Journal Article

Initial treatment with a single capsule containing half-dose quadruple therapy vs standard-dose dual therapy in hypertensive patients (QUADUAL): a randomized, blinded, crossover trial

Tang, Xiaohong, Cai, Jingjing, Li, Xiaogang, Zhao, Xiexiong, Li, Xingli, Wang, Wenjuan, Zhao, Lin, Li, Anying, Peng, Liping, Li, Ruixuan, Wen, Juan, Yang, Qiong, Zeng, Lixiong, Liang, Zhongshu, Yang, Guoping, Huang, Miao, Liu, Tao, Chen, Ye, Wang, Xiaoyan, Li, Jingle, Fu, Ru, Jiang, Weihong

2025

Overview

Background Guidelines recognized dual combination in initial antihypertensive therapy. Studies found that low-dose quadruple combination were superior to monotherapy. However, whether low-dose quadruple therapy is better than dual combination is unknown. Methods A randomized blinded crossover trial was conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg), both in a single pill, in the initial treatment of patients with mild to moderate hypertension. Patients were randomly assigned in a 1:1 ratio to two crossover sequences. Each sequence received four-weeks of either half-dose quadruple antihypertensives or standard-dose dual antihypertensives, followed by a two-week washout and crossover for four-weeks. Participants and researchers were blinded. The main outcomes were the reduction of blood pressure and safety outcomes. Analyses were per intention to treat. Results A total of 90 eligible participants were randomized between July 13, 2022, and April 20, 2023. The mean age was 43.88 years (SD 10.31), and 25.6% were women. The mean baseline 24-h blood pressure was 145.59/93.84 mm Hg. Compared to the standard-dose dual treatment, the half-dose quadruple treatment resulted in a further reduction in mean 24-h blood pressure by 4.72/4.17 mm Hg ( P  < 0.001 for both systolic and diastolic blood pressure), mean daytime blood pressure by 5.52/4.73 mm Hg ( P  < 0.001 for both), mean nighttime blood pressure by 2.37/2.25 mm Hg ( P  = 0.034 and 0.014, respectively), and mean office blood pressure by 2.91/1.73 mm Hg ( P  < 0.001 and 0.014, respectively). Apart from significant increases of fasting blood glucose ( P  = 0.029) and blood uric acid ( P  < 0.001) in the half-dose quadruple group, no other adverse events or changes in laboratory values differed significantly between the two treatments. Conclusions Initiating treatment with half-dose quadruple combination therapy was more effective in lowering blood pressure than standard-dose dual therapy. The safety of half-dose quadruple therapy was comparable. Trial registration ClinicalTrials.gov Identifier: NCT05377203.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Aged / Amlodipine - administration & dosage / Amlodipine - adverse effects / Amlodipine - therapeutic use / Antihypertensive / Antihypertensive Agents - administration & dosage / Antihypertensive Agents - adverse effects / Antihypertensive Agents - therapeutic use / Antihypertensives / Biomedicine / Blood pressure / Blood Pressure - drug effects / Capsules / Cardiovascular disease / Cerebrovascular disease / Combination therapy / Comparative analysis / COVID-19 / Cross-Over Studies / Diabetes / Drug dosages / Drug therapy / Drug Therapy, Combination / Effectiveness / Female / Humans / Hypertension / Hypertension - drug therapy / Indapamide / Indapamide - administration & dosage / Low-dose combination / Male / Medicine / Medicine & Public Health / Metoprolol / Metoprolol - administration & dosage / Metoprolol - adverse effects / Metoprolol - therapeutic use / Middle Aged / Pharmacists / Pharmacology, Experimental / Physiological aspects / Randomized controlled trial / Safety / Statistical analysis / Testing / Therapy / Treatment Outcome / Uric acid