log-rank检验结果均具有统计学意义(P<0.05)。此外,使用硝苯地平的患者在随访期内的累积生存率高于使用美托洛尔的患者。Cox比例风险回归模型显示,硝苯地平较美托洛尔对药源性肝损伤风险更低(HR=0.39,95%CI:0.16~0.93,P=0.025)且具有更低的全因死亡风险(HR=0.53,95%CI:0.28~0.98,P=0.034),未发现硝苯地平和美托洛尔预防主要心血管事件的效果差异(HR=1.30,95%CI:0.97~1.90,P=0.061)。结论相较于美托洛尔,硝苯地平可降低心脏病患者的全国死亡风险,且其药源性肝损伤的风险更低,本研究结果可以为心脏病患者安全用药提供补充证据,尤其可为评估药源性肝损伤风险提供参考。

关键词: 硝苯地平, 美托洛尔, 主要不良心血管事件, 药源性肝损伤, 真实世界研究, 倾向性评分, 平均因果效应

Abstract: Objective To investigate the effects of nifedipine and metoprolol on major cardiovascular events, all-cause mortality, and drug-induced liver injury in patients with heart disease using real-world data. Methods Based on Cheeloo Lifespan Electronic Health Research Data-library(Cheeloo LEAD), a real-world study was conducted through a new user cohort design matched by a propensity score, including patients who were first diagnosed with heart disease between January 1, 2012 and December 31, 2022. A large-scale L1 regularized propensity score was used to match covariates and achieve quasi-randomization. The Cox proportional hazards regression model was then employed to assess the average causal effects of nifedipine(exposure group)and metoprolol(control group)on major cardiovascular events, all-cause mortality, and drug-induced liver injury, respectively. Results Men with heart disease were more likely to have major cardiovascular events, all-cause mortality, and drug-induced liver injury. Following the implementation of L1 regularized propensity score matching, the standardized differences of covariates were found to be less than 0.2, with the majority falling below 0.1, and the Kaplan-Meier survival curve revealed no discernible crossover between the exposed group and the control group. The log-rank tests for both drug-induced liver injury and all-cause mortality revealed statistically significant differences between groups(both P<0.05). Furthermore, the cumulative survival rate of patients who received nifedipine during the follow-up period was higher than that of patients who received metoprolol. The Cox proportional hazard regression model showed that nifedipine had a lower risk of drug-induced liver injury(HR=0.39, 95%CI: 0.16-0.93, P=0.025)and all-cause mortality(HR=0.53, 95%CI: 0.28-0.98, P=0.034)than metoprolol, no significant difference was observed between nifedipine and metoprolol in the prevention of major cardiovascular events(HR=1.30, 95%CI: 0.97-1.90, P=0.061). Conclusion Nifedipine may reduce the risk of all-cause mortality in patients with heart disease compared to metoprolol and is associated with a lower risk of drug-induced liver injury. These results provide supplementary evidence to support the safe usage of medications in patients with heart disease, particularly a reference for assessing the risk of pharmacogenetic liver injury.

Key words: Nifedipine, Metoprolol, Major adverse cardiovascular events, Drug-induced liver injury, Real-world research, Propensity score, Average causal effect

中图分类号:

R453

吕明阅,孙汉辰,罗清馨,徐朝珂,徐瑞泽,张硕,严鲁宁,胡锡峰,赵青波,朱高培,薛付忠. 硝苯地平和美托洛尔对心脏病的治疗效果[J]. 山东大学学报 (医学版), 2025, 63(9): 1-10.

LYU Mingyue, SUN Hanchen, LUO Qingxin, XU Zhaoke, XU Ruize, ZHANG Shuo, YAN Luning, HU Xifeng, ZHAO Qingbo, ZHU Gaopei, XUE Fuzhong. Therapeutic effect of nifedipine and metoprolol on heart disease[J]. Journal of Shandong University (Health Sciences), 2025, 63(9): 1-10.

