Low-Dose Triple Antihypertensive Combination Therapy in Patients with Hypertension: A Randomized, Double-Blind, Phase II Study

Soon Jun Hong, Ki-Chul Sung, Sang-Wook Lim, Seok-Yeon Kim, Weon Kim, Jinho Shin, Sungha Park, Hae-Young Kim, Moo-Yong Rhee, HM_APOLLO Investigators, Soon Jun Hong, Ki-Chul Sung, Sang-Wook Lim, Seok-Yeon Kim, Weon Kim, Jinho Shin, Sungha Park, Hae-Young Kim, Moo-Yong Rhee, HM_APOLLO Investigators

Abstract

Purpose: We evaluated the dose-responsiveness, efficacy, and safety of low-dose triple antihypertensive combination therapies in patients with mild-to-moderate hypertension.

Patients and methods: After a 1 to 2-week placebo run-in period, 248 patients were randomized to the half-dose triple combination (amlodipine 2.5 mg + losartan 25 mg + chlorthalidone 6.25 mg), third-dose triple combination (amlodipine 1.67 mg + losartan 16.67 mg + chlorthalidone 4.17 mg), quarter-dose triple combination (amlodipine 1.25 mg + losartan 12.5 mg + chlorthalidone 3.13mg), amlodipine 10mg, amlodipine 5mg, losartan 100mg, and placebo groups for 8 weeks. The primary outcome was the mean change in systolic blood pressure (SBP) from baseline to week 8.

Results: The placebo-corrected SBP reductions of the half-dose, third-dose, quarter-dose combination, amlodipine 10 mg, amlodipine 5 mg and losartan 100 mg treatments were -17.2, -19.5, -14.9, -18.5, -11.3 and -9.9 mmHg, respectively. The BP control and response rates were significantly higher in the half-dose, third-dose, and quarter-dose combination groups than in the placebo group (all p < 0.01). Despite no intergroup differences in study drug-related adverse events, ankle circumference increased significantly in the amlodipine group compared to those in the combination treatment groups. The quarter-dose combination, amlodipine 5 mg, and losartan 100 mg groups showed similar SBP reduction and BP response rates. The SBP reduction and BP response rate in the third-dose and half-dose combination groups were not significantly different from those in the amlodipine 10 mg group but superior to those in the losartan 100 mg group.

Conclusion: Low-dose triple combination therapies could be effective as antihypertensive therapies.

Trial registration: ClinicalTrials.gov identifier NCT03897868.

Keywords: amlodipine; blood pressure; chlorthalidone; combination therapy; hypertension; losartan; low-dose.

Conflict of interest statement

M.Y. Rhee has received lecture honoraria from Pfizer Inc., LG Life Sciences Ltd., Boehringer Ingelheim Pharma GmbH & Co. KG., Hanmi Pharm. Co. Ltd., Yuhan Co. Ltd., and Boryung Pharmaceutical Co. Ltd.; consulting fees from Hanmi Pharm. Co. Ltd. and Shin Poong Pharma. Co. Ltd.; and research grants from Boryung Pharmaceutical Co. Ltd. and Dong-A Pharmaceutical Co. Ltd. J. Shin has received lecture honoraria from Pfizer Inc., Hanmi Pharm. Co. Ltd., Yuhan Co. Ltd., and Boryung Pharmaceutical Co. Ltd.; consulting fees from Hanmi Pharm. Co. Ltd.; and research grants from Sanofi Pharm. and Hanmi Pharm. Co. Ltd. S. Park has received lecture honoraria from Pfizer Inc., Hanmi Pharm. Co. Ltd, Boryung Pharmaceutical Co. Ltd, Daewoong Pharmaceutical Co. Ltd, Sankyo Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Dong-A Pharmaceutical Co. Ltd. and Servier Pharmaceutical Co. Ltd., and a research grant from Sankyo Pharmaceutical Co. Ltd. The other authors have indicated that they have no conflicts of interest with regard to the content of this article.

© 2020 Hong et al.

Figures

Figure 1
Figure 1
Study flow.
Figure 2
Figure 2
Patient disposition.
Figure 3
Figure 3
Change of sitting systolic blood pressure from baseline at week 8. (A) Full analysis set, (B) patients with sitting systolic blood pressure < 160 mmHg at baseline.
Figure 4
Figure 4
Control and response rate of blood pressure at week 8. (A) control rate, (B) response rate.
Figure 5
Figure 5
Changes in ankle circumference from baseline at week 8.

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