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

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:

• hypertension
• blood pressure
• combination therapy
• low-dose
• amlodipine
• losartan
• chlorthalidone

View correction statement:

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

Acknowledgments

HM_APOLLO investigators: Moo-Yong Rhee (Dongguk University Ilsan Hospital, College of Medicine, Dongguk University) Soon Jun Hong (Korea University Anam Hospital, Korea University College of Medicine), Ki-Chul Sung (Gangbuk Samsung Hospital, Sungkyunkwan University College of Medicine), Sang-Wook Lim (CHA Bundang Medical Center, CHA university), Seok-Yeon Kim (Seoul Medical Center), Weon Kim (Kyung Hee University Medical Center, Kyung Hee University), Jinho Shin (Hanyang University College of Medicine), Sungha Park (Severance Hospital, Yonsei University College of Medicine), Taek-Jong Hong (Pusan National University Hospital, Pusan National University Pusan, Republic of Korea), Chang-Gyu Park, Prof. (Korea University Guro Hospital, Korea University, Seoul, Republic of Korea), Sang-Hyun Ihm, Prof. (Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea), Hae-Young Lee, Prof. (Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea), Sang-Hyun Kim, Prof. (Seoul Boramae Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea), Kwang-Il Kim, Prof. (Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea), Jin-Ok Jeong, Prof. (Chungnam National University Hospital, Chungnam National University, Daejeon, Republic of Korea), and Jin-A Jung and Jong-Soo Woo (Hanmi Pharm.Co., Ltd., Seoul, Republic of Korea). We thank Hyoeun Kang for statistical assistance; Yirang Lim and Minsook Jung for writing assistance; and Donghwan Lee, Jihyun Kwon, and Mijung Jang for study monitoring. Soon Jun Hong and Ki-Chul Sung are co-first authors for this study.

Abbreviations

AEs, adverse events; ANCOVA, analysis of covariance; BP, blood pressure; DBP, diastolic blood pressure; FAS, full-analysis set; LOCF, last-observation-carried-forward; PPS, per-protocol set; SBP, systolic blood pressure; TEAEs, treatment-emergent adverse events.

Data Sharing Statement

We are not planning to share data besides what is included in the manuscript.

Author Contributions

All authors made substantial contributions to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

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.