-
摘要: 目的 评价国产氢氯噻嗪的安全性及其影响因素。方法 本研究采用前瞻性队列研究设计，利用一项多中心随机对照试验(ESPRIT研究)2019年9月—2022年1月的处方和安全性监测数据，纳入心血管疾病高危风险的高血压患者，分析国产氢氯噻嗪安全性复合事件的发生情况。利用广义估计方程模型，探究用药情况及个体因素对其发生风险的影响。结果 研究共纳入10 179例次处方，对应1851例患者，平均年龄为(65.1±7.1)岁，40.7%为女性。氢氯噻嗪安全性复合事件发生率为4.2%，其中定期监测发现的低钾血症(2.5%)和低钠血症(1.6%)最常见。中重度低钾血症和中重度低钠血症发生率分别为0.07%和0.11%。无需停药，69.4%低钾血症和73.2%低钠血症可恢复正常。处方前血钾3.5~3.9 mmol/L(RR=1.45，95%CI：1.20~1.75)和血钠135~139 mmol/L(RR=1.43，95%CI：1.17~1.74)、非每天摄入新鲜水果(RR=1.32，95%CI：1.04~1.67)与发生安全性复合事件风险升高相关。结论 国产氢氯噻嗪安全性良好。定期监测血钾、血钠，关注血钾、血钠处于正常低值和不能每天摄入新鲜水果的患者，采取必要的预防措施，可降低安全性事件发生风险。即使发生低钾血症或低钠血症，大多数患者减低剂量或经补钾、补钠治疗后仍可继续使用氢氯噻嗪。Abstract: Objective To examine the profile of domestic hydrochlorothiazide safety and identify any associatedfactors.Methods Based on data collected in ESPRIT which was a multi-center randomized controlled trial between September 2019 and January 2022, we designed a prospective cohort study and enrolled hypertensive patients with high risk of cardiovascular disease to describe the incidence of a composite of safety events related to hydrochlorothiazide. We then examined potential factors associated with the risk of composite safety events, such as patient characteristics, dosage, and drug combination by using a generalized estimating equation model.Results A total of 1851 patients and 10 179 prescriptions were included in our analyses. Patients aged(65.1±7.1) years; 40.7% were female. The prescription-level incidence of the composite safety events was 4.2%, with the most common components being hypokalemia(2.5%) or hyponatremia(1.6%). The incidence of moderate to severe hypokalemia and moderate to severe hyponatremia was 0.07% and 0.11%, respectively. Among the patients with hypokalemia, 69.4% of patients recovered without drug withdrawal, the proportion in the patients with hyponatremia was 73.2%. Subsequent analyses identified the independent risk factors for incident composite safety events; serum potassium level between 3.5 to 3.9 mmol/L(RR=1.45, 95%CI: 1.20—1.75); serum sodium between 135 to 139 mmol/L(RR=1.43, 95%CI: 1.17—1.74); non-daily intake of fresh fruits(RR=1.32, 95%CI: 1.04—1.67).Conclusion Hydrochlorothiazide exhibited a satisfying safety profile. It would further improve the safety to monitor blood potassium and sodium and take necessary preventive measures, particularly in the patients with a lower-normal level of blood potassium or sodium, or in those non-daily taking fresh fruits. Even if hypokalemia or hyponatremia occurs, most patients can still use hydrochlorothiazide after reducing the dose or treating with potassium or sodium supplement.
