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Study Finds Long-Term Treatment with TRIBENZOR™ was Effective and Well-Tolerated Regardless of Age, Race, or Diabetes Status
Date:5/23/2011

PARSIPPANY, N.J., May 23, 2011 /PRNewswire/ -- Data evaluating the long-term efficacy and safety of olmesartan medoxomil, amlodipine besylate, plus hydrochlorothiazide (OM/AML + HCTZ) in patients with hypertension aged <65 years and greater than or equal to 65 years, showed that the triple therapy at Week 52 was both well-tolerated and effective in maintaining the blood pressure reductions seen in the pivotal study regardless of age.(1)

The pre-specified subgroup analysis results, presented for the first time at the American Society of Hypertension, Inc. (ASH) Twenty-Sixth Annual Scientific Meeting and Exposition (ASH 2011) in New York, found that a similar percentage of patients treated with the triple therapy achieved BP goal in both age groups. The triple therapy was well-tolerated in both age groups and most adverse events (AE) were mild or moderate in severity.(1)

"Older patients generally have a more difficult time achieving recommended blood pressure levels and as a result, their hypertension often remains uncontrolled," said Suzanne Oparil, MD, Professor of Medicine and Physiology and Biophysics at the University of Alabama School of Medicine. "However this analysis shows that long-term blood pressure control can be achieved safely and effectively across all studied dosing strengths with a triple combination therapy regardless of age. This is important given the fact that more than 64 percent of men and 75 percent of women 70 years or older have high blood pressure."(5)

The long-term open-label extension of the TRINITY study (Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study) evaluated the safety and efficacy of olmesartan medoxomil (OM)/amlodipine (AML) + hydrochlorothiazide (HCTZ) in 2,098 patients with hypertension.(1) After completing a 12-week double-blind period, eligible patients were enrolled into a 40-week open label extension period and were initially administered without washout, OM 40 mg/AML 5 mg + HCTZ 12.5 mg. Study participants who did not achieve blood pressure goal (<140/90 or <130/80 mm Hg for patients with diabetes, chronic renal disease, or cardiovascular disease) at Week 14 were randomly titrated to either OM 40/AML 10+HCTZ 12.5 mg or OM 40/AML 5+HCTZ 25 mg. If by Week 16, patients still did not achieve blood pressure goal they were further titrated to OM 40/AML 10 + HCTZ 25 mg. Back-titration to a lower dose of triple therapy was allowed at the investigator's discretion. This subgroup analysis evaluated the efficacy and safety of OM/AML + HCTZ in patients aged <65 years (80.4%) and greater than or equal to 65 years (19.6%).  Within each age subgroup, efficacy and safety data were reported for each dose-strength that was part of the titration regimen.(1)

At the start of the open-label period, mean seated blood pressure (SeBP) was 134.2/83.3 mm Hg in patients aged <65 years and 137.5/78.0 mm Hg in patients aged greater than or equal to 65 years. At week 52/early termination (ET), patients aged greater than or equal to 65 years achieved a mean SeSBP and mean diastolic blood pressure (SeDBP) ranging from 126.2/74.0 to 137.8/77.5 mm Hg. Patients aged <65 years of age achieved a mean SeSBP and mean SeDBP ranging from 124.7/78.5 to 136.6/83.8 mm Hg.

In patients aged <65 years and greater than or equal to 65 years, the reported incidence of AEs was 36.0% to 58.7% and 37.2% to 60.9% respectively, and the incidence of drug related AEs was 9.9% to 19.4% and 13.3% to 21.1%, respectively. Dizziness, peripheral edema, nasopharyngitis and upper respiratory tract infection were the most common AEs for both age groups.(1)

Additional Subgroup Analyses

Results from additional pre-specified subgroup analyses of the TRINITY open-label extension looking at obese (BMI greater than or equal to 30 kg/m2) and non-obese (BMI <30 kg/m2) patients, patients with and without diabetes, as well as black and non-black patients, were also presented at ASH 2011.  The data demonstrated that long-term treatment with the triple combination therapy, OM/AML + HCTZ was effective and well-tolerated regardless of diabetes or BMI status, as well as race, and confirm that the blood pressure reductions seen at Week 12 of the double-blind portion of the study were maintained at Week 52.(2,3)

