Reinilde Heyrman

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*

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.

Efficacy and Safety of Long‐Term Treatment With the Combination of Amlodipine Besylate and Olmesartan Medoxomil in Patients With Hypertension

The authors report on the 44‐week open‐label extension of the 8‐week, double‐blind Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial in 1684 patients. Initial therapy was amlodipine (AML) plus olmesartan medoxomil (OM) 5+40 mg/d, up‐titrated to AML+OM 10+40 mg/d plus hydrochlorothiazide (HCTZ) 12.5 mg then 25 mg if patients did not achieve blood pressure (BP) goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes). Baseline mean BP decreased from 164/102 mm Hg to 131/82 mm Hg at end of study, with an overall 66.7% of patients, including those with diabetes, achieving BP goal. The BP goal achievement was 80% for AML+OM 5+40 mg/d, 70.6% for AML+OM 10+40 mg/d, 66.6% for AML+OM+HCTZ 10+40+12.5 mg/d, and 46.3% for AML+OM+HCTZ 10+40+25 mg/d. Study medication was safe and well tolerated. Combination antihypertensive therapy with AML+OM±HTCZ, up‐titrated as necessary, allowed a majority of patients to achieve BP goal.

A Double-Blind, Dose-Response Study of the Efficacy and Safety of Olmesartan Medoxomil in Children and Adolescents with Hypertension

The current study investigated the efficacy and safety of olmesartan medoxomil in children with hypertension, defined as systolic blood pressure measured at or above the 95th percentile (90th percentile for patients with diabetes, glomerular kidney disease, or family history of hypertension) for age, gender, and height while off any antihypertensive medication. The active treatment phase was conducted in 2 periods, with 2 cohorts in each period (cohort A, 62% white; cohort B, 100% Black). In period 1, patients stratified by weight received low-dose (2.5 or 5 mg) or high-dose (20 or 40 mg) olmesartan medoxomil daily for 3 weeks. In period 2, patients maintained their olmesartan medoxomil dose or initiated placebo washout for an additional 2 weeks. Period 1 efficacy results showed a dose-dependent, statistically significant reduction in seated trough systolic and diastolic blood pressure for both cohorts, with mean blood pressure reductions numerically smaller in cohort B than in cohort A. The olmesartan medoxomil dose response remained statistically significant when adjusted for body weight. In period 2, blood pressure control decreased in those patients switching to placebo, whereas patients continuing to receive olmesartan medoxomil therapy maintained consistent blood pressure reduction. Adverse events were generally mild and unrelated to study medication. Olmesartan medoxomil was safe and efficacious in children with hypertension, resulting in significant blood pressure reductions.

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

J Clin Hypertens (Greenwich). 2011;13:873–880. ©2011 Wiley Periodicals, Inc.

Efficacy and safety of triple-combination therapy with olmesartan, amlodipine, and hydrochlorothiazide in study participants with hypertension and diabetes: a subpopulation analysis of the TRINITY study

BACKGROUND Most patients with hypertension and diabetes require two or more antihypertensive agents to achieve the recommended blood pressure (BP) goal of <130/80 mm Hg. This prespecified subgroup analysis from the TRIple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in HyperteNsIve PatienTs StudY assessed the efficacy and safety of triple-combination treatment (olmesartan medoxomil 40/amlodipine besylate 10/hydrochlorothiazide 25 mg) versus the component dual-combination treatments according to diabetes status (diabetes; non-diabetes). METHODS Participants received dual-combination treatment for 4 weeks or placebo for 2 weeks. Participants receiving placebo switched to dual-combination treatment from week 2 to week 4. At week 4, participants switched to triple-combination treatment or continued on dual-combination treatment until week 12. RESULTS The prespecified changes in BP from baseline for the diabetes subgroup receiving triple-combination treatment were greater than the respective dual-combination treatments (P ≤ .0013). Also, more participants with diabetes receiving triple-combination treatment reached BP goal (<130/80 mm Hg) versus those receiving dual-combination treatments (P ≤ .0092). In a post hoc analysis, significantly greater proportions of study participants with diabetes achieved BP targets with triple-combination treatment compared with each dual-combination treatment. Most treatment-emergent adverse events were mild to moderate in severity. CONCLUSIONS In participants with hypertension and diabetes, triple-combination treatment led to greater BP reductions and enabled greater proportions of participants to reach BP goal versus the dual-combination treatments. Triple-combination treatment was well tolerated in both diabetes and non-diabetes subgroups.