-
Key words:
- hypertension /
- safety /
- hydrochlorothiazide /
- hypokalemia /
- hyponatremia
-
-
表 1 处方及其对应的患者特征
Table 1. The patients and prescriptions information
例次(%) 基本特征 总体(10 179例次) 未发生安全性复合事件(9751例次) 发生安全性复合事件(428例次) P值 年龄 0.232 50~59岁 2198(21.6) 2100(21.5) 98(22.9) 60~69岁 5388(52.9) 5152(52.9) 236(55.1) ≥70岁 2593(25.5) 2499(25.6) 94(22.0) 性别 0.422 女 4138(40.7) 3972(40.7) 166(38.8) 男 6041(59.3) 5779(59.3) 262(61.2) ASCVD 冠心病 2794(27.4) 2678(27.5) 116(27.1) 0.870 脑卒中 2775(27.3) 2673(27.4) 102(23.8) 0.104 外周血管疾病 94(0.9) 90(0.9) 4(0.9) 0.980 危险因素 糖尿病 3321(32.6) 3173(32.5) 148(34.6) 0.379 血脂异常 4371(42.9) 4196(43.0) 175(40.9) 0.381 目前吸烟 3894(38.3) 3745(38.4) 149(34.8) 0.134 肥胖 3401(33.4) 3267(33.5) 134(31.3) 0.346 新鲜蔬菜摄入 0.461 每天 8411(82.6) 8063(82.7) 348(81.3) 非每天 1768(17.4) 1688(17.3) 80(18.7) 新鲜水果摄入 0.019 每天 3684(36.2) 3552(36.4) 132(30.8) 非每天 6495(63.8) 6199(63.6) 296(69.2) 处方前血钾 < 0.001 ≥4.0 mmol/L 6187(60.8) 5968(61.2) 219(51.2) 3.5~3.9 mmol/L 3992(39.2) 3783(38.8) 209(48.8) 处方前血钠 < 0.001 ≥140 mmol/L 5806(57.0) 5598(57.4) 208(48.6) 135~139 mmol/L 4373(43.0) 4153(42.6) 220(51.4) 处方前eGFR 0.771 ≥90 mL·min-1·(1.73m2)-1 6321(62.1) 6050(62.0) 271(63.3) 60~89 mL·min-1·(1.73m2)-1 3289(32.3) 3153(32.4) 136(31.8) < 60 mL·min-1·(1.73m2)-1 569(5.6) 548(5.6) 21(4.9) 氢氯噻嗪日剂量 0.154 ≥25 mg 5174(50.8) 4942(50.7) 232(54.2) < 25 mg 5005(49.2) 4809(49.3) 196(45.8) 药物种类 0.046 HCTZ 119(1.2) 110(1.1) 9(2.1) HCTZ+ACEI/ARB 451(4.4) 432(4.4) 19(4.4) HCTZ+CCB 800(7.9) 763(7.8) 37(8.6) HCTZ+BB 119(1.2) 116(1.2) 3(0.7) HCTZ+ACEI/ARB+CCB 3142(30.9) 3000(30.8) 142(33.2) HCTZ+CCB+BB 1084(10.7) 1047(10.7) 36(8.4) HCTZ+ACEI/ARB+BB 462(4.5) 432(4.5) 30(7.0) HCTZ+ ACEI/ARB +CCB+BB 3528(34.7) 3391(34.8) 137(32.0) HCTZ+其他联合 474(4.7) 460(4.7) 14(3.3) 注：HCTZ：氢氯噻嗪；CCB：钙离子拮抗剂；BB：β受体阻滞剂；ACEI/ARB：血管紧张素转换酶抑制剂/血管紧张素Ⅱ受体拮抗剂。 
下载: 导出CSV
表 2 氢氯噻嗪安全性不良事件的发生情况
Table 2. The incidence of adverse events under hydrochlorothiazide
安全性不良事件 事件数(10179例次) 发生率/% 定期监测发现的低钾血症 250 2.46 轻度(3.0~3.4 mmol/L) 243 2.39 中度(2.5~2.9 mmol/L) 7 0.07 重度(< 2.5 mmol/L) 0 0 定期监测发现的低钠血症 159 1.56 轻度(130~134 mmol/L) 148 1.45 中度(125~129 mmol/L) 10 0.10 重度(< 125 mmol/L) 1 0.01 因不良反应停药 33 0.32 低血压 7 0.07 低血钾 4 0.04 血尿酸升高 3 0.03 过敏 1 0.01 其他 18 0.18 因低钾血症急诊就诊或住院 0 0 因低钠血症急诊就诊或住院 0 0 安全性复合事件* 428 4.20 注：*当同一处方同时出现不同类别的安全性不良事件时，安全性复合事件中记录为1次。
下载: 导出CSV
表 3 发生低钾血症或低钠血症患者血钾血钠水平恢复正常对应的氢氯噻嗪调整情况