Obesity and Diabetes
This pre-specified subgroup analysis evaluated patients with and without diabetes and obese and non-obese patients. Of the study subgroup, 15.8% had type 2 diabetes and 63.1% were obese (BMI of greater than or equal to 30 kg/m2). At the start of the open-label period, mean baseline blood pressure was 138.9/81.2 mm Hg in patients with diabetes and 135.7/83.2 mm Hg in obese patients (BMI of greater than or equal to 30 kg/m2). At Week 52/ET, mean SeSBP and SeDBP ranged from 121.4/74.9 to 136.7/79.7 mm Hg in patients with diabetes, 125.2/78.0 to 136.8/83.5 mm Hg in non-diabetes patients, 125.0/78.3 to 137.2/83.1 mm Hg in obese patients, and 124.9/76.9 to 135.9/81.2 mm Hg in non-obese patients. Further, the analysis showed treatment with OM/AML + HCTZ was effective in BP goal attainment in both obese patients and patients with diabetes.

Most adverse events were mild or moderate in severity in patients with diabetes and in obese patients. Dizziness, upper respiratory tract infection, peripheral edema, urinary tract infection, and nasopharyngitis were the most common AEs for participants with diabetes and participants with BMI greater than or equal to 30 kg/m2 (with the exception of urinary tract infection in obese patients).(2)  

Black and Non-black
This pre-specified subgroup analysis evaluated black versus non-black patients with hypertension. Of the total study group, 29.5% were black. At the start of the open-label period, mean blood pressure was 135.7/84.0 mm Hg in the black population and 134.5/81.6 mm Hg in the non-black population. At Week 52/ET, mean SeSBP and SeDBP ranged from 125.6/79.5 to 136.2/83.5 mm Hg in black patients and from 124.8/77.2 to 137.1/82.0 mm Hg in non-black patients. In addition, treatment with OM/AML +HCTZ was effective in BP goal attainment in both black and non-black patients.

Adverse events (AE) occurred in 30.2%-56.6% of black patients and in 39.3%-60.5% of non-black patients and drug-related AEs occurred in 5.4%-16.8% of black patients and 12.8% to 21.3% of non-black patients.  The most common AEs were dizziness, upper respiratory tract infection, nasopharyngitis, and peripheral edema. The majority of AEs were mild or moderate in severity.(3)

Primary Data Study Design
The TRINITY study, (Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study) was a Phase 3, multicenter, randomized, parallel-group study, which included 2,492 patients with hypertension. The study consisted of a double-blind 12 week treatment period, followed by a 40 week open-label period.(4) The primary data from TRINITY was previously presented at ASH 2010 and the subgroup analysis data from the 40 week open-label extension was disclosed for the first time at ASH 2011. In addition, the open label extension primary data was presented at the 23rd Scientific Meeting of the International Society of Hypertension (ISH) in September 2010 in Vancouver, Canada.

In this first trial to investigate the efficacy of TRIBENZOR, patients received one of three dual combination therapies or placebo (n=36) for the first two weeks of the study: olmesartan medoxomil (40 mg)/amlodipine besylate (10 mg), olmesartan medoxomil (40 mg)/hydrochlorothiazide (25 mg) or amlodipine besylate (10 mg) and hydrochlorothiazide (25 mg). After the first two weeks, until week four, the 36 patients on placebo were switched to one of the dual combination therapies. At Week 4, the triple combination therapy of olmesartan medoxomil (40 mg) / amlodipine besylate (10 mg)/ hydrochlorothiazide (25 mg) was started in a subset of patients (n=627) from each of the three dual combination groups and continued until Week 12 followed by a 40 week open-label treatment period.(4)

About Hypertension and the Elderly
Hypertension is very common among the elderly population and is increasing in prevalence. According to the American Heart Association (AHA) and the American College of Cardiology Foundation (ACCF), by age 70, 64 percent of men and 75 percent of women have high blood pressure, placing them at an increased risk for cardiovascular disease, as well as chronic kidney disease and diabetes mellitus. As people get older, they become more susceptible to hypertension due to changes in arterial structure and function accompanied by aging. Rates of blood pressure control remain substantially lower in the elderly population as compared to younger patients. At age 70, only one in three men and one in four women have adequate control of their blood pressure and as the elderly population increases, so does uncontrolled hypertension.(5)

About TRIBENZOR
TRIBENZOR is a three-in-one combination product taken once-daily for the treatment of high blood pressure in patients who are not adequately controlled on any two of the following antihypertensive drug classes: angiotensin receptor blockers, calcium channel blockers and diuretics. TRIBENZOR is not indicated for initial therapy of hypertension.(6)

IMPORTANT SAFETY INFORMATION ABOUT TRIBENZOR

WARNING: AVOID USE IN PREGNANCY

When pregnancy is detected, discontinue TRIBENZOR as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. See WARNINGS AND PRECAUTIONS. Fetal/Neonatal Morbidity and Mortality.