Pharmacokinetics of Amlodipine and Olmesartan After Administration of Amlodipine Besylate and Olmesartan Medoxomil in Separate Dosage Forms and as a Fixed‐Dose Combination

The pharmacokinetics of amlodipine and olmesartan in healthy volunteers after coadministration of amlodipine besylate and olmesartan medoxomil concomitantly as separate dosage forms and together in a fixed‐dose combination tablet were characterized in 5 phase I, randomized, crossover studies. The mean steady‐state pharmacokinetics of amlodipine and olmesartan were similar when olmesartan medoxomil 40 mg/day and amlodipine 10 mg/day were administered separately or concomitantly for 10 days. The total and maximum exposure to amlodipine and olmesartan after administration of fixed‐dose combination amlodipine/olmesartan medoxomil 10 mg/40 mg was bioequivalent to amlodipine 10 mg plus olmesartan medoxomil 40 mg. The ratio of least squares mean and 90% confidence intervals for the area under the drug concentration‐time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of amlodipine and olmesartan fell within the prespecified range for bioequivalence (80.0%‐125.0%). The area under the drug concentration‐time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of both drugs also met the prespecified criterion for bioequivalence when the fixed‐dose combination tablet was taken 30 minutes after a high‐fat breakfast. Total exposure to amlodipine and olmesartan was dose‐proportional after administration of olmesartan medoxomil 10 mg to 40 mg in the fixed‐dose combination formulation with amlodipine 5 mg to 10 mg. From a pharmacokinetic perspective, the 2 drugs are well suited to coadministration in a fixed‐dose combination.

Long‐Term Efficacy and Safety of Triple‐Combination Therapy With Olmesartan Medoxomil and Amlodipine Besylate and Hydrochlorothiazide for Hypertension

J Clin Hypertens (Greenwich). 2012;14:149–157. ©2012 Wiley Periodicals, Inc.

Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double-blind, parallel-group TRINITY study

BackgroundPatients with hypertension and cardiovascular disease (CVD), diabetes, or chronic kidney disease (CKD) usually require two or more antihypertensive agents to achieve blood pressure (BP) goals.MethodsThe efficacy/safety of olmesartan (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg versus the component dual-combinations (OM 40/AML 10 mg, OM 40/HCTZ 25 mg, and AML 10/HCTZ 25 mg) was evaluated in participants with diabetes, CKD, or chronic CVD in the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY). The primary efficacy end point was least squares (LS) mean reduction from baseline in seated diastolic BP (SeDBP) at week 12. Secondary end points included LS mean reduction in SeSBP and proportion of participants achieving BP goal (<130/80 mm Hg) at week 12 (double-blind randomized period), and LS mean reduction in SeBP and BP goal achievement at week 52/early termination (open-label period).ResultsAt week 12, OM 40/AML 10/HCTZ 25 mg resulted in significantly greater SeBP reductions in participants with diabetes (−37.9/22.0 mm Hg vs −28.0/17.6 mm Hg for OM 40/AML 10 mg, −26.4/14.7 mm Hg for OM 40/HCTZ 25 mg, and −27.6/14.8 mm Hg for AML 10/HCTZ 25 mg), CKD (−44.3/25.5 mm Hg vs −39.5/23.8 mm Hg for OM 40/AML 10 mg, −25.3/17.0 mm Hg for OM 40/HCTZ 25 mg, and −33.4/20.6 mm Hg for AML 10/HCTZ 25 mg), and chronic CVD (−37.8/20.6 mm Hg vs −31.7/18.2 mm Hg for OM 40/AML 10 mg, −30.9/17.1 mm Hg for OM 40/HCTZ 25 mg, and −27.5/16.1 mm Hg for AML 10/HCTZ 25 mg) (P<0.05 for all subgroups vs dual-component treatments). BP goal achievement was greater for participants receiving triple-combination treatment compared with the dual-combination treatments, and was achieved in 41.1%, 55.0%, and 38.9% of participants with diabetes, CKD, and chronic CVD on OM 40/AML 10/HCTZ 25 mg, respectively. At week 52, there was sustained BP lowering with the OM/AML/HCTZ regimen. Overall, the triple combination was well tolerated.ConclusionsIn patients with diabetes, CKD, or chronic CVD, short-term (12 weeks) and long-term treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated, lowered BP more effectively, and enabled more participants to reach BP goal than the corresponding 2-component regimens.Trial Identification NumberNCT00649389

Triple-Combination Therapy with Olmesartan, Amlodipine, and Hydrochlorothiazide in Black and Non-Black Study Participants with Hypertension