Table 3. The prescription adjustment of hydrochlorothiazide for poassium or sodium resumed in patients with hypokalemia or hyponatremia
例次(%) 项目 血钾水平/(mmol·L-1) 血钠水平/(mmol·L-1) 3.0~3.4 (222例次) 2.5~2.9 (7例次) < 2.5 (0例次) 合计(229例次) 130~134 (132例次) 125~129 (9例次) < 125(1例次) 合计(142例次) 原量恢复 148(66.7) 2(28.6) 0(0) 150(65.5) 91(68.9) 7(77.8) 0(0) 98(69.0) 减量恢复 9(4.1) 0(0) 0(0) 9(3.9) 6(4.5) 0(0) 0(0) 6(4.2) 停药恢复 43(19.4) 4(57.1) 0(0) 47(20.5) 27(20.5) 1(11.1) 1(100) 29(20.4) 未恢复 22(9.9) 1(14.3) 0(0) 23(10.0) 8(6.1) 1(11.1) 0(0) 9(6.3)
下载: 导出CSV
表 4 氢氯噻嗪安全性的影响因素
Table 4. The factors influencing safety of hydrochlorothiazide
项目 单因素分析 多因素分析 RR(95%CI) P值 RR(95%CI) P值 年龄 50~59岁 1.00 1.00 60~69岁 0.98(0.76~1.26) 0.889 0.95(0.74~1.23) 0.694 ≥70岁 0.80(0.59~1.08) 0.140 0.76(0.56~1.04) 0.086 性别 男 1.07(0.87~1.32) 0.528 1.02(0.81~1.29) 0.836 ASCVD史 冠心病 1.01(0.81~1.27) 0.910 0.88(0.68~1.14) 0.337 脑卒中 0.83(0.65~1.05) 0.126 0.78(0.60~1.01) 0.061 心血管病危险因素 糖尿病 0.92(0.75~1.13) 0.439 0.85(0.68~1.06) 0.142 血脂异常 0.93(0.74~1.15) 0.179 0.79(0.62~1.00) 0.047 目前吸烟 1.09(0.87~1.35) 0.454 0.91(0.71~1.18) 0.491 肥胖 0.93(0.74~1.15) 0.494 0.94(0.76~1.17) 0.576 新鲜蔬菜摄入 每天 1.00 1.00 非每天 1.09(0.84~1.43) 0.512 1.04(0.78~1.37) 0.803 新鲜水果摄入 每天 1.00 1.00 非每天 1.32(1.05~1.64) 0.016 1.32(1.04~1.67) 0.023 处方前血钾 ≥4.0 mmol/L 1.00 1.00 3.5~3.9 mmol/L 1.46(1.21~1.76) < 0.001 1.45(1.20~1.75) < 0.001 处方前血钠 ≥140 mmol/L 1.00 1.00 135~139 mmol/L 1.40(1.15~1.70) 0.001 1.43(1.17~1.74) < 0.001 处方前eGFR ≥90 mL·min-1·(1.73m2)-1 1.00 1.00 60~89 mL·min-1·(1.73m2)-1 0.99(0.80~1.22) 0.935 1.03(0.84~1.27) 0.755 < 60 mL·min-1·(1.73m2)-1 0.79(0.49~1.27) 0.331 1.03(0.65~1.64) 0.889 氢氯噻嗪日剂量 < 25 mg 1.00 1.00 ≥25 mg 0.86(0.71~1.05) 0.149 0.86(0.70~1.06) 0.151 药物联合种类 HCTZ+ACEI/ARB 1.00 1.00 HCTZ+CCB 1.10(0.63~1.92) 0.744 0.98(0.56~1.71) 0.948 HCTZ+ACEI/ARB+CCB 1.07(0.66~1.73) 0.786 1.02(0.64~1.65) 0.925 HCTZ+CCB+BB 0.81(0.47~1.40) 0.453 0.74(0.43~1.28) 0.286 HCTZ+ACEI/ARB+BB 1.49(0.85~2.61) 0.159 1.47(0.85~2.57) 0.170 HCTZ+ ACEI/ARB +CCB+BB 0.92(0.57~1.48) 0.717 0.89(0.55~1.43) 0.624 HCTZ+其他联合 0.70(0.36~1.38) 0.304 0.68(0.35~1.34) 0.268
下载: 导出CSV
-
[1] Freis ED, Wanko A, Wilson IM, et al. Treatment of essential hypertension with chlorothiazide(diuril); its use alone and combined with other antihypertensive agents[J]. J Am Med Assoc, 1958, 166(2): 137-140. doi: 10.1001/jama.1958.02990020025004
