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

Abstract

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 halfdose 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.

Comparison of efficacy and safety between third-dose triple and third-dose dual antihypertensive combination therapies in patients with hypertension

“…The level of BP reduction by third-dose triple antihypertensive combination therapy is expected to be superior to that of monotherapy at a standard dose. Therefore, we believe that a third-dose triple antihypertensive combination in a single-pill is an effective initial antihypertensive treatment option in patients with mild-to-moderate hypertension, with relatively greater and rapid BP-lowering e cacy and low ADRs as shown in our present and previous studies [12]. We are conducting a Phase III study to show greater BP reduction and comparable tolerability of third-dose triple combination therapy to amlodipine 5 mg monotherapy after 8 weeks of treatment (HM-APOLLO-301, NCT05362110).…”

“…In our previous study, SBP reduction after 8 weeks of monotherapy with amlodipine 5 mg and losartan 100 mg was − 12.4 ± 13.1 mg and − 11.1 ± 15.9 mmHg, respectively [12]. In this study, the mean SBP reductions (at week 8 from baseline) were − 18.3 ± 13.2, -13.0 ± 13.3, -16.3 ± 12.4, and − 13.8 ± 13.2 mmHg in the ALC, AL, LC and AC groups, respectively.…”

“…Participants with a mean sitting SBP ≥ 180 mmHg or DBP ≥ 110 mmHg, at any visit after randomization and/or with a mean sitting SBP < 100 mmHg or DBP < 60 mmHg, at any visit during the study were withdrawn. Other exclusion and withdrawal criteria were the same as those used in the previous study [12]. All participants provided written informed consent prior to participation in the study.…”

Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial

“…3,16,17 For example, lowdose triple therapy reduces pedal oedema compared to the maximal dose of amlodipine. 18 Further research should assess comparative efficacy and tolerability compared to other regimens, such as initial dual combination therapy now recommended for numerous patient groups in recent guidelines. [19][20][21] However the current trial results are highly relevant to current practise since monotherapy remains the most common initial treatment, even in high income countries.…”

“…None met the criteria of quarter dose combination therapy compared to monotherapy or placebo, although the authors were aware of one trial. 18 Overall, there was only one unblinded study comparing quadruple quarter-dose combination therapy to standard doses of the four components showed short-term benefits favouring the ultra-low dose combination. 6 A small randomised, placebo-controlled crossover trial of quadruple quarter-dose combination therapy demonstrated significant blood pressure reductions in the short term and served as proof-of-concept to pursue this trial.…”