PARSIPPANY, N.J., May 3 /PRNewswire/ -- Preliminary results from a dose titration study showed that treatment with the fixed-dose combination therapy AZOR® (amlodipine and olmesartan medoxomil) helped the majority (cumulative 75.8 percent) of hypertensive patients to reach systolic blood pressure goals of <140 mm Hg (<130 mm Hg for patients with diabetes) at any time point during the first 12 weeks and 66.1 percent non-cumulative at Week 12. The primary endpoint of the study was the percentage of patients achieving seated systolic blood pressure goal of <140 mm Hg (<130 mm Hg patients with diabetes) cumulatively by Week 12. A total of 71.3 percent of patients achieved a blood pressure goal of <140/90 mm Hg or 130/80 mm Hg for patients with diabetes during the first 12 weeks (60.6 percent at Week 12).(1)

The study enrolled 999 patients unable to attain blood pressure control on monotherapy and switched to AZOR for a 20 week duration.(1) Uncontrolled hypertension was defined as mean systolic blood pressure (SBP) greater than or equal to 140 mm Hg and less than or equal to 180 mm Hg AND mean diastolic blood pressure (DBP) less than or equal to 110 mm Hg or mean SBP greater than or equal to 130 mm Hg and < 180 mm Hg AND mean DBP less than or equal to 110 mm Hg for patients with diabetes. Data were presented during the late breaker poster session of the American Society of Hypertension (ASH) annual meeting in New York.

The prospective, open-label, multicenter, single-arm, dose titration Blood Pressure Control in All Subgroups with Hypertension (BP CRUSH) sought to examine whether there would be a benefit of switching patients from monotherapy to AZOR without a washout period. The findings showed that patients treated with AZOR 10/40 mg experienced significant reductions in systolic blood pressure (SBP) of 20.3 mm Hg (mean baseline systolic blood pressure 154.0 mm Hg) and diastolic blood pressure (DBP) of 11.3 mm Hg (mean baseline diastolic blood pressure 92.3 mm Hg), P< 0.0001.(1)

A total of 229 patients in BP CRUSH underwent pre-specified 24-hour ambulatory blood pressure measurement (ABPM). Patients achieved a mean 24-hour ambulatory blood pressure reduction of 14.8/9.4 mm Hg from baseline (136.2/81.6 mm Hg) to Week 12.(1)

“The results of this study may be of immediate practical use to physicians, as they show that switching patients from monotherapy to combination therapy was widely effective in helping patients better achieve blood pressure control,” said Dr. Joel Neutel, MD, Director, Orange County Heart Institute and Research Center, Tustin, CA. “What makes these results so valuable is that there was no period of non-treatment before switching from one medication to another, so it allows us to see that patients responded safely and effectively to switching from monotherapy to AZOR."(1)

In BP CRUSH, treatment with AZOR was well tolerated, with no deaths or drug-related serious adverse events (AEs). Treatment emergent adverse events (TEAEs) occurred in 429 out of 999 (42.9 percent) patients, but the majority of TEAEs were mild-to-moderate in severity. Treatment emergent adverse events leading to discontinuation occurred in 53 out of 999 (5.3 percent) of patients.(1)

Study Design

BP CRUSH was a prospective, open-label, multicenter, titration study evaluating blood pressure goal attainment after switching to the combination therapy AZOR in 999 patients with hypertension uncontrolled on monotherapy. The 20 week active treatment period consisted of consecutive four-week intervals with dosages up-titrated as follows: AZOR 5/20 mg; AZOR 5/40 mg; AZOR 10/40 mg (to achieve blood pressure <120/70 mm Hg); AZOR 10/40 mg plus hydrochlorothiazide 12.5 mg; AZOR 10/40 mg plus hydrochlorothiazide 25 mg (to achieve blood pressure <125/75 mm Hg).(1) A total of 229 patients underwent ambulatory blood pressure monitoring (ABPM) at baseline, Week 12, and Week 20 (n=199).(2)

