24-Hour Efficacy and Safety of Triple-Combination Therapy With Olmesartan, Amlodipine, and Hydrochlorothiazide: The TRINITY Ambulatory Blood Pressure Substudy

Abstract

This 12-week, multicenter, randomized, double-blinded, 4-arm study in 440 patients with moderate to severe hypertension compared ambulatory blood pressure (ABP) responses with a triple-combination regimen (olmesartan medoxomil [OM] 40 mg, amlodipine besylate [AML] 10 mg, and hydrochlorothiazide [HCTZ] 25 mg) and its component dual-combination regimens at similar doses. At week 12, the triple combination resulted in a greater reduction in mean 24-hour systolic and diastolic blood pressure ()30.3 ⁄)18.0 mm Hg) compared with the 3 dual-combination regimens (OM 40 mg ⁄AML 10 mg:)23.5 ⁄)13.9, OM 40 mg ⁄HCTZ 25 mg: )23.9 ⁄)14.5, and AML 10 mg ⁄HCTZ 25 mg: )18.5 mm Hg ⁄)10.7 mm Hg; P<.0001 each). Greater efficacy was also found during daytime and nighttime hours and during the last 6, 4, or 2 hours of the dosing interval. 1 Achieving this level of control typically requires the use of !2 classes of antihypertensive drugs 2-4 that have complementary mechanisms of action. Ideal combinations should also incorporate component drugs with sufficient durations of action in order to reduce the morning surge in BP and the early morning peak in myocardial infarction and stroke. [5][6][7] In order to study such effects, it is necessary to use ambulatory BP monitoring (ABPM), which not only distinguishes sustained hypertension from white-coat hypertension, but also allows the study of diurnal variation and true 24-hour drug efficacy. 2,7-11The Triple Therapy With Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) demonstrated that a 3-drug regimen of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg reduced office seated DBP (SeDBP) and SBP (SeSBP) to a greater degree and achieved a higher rate of BP goal attainment than any of the 3 component dual-combinations. 12 The objective of this prespecified TRINITY substudy was to compare 24-hour BP patterns and control rates at baseline and week 12 in a nested subgroup. Specific measured variables included mean daytime (8 AM-4 PM) and nighttime (10 PM-6 AM) BP values, with additional comparisons among treatments during the final 6, 4, and 2 hours of the dosing interval. METHODS Study DesignMethods for TRINITY have previously been described in detail.12 This multicenter (N=317), randomized, double-blind, 12-week, parallel-group study compared the triple-combination regimen (OM 40 mg ⁄AML 10 mg ⁄HCTZ 25 mg) with its component dual-combination regimens in patients with moderate to severe hypertension. To be eligible for randomization, all patients had to be 18 years or older and had to have a mean SeBP !140 ⁄100 mm Hg (SeSBP !140 mm Hg and SeDBP !100 mm Hg) or SeBP !160 ⁄90 mm Hg (SeSBP !160 mm Hg and SeDBP !90 mm Hg) at two consecutive visits during the washout period. Excluded were patients with secondary hypertension, recent ( 6 months) cerebrovascular or coronary artery disease, New York Heart Association class III or IV heart failure, uncontrolled diabetes (defined as glycated hemog...

Current perspectives on combination therapy in the management of hypertension

“…At 12 weeks, the triple-combination therapy resulted in significantly more BP reduction when compared with dual therapy, with no significant difference in adverse events 72. The 24-hour ambulatory BP substudies of the two trials discussed here confirmed significantly larger reductions in mean 24-hour, daytime, and nighttime systolic and diastolic BP in the triple-combination groups 73,74. Furthermore, in an open-label extension of the TRINITY trial, the triple-combination therapy allowed up to 80% of patients to achieve BP target after 52 weeks and was well-tolerated 75.…”

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension

“…When the lower dose of chlorthalidone was used in the combination studies with azilsartan medoxomil, BP reductions were similar to those observed in the present study using the 5 mg dose of amlodipine in combination with azilsartan medoxomil 27. As shown previously, the combination of the angiotensin receptor blockers with either amlodipine or a thiazide diuretic will likely provide effective therapy for patients with more difficult-to-control hypertension 28,29.…”

Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic

“…Also, a significantly greater proportion of patients using triple therapy reached target blood pressures ( P < 0.001 versus dual combinations). Significantly greater reductions in mean 24-hour blood pressure were also observed for the triple combination compared with dual therapy ( P < 0.0001), showing that duration of action is increased as well as magnitude of effect 56. Triple combination therapy was well tolerated, with the majority of adverse events being mild-or-moderate in severity.…”