AbstractBackground Although awareness of hypertension in Black patients has increased, blood pressure (BP) is frequently inadequately controlled. Objective This prespecified subgroup analysis of the TRINITY study evaluated the efficacy and safety of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the component dual-combination treatments in Black and non-Black study participants. Study Design TRINITY was a 12-week, randomized, double-blind, parallel-group evaluation. The first patient was enrolled in May 2008 and the last patient completed the study in February 2009. The study consisted of a 3-week washout period for participants receiving antihypertensive therapy and a 12-week double-blind treatment period. For the treatment phase, all study participants were stratified by age, race, and diabetes mellitus status and randomized to a treatment sequence that led to their final treatment assignment, which they received from weeks 4 to 12 (OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg). In the first 2 weeks of the double-blind treatment period, all participants received either dual-combination treatment or placebo. Participants assigned to dual-combination treatment continued treatment until week 4, and participants receiving placebo were switched at week 2 to receive one of the dual-combination treatments until week 4. At week 4, participants either continued dual-combination treatment or randomly received triple-combination treatment until week 12. Setting 317 clinical sites in the USA and Puerto Rico were included in the study. Patients Study participants eligible for randomization (N = 2492) were ≥18 years of age with mean seated blood pressure (SeBP) ≥140/100 mmHg or ≥160/90 mmHg (off antihypertensive medication). Intervention The intervention was with dual- or triple-combination antihypertensive treatment: OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg. Main Outcome Measure The primary efficacy variable was the change in least squares (LS) mean seated diastolic BP (SeDBP) from baseline to week 12. Secondary efficacy variables included the LS mean change in seated systolic BP (SeSBP), percentage of study participants reaching BP goal, and safety parameters. >Results In both Black and non-Black participants, triple-combination treatment resulted in significant and similar mean reductions in SeDBP and SeSBP (p≤0.0001 vs each dual-combination treatment) with a greater proportion of participants reaching BP goal compared with dual-combination treatments, regardless of race. Most treatment-emergent adverse events were mild or moderate in severity and no new safety concerns were identified. Conclusion Triple-combination treatment provided greater BP reductions than dual-combination treatments regardless of race. Clinical Trial Registration Registered at ClinicalTrials.gov as NCT00649389.

Triple-Combination therapy with olmesartan, amlodipine, and hydrochlorothiazide in black and non-black study participants with hypertension: the TRINITY randomized, double-blind, 12-week, parallel-group study.

BACKGROUND Although awareness of hypertension in Black patients has increased, blood pressure (BP) is frequently inadequately controlled. OBJECTIVE This prespecified subgroup analysis of the TRINITY study evaluated the efficacy and safety of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the component dual-combination treatments in Black and non-Black study participants. STUDY DESIGN TRINITY was a 12-week, randomized, double-blind, parallel-group evaluation. The first patient was enrolled in May 2008 and the last patient completed the study in February 2009. The study consisted of a 3-week washout period for participants receiving antihypertensive therapy and a 12-week double-blind treatment period. For the treatment phase, all study participants were stratified by age, race, and diabetes mellitus status and randomized to a treatment sequence that led to their final treatment assignment, which they received from weeks 4 to 12 (OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg). In the first 2 weeks of the double-blind treatment period, all participants received either dual-combination treatment or placebo. Participants assigned to dual-combination treatment continued treatment until week 4, and participants receiving placebo were switched at week 2 to receive one of the dual-combination treatments until week 4. At week 4, participants either continued dual-combination treatment or randomly received triple-combination treatment until week 12. SETTING 317 clinical sites in the USA and Puerto Rico were included in the study. PATIENTS Study participants eligible for randomization (N = 2492) were ≥18 years of age with mean seated blood pressure (SeBP) ≥140/100 mmHg or ≥160/90 mmHg (off antihypertensive medication). INTERVENTION The intervention was with dual- or triple-combination antihypertensive treatment: OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg. MAIN OUTCOME MEASURE The primary efficacy variable was the change in least squares (LS) mean seated diastolic BP (SeDBP) from baseline to week 12. Secondary efficacy variables included the LS mean change in seated systolic BP (SeSBP), percentage of study participants reaching BP goal, and safety parameters. RESULTS In both Black and non-Black participants, triple-combination treatment resulted in significant and similar mean reductions in SeDBP and SeSBP (p ≤ 0.0001 vs each dual-combination treatment) with a greater proportion of participants reaching BP goal compared with dual-combination treatments, regardless of race. Most treatment-emergent adverse events were mild or moderate in severity and no new safety concerns were identified. CONCLUSION Triple-combination treatment provided greater BP reductions than dual-combination treatments regardless of race. CLINICAL TRIAL REGISTRATION Registered at ClinicalTrials.gov as NCT00649389.