Almost 38 percent (37.5 percent) of participants in the study had previously been treated with an angiotensin receptor blocker or calcium channel blocker. Male and female patients greater than or equal to 18 to 80 years (patients without diabetes: 140 less than or equal to SBP less than or equal to 180 mm Hg and DBP less than or equal to 110mm Hg; patients with diabetes: 130 less than or equal to SBP less than or equal to 180 mm Hg and DBP less than or equal to 110 mm Hg) were eligible for randomization. At least 100 subjects in each of the following subpopulations were recruited: elderly (greater than or equal to 65 years), Black, Hispanic, Asian, obese (BMI greater than or equal to 30 kg/m2), type 2 diabetes, and metabolic syndrome, which is defined as a multiplex of risk factor for cardiovascular disease.(1, 3)

The primary endpoint of the study was the proportion of subjects achieving cuff systolic blood pressure goal (<140 mm Hg-patients without diabetes; <130 mm Hg patients with diabetes) during the first 12 weeks. The secondary endpoints included: cuff diastolic blood pressure control (<90 mm Hg-non-diabetics; <80 mm Hg-diabetics) during the first 12 weeks, and cuff blood pressure goals (<140/90 or <130/80 for those with diabetes) during the first 12 and 20 weeks, change from baseline in mean blood pressure and percentage of subjects achieving blood pressure goals after each treatment interval, and proportions of patients tested using ambulatory blood pressure monitoring (ABPM) achieving blood pressure goals after 12 and 20 weeks.(2)

About Clinical Inertia

Many patients with high blood pressure can suffer from under-treatment due to clinical inertia, which occurs when medications or increased doses of existing medications are not provided when blood pressure treatment goals are not met.(4) Additionally, patients also may not be fully aware in understanding the importance of adhering to prescribed treatment regimens and making behavioral changes in order to meet blood pressure goals. While BP CRUSH did not evaluate the impact of AZOR on clinical inertia, it provides evidence that fixed-dose combination antihypertensive therapy can get patients to blood pressure goal.

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines recommend that patients with high blood pressure achieve a goal blood pressure of <140/90 mm Hg or <130/80 mm Hg for patients with diabetes.(5) Hypertension is often difficult to control, and of those with high blood pressure, approximately 55 percent do not have the condition under control.(6)

Despite 50 years of treating hypertension and seven evolutions of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC) guidelines, a gap remains between guidelines and their implementation to achieve optimal blood pressure goals.(7) It is thought that clinical inertia is a major contributing factor in this gap. Recent work suggests that clinical inertia related to the management of diabetes, hypertension and lipid disorders may contribute to up to 80 percent of heart attacks and strokes. As a result, clinical inertia is considered a leading cause of potentially preventable adverse events, disability, death and excess medical care costs. Contributing factors to the inertia may include inaccurate understanding of normal blood pressure control, side effects associated with aggressive treatment, or the belief that higher blood pressure levels in some patients is acceptable.(2)

About AZOR

AZOR is a convenient, once daily, single tablet combination of amlodipine, the most prescribed CCB on the market, which inhibits the entrance of calcium into the blood vessel walls, with olmesartan medoxomil, the active ingredient in Benicar®, which blocks angiotensin II receptors. Angiotensin II is a hormone that causes blood vessels to tighten and narrow. Together the two medicines relax the blood vessels so that blood can flow more easily. Benicar (olmesartan medoxomil), Daiichi Sankyo’s flagship ARB product, is the fastest growing medication in the fastest growing class of blood pressure-lowering drugs.