[2] Trimarco V, de Simone G, Izzo R, et al. Persistence and adherence to antihypertensive treatment in relation to initial prescription: diuretics versus other classes of antihypertensive drugs[J]. J Hypertens, 2012, 30(6): 1225-1232. doi: 10.1097/HJH.0b013e328353398b
[3] 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. doi: 10.1016/S0140-6736(19)32317-7
[4] Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/ APhA/ASH/ ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[J]. Hypertension, 2018, 71(6): e13-e115.
[5] Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension[J]. Eur Heart J, 2018, 39(33): 3021-3104. doi: 10.1093/eurheartj/ehy339
[6] WHO. Guideline for the pharmacological treatment of hypertension in adults[R]. Geneva: World Health Organization, 2021: 28-29.
[7] 中国高血压防治指南修订委员会, 高血压联盟, 中华医学会心血管病学分会中国医师协会高血压专业委员会, 等. 中国高血压防治指南(2018年修订版)[J]. 中国心血管杂志, 2019, 24(1): 24-56. doi: 10.3969/j.issn.1007-5410.2019.01.002
[8] 白京京, 张伟丽, 王璐, 等. 北京市基层医疗卫生机构降压药物使用情况及合理性分析[J]. 中华心血管病杂志, 2021, 49(10): 993-999. doi: 10.3760/cma.j.cn112148-20201231-01022
[9] 中华医学会心血管病学分会高血压学组. 利尿剂治疗高血压的中国专家共识[J]. 中华高血压杂志, 2011, 19(3): 214-22. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGGZ201103006.htm
[10] Moser M, Feig PU. Fifty years of thiazide diuretic therapy for hypertension[J]. Arch Intern Med, 2009, 169(20): 1851-1856. doi: 10.1001/archinternmed.2009.342
[11] 刘晓斌, 范金茂, 朱雁洲, 等. 高血压患者血清钠、钾浓度及两者比值与左心室肥厚的相关性[J]. 临床心血管病杂志, 2020, 36(7): 631-636. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXB202007011.htm
[12] Du S, Wang H, Zhang B, et al. Dietary Potassium Intake Remains Low and Sodium Intake Remains High, and Most Sodium is Derived from Home Food Preparation for Chinese Adults, 1991-2015 Trends[J]. J Nutr, 2020, 150(5): 1230-1239. doi: 10.1093/jn/nxz332
[13] 中国成人血脂异常防治指南修订联合委员会. 中国成人血脂异常防治指南(2016年修订版)[J]. 中华全科医师杂志, 2017, 16(1): 15-35. doi: 10.3760/cma.j.issn.1671-7368.2017.01.006
[14] 中国肥胖问题工作组数据汇总分析协作组. 我国成人体重指数和腰围对相关疾病危险因素异常的预测价值: 适宜体重指数和腰围切点的研究[J]. 中华流行病学杂志, 2002, 23(1): 10-15. doi: 10.3760/j.issn:0254-6450.2002.01.025
[15] Krogager ML, Mortensen RN, Lund PE, et al. Risk of Developing Hypokalemia in Patients With Hypertension Treated With Combination Antihypertensive Therapy[J]. Hypertension, 2020, 75(4): 966-972. doi: 10.1161/HYPERTENSIONAHA.119.14223
[16] Hripcsak G, Suchard MA, Shea S, et al. Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension[J]. JAMA Intern Med, 2020, 180(4): 542-551. doi: 10.1001/jamainternmed.2019.7454