Contraindications
TRIBENZOR is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Hypotension in Volume- or Salt-Depleted Patients
In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients, symptomatic hypotension due particularly to the olmesartan component may occur after initiation of treatment with TRIBENZOR. Treatment should start under close medical supervision.

Increased Angina and Myocardial Infarction
Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase.

Impaired Renal Function
Avoid use in patients with severely impaired renal function (creatinine clearance less than or equal to 30 mL/min). If progressive renal impairment becomes evident, consider withholding or discontinuing TRIBENZOR.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with TRIBENZOR because of the olmesartan medoxomil component.

Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function.

Hepatic Impairment
Avoid use in patients with severely impaired hepatic function.

Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with severely impaired hepatic function.

Minor alterations of fluid and electrolyte balance due to hydrochlorothiazide may precipitate hepatic coma.

Electrolyte and Metabolic Imbalances
Due to the hydrochlorothiazide component, observe patients for clinical signs of fluid or electrolyte imbalance.

Hypersensitivity Reaction
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such history.

Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Vasodilation
Although vasodilation attributable to amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Patients with severe aortic stenosis may be at particular risk.

Lithium Interaction
Lithium generally should not be given with thiazides.

Adverse Reactions
The most frequently reported adverse reaction was dizziness (5.8 to 8.9%). The other most frequent adverse reactions occurring in greater than or equal to 2% of patients treated with TRIBENZOR are peripheral edema (7.7%), headache (6.4%), fatigue (4.2%), nasopharyngitis (3.5%), muscle spasms (3.1%), nausea (3.0%), upper respiratory tract infection (2.8%), diarrhea (2.6%), urinary tract infection (2.4%), and joint swelling (2.1%).

About Daiichi Sankyo
The Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address the diversified, unmet medical needs of patients in both mature and emerging markets. While maintaining its portfolio of marketed pharmaceuticals for hypertension, hyperlipidemia, and bacterial infections, the Group is engaged in the development of treatments for thrombotic disorders and focused on the discovery of novel oncology and cardiovascular-metabolic therapies. Furthermore, the Daiichi Sankyo Group has created a "Hybrid Business Model," which will respond to market and customer diversity and optimize growth opportunities across the value chain. For more information, please visit www.daiichisankyo.com.

Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is a member of the Daiichi Sankyo Group. For more information on Daiichi Sankyo, Inc., please visit www.dsi.com.

(1) Chrysant, S. et al. Long-Term Efficacy and Safety of Combination Olmesartan Medoxomil (OM)/Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ) in Study Participants With Hypertension Based on Age: The TRINITY Study. Poster Presented at: American Society of Hypertension Annual Meeting; May 21-24, 2011; New York, NY

(2) Oparil, S. et al. Long-Term Efficacy and Safety of Combination Olmesartan Medoxomil (OM)/Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ)—The TRINITY Study: Subgroup Analyses Based on Study Participant Diabetes Status and BMI. Poster Presented at: American Society of Hypertension Annual Meeting; May 21-24, 2011; New York, NY.

(3) Chrysant, S. et al. Long-Term Efficacy and Safety of Combination Olmesartan Medoxomil (OM)/Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ)—The TRINITY Study: A Subgroup Analysis by Study Participant Race. Poster Presented at: American Society of Hypertension Annual Meeting; May 21-24, 2011; New York, NY.

(4) Oparil, S. et al. Long-Term Efficacy and Safety of Combination Olmesartan Medoxomil (OM)/Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ)—The TRINITY Study. Poster Presented at: American Society of Hypertension Annual Meeting; May 1-4, 2010; New York, NY.

(5) American Heart Association. ACC/AHA Issue First Clinical Guidance for Controlling High Blood Pressure Those 65+ are at high risk for hypertension and related health problems – even death. Press Release issued on April 25, 2011. Available at: http://www.newsroom.heart.org/index.php?s=43&item=1325. Accessed May 13, 2011.

(6) Daiichi Sankyo, Inc.. TRIBENZOR Prescribing Information.

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SOURCE Daiichi Sankyo, Inc.
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