Single-pill low-dose triple combination therapy was noninferior to amlodipine and superior to losartan for SBP reduction at 8 weeks (-19.9 vs -16.4 mm Hg; 95% CI -6.6 to -0.2; P=0.037).
RCT
double-blind
randomized
Yes
Does a single-pill low-dose triple combination of amlodipine, losartan, and chlorthalidone improve systolic blood pressure reduction compared to standard-dose monotherapy in adults with mild-to-moderate hypertension?
A single-pill ultra-low-dose triple combination of amlodipine, losartan, and chlorthalidone provides effective blood pressure reduction comparable to standard-dose amlodipine and superior to standard-dose losartan, with good short-term tolerability.
Absolute Event Rate: -19.9% vs -16.4%
p-value: p=0.037
BACKGROUND Single-pill low-dose combination (LDC) antihypertensive therapy is an emerging strategy for improving blood pressure (BP) control. Although previous phase II and pragmatic studies suggested promise, these are the first phase III, double-blind, active-controlled trials comparing a single-pill ultra-low-dose triple combination with standard-dose monotherapy. OBJECTIVES In these studies, we sought to compare a single-pill combination of 1.67 mg amlodipine, 16.67 mg losartan potassium, and 4.17 mg chlorthalidone (LDC-ALC) with standard-dose monotherapy-5 mg amlodipine or 50 mg losartan potassium-in patients with mild-to-moderate hypertension. METHODS HM-APOLLO-301 (Study 301, May 2022-June 2023) and HM-APOLLO-302 (Study 302, March-December 2024) were multicenter, randomized, double-blind, active-controlled, phase III studies in South Korea. Study 301 compared LDC-ALC and amlodipine; Study 302 compared LDC-ALC and losartan. Adults (≥19 years of age) with systolic blood pressure (SBP) 140 to <180 mm Hg and diastolic blood pressure (DBP) <110 mm Hg after 4-week placebo run-in were randomized to 8 weeks of treatment. The primary endpoint was SBP reduction at week 8, assessed first for noninferiority, then for superiority. RESULTS In Study 301, LDC-ALC exhibited noninferiority to amlodipine in reducing SBP at week 8 (upper bound of 1-sided 97.5% CI: 2.8 mm Hg <3 mm Hg noninferiority margin), and similar efficacy (least-squares mean change: -19.1 vs -19.9 mm Hg; 95% CI: -1.5 to 3.1; P = 0.495), with similar DBP reduction and blood pressure control rate. In Study 302, LDC-ALC was both noninferior (upper bound of one-sided 97.5% CI: -0.6 mm Hg) and superior to losartan (least-squares mean change: -19.9 vs -16.4 mm Hg; 95% CI: -6.6 to -0.2; P = 0.037) in SBP reduction at week 8, with greater DBP reduction and a higher blood pressure control rate than losartan. Adverse events were similar between groups (LDC-ALC vs amlodipine: 11.7% vs 13.9%; LDC-ALC vs losartan: 6.4% vs 3.3%), with ≤1% treatment withdrawals and no serious drug-related events. CONCLUSIONS Single-pill LDC-ALC achieved BP reductions similar to those with amlodipine and greater than those with losartan monotherapy over 8 weeks, with similar short-term tolerability. These findings support LDC-ALC as an effective and well tolerated alternative initial therapy for mild-to-moderate hypertension, expanding the set of validated strategies alongside established monotherapies. (A Study to Evaluate Efficacy and Safety of HCP1803 in Patients With Essential Hypertension HM-APOLLO-301; NCT05362110; A Study to Evaluate Efficacy and Safety of HCP1803 Compared to RLD2001-1 in Patients with Essential Hypertension HM-APOLLO-302, NCT06438172).
Sung et al. (Sun,) conducted a rct in mild-to-moderate hypertension. Single-pill low-dose combination (LDC-ALC) vs. 5 mg amlodipine or 50 mg losartan potassium was evaluated on Systolic blood pressure (SBP) reduction at week 8 (Study 302 vs losartan) (95% CI -6.6 to -0.2, p=0.037). Single-pill low-dose triple combination therapy was noninferior to amlodipine and superior to losartan for SBP reduction at 8 weeks (-19.9 vs -16.4 mm Hg; 95% CI -6.6 to -0.2; P=0.037).