参考文献

[1] Woodruff RC, Tong X, Khan SS, et al. Trends in cardiovascular disease mortality rates and excess deaths, 2010-2022[J]. Am J Prev Med, 2024, 66(4): 582-589.
[2] Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice(constituted by representatives of 10 societies and by invited experts)developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation(EACPR)[J]. Eur Heart J, 2016, 37(29): 2315-2381.
[3] Andrade RJ, Isabel Lucena M, Kaplowitz N, et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry[J]. Hepatology, 2006, 44(6): 1581-1588.
[4] 于乐成, 茅益民, 陈成伟. 药物性肝损伤诊治指南[J]. 实用肝脏病杂志, 2017, 20(2): 257-274. YU Lecheng, MAO Yimin, CHEN Chengwei. Guidelines for diagnosis and treatment of drug-induced liver injury[J]. Journal of Practical Hepatology, 2017, 20(2): 257-274.
[5] Soumerai SB, McLaughlin TJ, Spiegelman D, et al. Adverse outcomes of underuse of beta-blockers in elderly survivors of acute myocardial infarction[J]. JAMA, 1997, 277(2): 115-121.
[6] 黄榕翀, 郭宏洲. 《2019欧洲心脏病学会慢性冠脉综合征的诊断和管理指南》解读[J]. 实用心脑肺血管病杂志, 2019, 27(10): 1-5. HUANG Rongchong, GUO Hongzhou. Interpretation of 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes[J]. Practical Journal of Cardiac Cerebral Pulmonary and Vascular Disease, 2019, 27(10): 1-5.
[7] World Health Organization. Guideline for the pharmacological treatment of hypertension in adults[EB/OL].(2021-08-24)[2025-06-04]. https://www.who.int/publications/i/item/9789240033986
[8] Jones NR, McCormack T, Constanti M, et al. Diagnosis and management of hypertension in adults: nice guideline update 2019[J]. Br J Gen Pract, 2020, 70(691): 90-91.
[9] Revision JCFG. 2018 Chinese guidelines for prevention and treatment of hypertension-a report of the revision committee of Chinese guidelines for prevention and treatment of hypertension[J]. J Geriatr Cardiol, 2019, 16(3): 182-241.
[10] Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice[J]. Eur Heart J, 2021, 42(34): 3227-3337.
[11] Messerli FH, Williams B, Ritz E. Essential hypertension[J]. Lancet, 2007, 370(9587): 591-603.
[12] Opie LH, Yusuf S, Kübler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: a critical analysis based on 100 studies[J]. Prog Cardiovasc Dis, 2000, 43(2): 171-196.
[13] Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland[J]. Gastroenterology, 2013, 144(7): 1419-1425.
[14] Du YK, Zhang MT, Luo ZY, et al. Metoprolol adverse events and literature analyses: case/non-case analyses using the FDA Adverse Event Reporting System(FAERS)[J]. Expert Opin Drug Saf, 2024: 1-8. doi:10.1080/14740338.2024.2446420
[15] Yan YL, An WS, Mei SH, et al. Real-world research on beta-blocker usage trends in China and safety exploration based on the FDA Adverse Event Reporting System(FAERS)[J]. BMC Pharmacol Toxicol, 2024, 25(1): 86. doi:10.1186/s40360-024-00815-w
[16] Suchard MA, Schuemie MJ, Krumholz HM, et al. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis[J]. Lancet, 2019, 394(10211): 1816-1826.
[17] Wang SV, Schneeweiss S, Initiative RD, et al. Emulation of randomized clinical trials with nonrandomized database analyses: results of 32 clinical trials[J]. JAMA, 2023, 329(16): 1376-1385.
[18] Zhang SJ, Wang Q, Hu XF, et al. Interpretable machine learning model for digital lung cancer prescreening in Chinese populations with missing data[J]. NPJ Digit Med, 2024, 7(1): 327. doi:10.1038/s41746-024-01309-z