[17] Chekka L, Chapman AB, Gums JG, et al. Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone[J]. Am J Med, 2021, 134(7): 918-925. e2. doi: 10.1016/j.amjmed.2020.12.015
[18] Rodenburg EM, Visser LE, Hoorn EJ, et al. Thiazides and the risk of hypokalemia in the general population[J]. J Hypertens, 2014, 32(10): 2092-2097;discussion 2097. doi: 10.1097/HJH.0000000000000299
[19] Leung A, Wright A, Pazo V, et al. Risk of thiazide-induced hyponatremia in patients with hypertension[J]. Am J Med, 2011, 124(11): 1064-1072. doi: 10.1016/j.amjmed.2011.06.031
[20] Jiang JY, Wong MC, Ali MK, et al. Association of antihypertensive monotherapy with serum sodium and potassium levels in Chinese patients[J]. Am J Hypertens, 2009, 22(3): 243-249. doi: 10.1038/ajh.2008.359
[21] Al Qahtani M, Alshahrani A, Alskaini A, et al. Prevalence of hyponatremia among patients who used indapamide and hydrochlorothiazide: a single center retrospective study[J]. Saudi J Kidney Dis Transpl, 2013, 24(2): 281-285. doi: 10.4103/1319-2442.109574
[22] Kardalas E, Paschou SA, Anagnostis P, et al. Hypokalemia: a clinical update[J]. Endocr Connect, 2018, 7(4): R135-R146. doi: 10.1530/EC-18-0109
[23] 国家卫生计生委合理用药专家委员会, 中国医师协会高血压专业委员会. 高血压合理用药指南(第2版)[J]. 中国医学前沿杂志, 2017, 9(7): 28-126. https://www.cnki.com.cn/Article/CJFDTOTAL-YXQY201707010.htm
[24] Makam AN, Boscardin WJ, Miao Y, et al. Risk of thiazide-induced metabolic adverse events in older adults[J]. J Am Geriatr Soc, 2014, 62(6): 1039-1045. doi: 10.1111/jgs.12839
[25] Krogager M, Kragholm K, Thomassen J, et al. Update on management of hypokalemia and goals for the lower potassium level in patients with cardiovascular disease: A review in collaboration with the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy[J]. Eur Heart J Cardiovasc pharmacother, 2021, 7(6): 557-567.
[26] Krogager ML, Torp-Pedersen C, Mortensen RN, et al. Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data[J]. Eur Heart J, 2017, 38(2): 104-112.
[27] Peterzan MA, Hardy R, Chaturvedi N, et al. Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum potassium, and urate[J]. Hypertension, 2012, 59(6): 1104-1109.
-
| 引用本文: |
李佳颖, 李艳, 刘佳敏, 等. 国产氢氯噻嗪的安全性及其影响因素[J]. 临床心血管病杂志, 2022, 38(12): 994-1000. doi: 10.13201/j.issn.1001-1439.2022.12.012
|
| Citation: |
LI Jiaying, LI Yan, LIU Jiamin, et al. Safety profile of hydrochlorothiazide and its modifiers[J]. J Clin Cardiol, 2022, 38(12): 994-1000. doi: 10.13201/j.issn.1001-1439.2022.12.012
|