Triple therapy with olmesartan medoxomil, amlodipine besylate, and
hydrochlorothiazide in adult patients with hypertension: The TRINITY multicenter,
randomized, double-blind, 12-week, parallel-group study.
Author(s): Oparil S, Melino M, Lee J, Fernandez V, Heyrman R.
Affiliation(s): University of Alabama at Birmingham, 35294-0007, USA. suzanne.oparil@ccc.uab.edu
Publication date & source: 2010, Clin Ther. , 32(7):1252-69
BACKGROUND: Patients with hypertension may require a combination of > or =2
antihypertensive agents to achieve blood pressure (BP) control.
OBJECTIVE: The aim of this study was to determine whether a triple combination of
olmesartan medoxomil (OM), amlodipine besylate (AML), and hydrochlorothiazide
(HCTZ) had a clinically significant benefit compared with dual combinations of
the individual components in patients with moderate to severe hypertension.
METHODS: This was a multicenter, randomized, doubleblind, parallel-group study in
which triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was
compared with dual combinations of the individual components-OM 40 mg/AML 10 mg
in fixed-dose combination, OM 40 mg/HCTZ 25 mg in fixed-dose combination, and AML
10 mg + HCTZ 25 mg-in patients aged > or =18 years who had a mean seated BP > or
=140/100 mm Hg or > or =160/90 mm Hg. The study consisted of a 3-week washout
period with no study medication and a 12-week double-blind treatment period. In
the first 2 weeks of the double-blind treatment period, all patients were
randomized to receive dual combination treatment or placebo. All patients
assigned to a dual combination treatment group continued the assigned treatment
until week 4, and all patients assigned to placebo were switched at week 2 to
receive 1 of the dual combination treatments until week 4. At week 4, patients
either continued dual combination treatment or switched to triple combination
treatment until week 12. The primary end point was the change in seated diastolic
BP (SeDBP) from baseline to week 12; SeDBP reduction of > or =2 mm Hg was
considered a clinically significant benefit. Secondary efficacy end points
included the change in seated systolic BP (SeSBP) at week 12 and the percentages
of patients achieving BP targets of <140/90 mm Hg, <120/80 mm Hg, SeSBP <140 mm
Hg, and SeDBP <90 mm Hg at week 12. The tolerability of the treatments was also
evaluated based on adverse events (AEs), clinical laboratory evaluations
(chemistry, hematology, and urinalysis), physical examinations, and 12-lead ECGs.
RESULTS: The 2492 randomized patients (52.9% male, 66.8% white, 30.4% black) had
a mean (SD) age of 55.1 (10.9) years and a mean weight of 96.0 (22.9) kg.
Diabetes was present in 15.5% of the population, chronic cardiovascular disease
in 9.1%, and chronic kidney disease in 4.1%. At baseline, the mean SeBP was
168.5/100.9 mm Hg. At week 12, triple combination treatment was associated with
significantly greater least squares mean reductions in SeBP compared with the
dual combinations (SeDBP: -21.8 vs -15.1 to -18.0 mm Hg, respectively [P <
0.001]; SeSBP: -37.1 vs -27.5 to -30.0 mm Hg [P < 0.001]). A significantly higher
proportion of patients receiving triple combination treatment reached BP targets
compared with the dual combinations at week 12 (P < 0.001). The proportions of
patients reaching the BP target of <140/90 mm Hg at week 12 was 69.9% in the
triple combination treatment group and 52.9%, 53.4%, and 41.1% in the treatment
groups receiving OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, and AML 10 mg + HCTZ 25
mg, respectively (P < 0.001, triple combination vs each dual combination). The
incidence of treatment-emergent AEs (TEAEs) was 58.4% for triple combination
treatment and 51.7% to 58.9% for the dual combinations; most TEAEs were mild or
moderate in severity. The most common TEAEs in the triple combination treatment
group were dizziness (9.9%), peripheral edema (7.7%), and headache (6.4%). In
total, 52 patients (2.3%) discontinued the study due to TEAEs-6 (1.0%) in the OM
40 mg/AML 10 mg group, 12 (2.1%) in the OM 40 mg/HCTZ 25 mg group, 11 (2.0%) in
the AML 10 mg + HCTZ 25 mg group, and 23 (4.0%) in the OM 40 mg + AML 10 mg +
HCTZ 25 mg group. Thirty-two patients (1.4%)-4 (0.7%), 5 (0.9%), 5 (0.9%), and 18
(3.1%) in the respective treatment groups-discontinued the study due to
drug-related TEAEs.
CONCLUSIONS: In these adult patients with moderate to severe hypertension, triple
combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was associated with
significant BP reductions compared with dual combinations of the individual
components. All treatments were generally well tolerated. ClinicalTrials. gov
identifier: NCT00649389.
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