[19] 张伯韬, 仉率杰, 孙爽爽, 等. 基于贝叶斯网络的缺血性脑卒中筛查模型构建[J]. 山东大学学报(医学版), 2024, 62(11): 73-84. ZHANG Botao, ZHANG Shuaijie, SUN Shuangshuang, et al. Development of the Bayesian network-based screening model for ischemic stroke [J]. Journal of Shandong University(Health Sciences), 2024, 62(11): 73-84.
[20] Casper M, Kramer MR, Quick H, et al. Changes in the geographic patterns of heart disease mortality in the United States: 1973 to 2010[J]. Circulation, 2016, 133(12): 1171-1180.
[21] 司书成. 大数据背景下真实世界研究设计与分析策略[D]. 济南: 山东大学, 2022.
[22] Lin JX, Guo QH, Lu ZQ, et al. Cardiovascular outcomes of β-blocker-calcium channel blocker initial dual therapy vs. other initial dual therapies in Chinese patients with hypertension: a real-world retrospective study[J]. J Clin Hypertens, 2023, 25(5): 440-452.
[23] Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study[J]. Gastroenterology, 2015, 148(7): 1340-1352.
[24] Yuristo NSE, Lubis FZ, Fatur Rachman MA, et al. Effect of garlic(alium sativum)supplementation on short term interdialytic blood pressure variability, oxidative stress and inflammation marker in haemodialysis patients with resistant hypertension: a randomized cross-over trial[J]. J Hypertens, 2024, 42(Suppl 2): e1. doi:10.1097/01.hjh.0001026784.40666.7c
[25] 黄丽红, 王永吉, 王素珍, 等. 倾向性评分方法及其规范化应用的统计学共识CSCO生物统计学专家委员会RWS方法学组[J]. 中国卫生统计, 2020, 37(6): 952-958.
[26] Huang YB, Shan YT, Zhang WJ, et al. Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes[J]. Nat Commun, 2023, 14(1): 175. doi:10.1038/s41467-023-35808-6
[27] Wikstrand J, Berglund G, Tuomilehto J. Beta-blockade in the primary prevention of coronary heart disease in hypertensive patients. Review of present evidence[J]. Circulation, 1991, 84(6 Suppl): 93-100.
[28] McLachlan AJ, Pont LG. Drug metabolism in older people: a key consideration in achieving optimal outcomes with medicines[J]. J Gerontol A Biol Sci Med Sci, 2012, 67(2): 175-180.
[29] Abrahami D, Hudson M, Suissa S. Statins and lower mortality in rheumatic diseases: an effect of immortal time bias?[J]. Semin Arthritis Rheum, 2021, 51(1): 211-218.
[30] Wiysonge CS, Bradley HA, Volmink J, et al. Beta-blockers for hypertension[J]. Cochrane Database Syst Rev, 2017, 1: CD002003. doi:10.1002/14651858.cd002003.pub5
[31] Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies[J]. BMJ, 2009, 338: b1665. doi:10.1136/bmj.b1665
[32] Rehnqvist N, Hjemdahl P, Billing E, et al. Effects of metoprolol vs. verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm(APSIS)[J]. Eur Heart J, 1996, 17(1): 76-81.
[33] Leitch JW, McElduff P, Dobson A, et al. Outcome with calcium channel antagonists after myocardial infarction: a community-based study[J]. J Am Coll Cardiol, 1998, 31(1): 111-117.
[34] McKeever RG, Patel P, Hamilton RJ. Calcium channel blockers[EB/OL].(2024-02-22)[2025-06-04]. https://www.ncbi.nlm.nih.gov/books/NBK470546/
[35] Blake CM, Kharasch ED, Schwab M, et al. A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics[J]. Clin Pharmacol Ther, 2013, 94(3): 394-399.
[36] Sawaya GF, Robertson PA. Hepatotoxicity with the administration of nifedipine for treatment of preterm labor[J]. Am J Obstet Gynecol, 1992, 167(2): 512-513.
[37] Philips C, Paramaguru R, Mahadevan P, et al. Metoprolol-induced severe liver injury and successful management with therapeutic plasma exchange[J]. Cureus, 2017, 9(5): e1209. doi:10.7759/cureus.1209
[38] Yu YC, Nie XL, Song ZY, et al. Signal detection of potentially drug-induced liver injury in children using electronic health records[J]. Front Pediatr, 2020, 8: 171. doi:10.3389/fped.2020.00171

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