The U.S. Food and Drug Administration (FDA) granted marketing approval for AZOR in September 2007. AZOR is indicated for the treatment of hypertension, alone or with other antihypertensive agents. AZOR may be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals. Initial therapy with AZOR is not recommended in patients greater than or equal to 75 years old or hepatically impaired patients. AZOR may be substituted for its individually titrated components. AZOR may also be used to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine CCB) alone or with olmesartan medoxomil (or another ARB) alone. In the pivotal registrational trial, AZOR demonstrated that eight weeks of double-blind treatment with combination therapy resulted in larger mean reductions in seated blood pressure and brought more patients to goal in comparison to the corresponding monotherapies. There are no studies with AZOR demonstrating a reduction in cardiovascular events.

IMPORTANT SAFETY INFORMATION ABOUT AZOR

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, AZOR should be discontinued as soon as possible. See WARNINGS AND PRECAUTIONS, Fetal/Neonatal Morbidity and Mortality.

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 AZOR®. Treatment should start under close medical supervision.

Vasodilation

Since the vasodilation attributable to amlodipine in AZOR is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering AZOR, particularly in patients with severe aortic stenosis.

Severe Obstructive Coronary Artery Disease

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.

Congestive Heart Failure

In general, calcium channel blockers should be used with caution in patients with heart failure.

Impaired Renal Function

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 AZOR because of the olmesartan medoxomil component.

Hepatic Impairment

Since 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, caution should be exercised when administering AZOR to patients with severe hepatic impairment. Initial therapy with AZOR is not recommended in hepatically impaired patients.

Laboratory Tests

There was a greater decrease in hemoglobin and hematocrit in the combination product compared to either component alone.

Adverse Reactions

The only adverse reaction that occurred in greater than or equal to 3 percent of patients treated with AZOR and more frequently than placebo was edema. The placebo-subtracted incidence was 5.7 percent (5/20 mg), 6.2 percent (5/40 mg), 13.3 percent (10/20 mg), and 11.2 percent (10/40 mg). The edema incidence for placebo was 12.3 percent.

Adverse reactions seen at lower rates but at about the same or greater incidence as in patients receiving placebo included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia.

In individual clinical trials of amlodipine and olmesartan medoxomil, other commonly reported adverse reactions included headache, dizziness, and flushing.

Geriatric Use

Elderly patients have decreased clearance of amlodipine. Initial therapy with AZOR is not recommended in patients greater than or equal to 75 years old.

For more information on AZOR®, call 877-4-DSPROD (877-437-7763) or go to the web site www.azor.com.

About Daiichi Sankyo

In keeping with its vision of becoming a “Global Pharma Innovator,” the Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address the diversified, unmet medical needs of customers in both developed 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 the U.S. subsidiary of Daiichi Sankyo Company, Ltd. For more information on Daiichi Sankyo, Inc., please visit www.dsi.com.

(1) BP CRUSH Abstract: Effects on BP Control of Amlodipine (AML)/Olmesartan Medoxomil (OM), with or without Hydrochlorothiazide (HCTZ), In Patients Not Controlled by Prior Antihypertensive Monotherapy. Presented at ASH 2010.

(2) BP-CRUSH Poster: Rationale and Design of Blood Pressure Control in All Subgroups with Hypertension Study (BP CRUSH) Evaluating the Efficacy and Safety of Amlodipine (AML)/Olmesartan Medoxomil (OM) in Patients Who are Non-Responders to Antihypertensive Monotherapy.

(3) American Heart Association. Metabolic Syndrome. Available at: http://www.americanheart.org/presenter.jhtml?identifier=3063528. Accessed April 19, 2010.

(4) U.S. Department of Health and Human Services. Advances in Patient Safety: From Research to Implementation. Vol 2. AHRQ Publication Nos. 050021 (1-4). February 2005, pg. 293. Available at http://www.ahrq.gov/downloads/pub/advances/vol2/OConnor.pdf. Accessed April 21, 2009.

(5) The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Bethesda, MD: National Institutes of Health: National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program; May 2003. NIH Publication 03-5233.

(6) American Heart Association. High Blood Pressure Statistics. Available at: http://www.americanheart.org/presenter.jhtml?identifier=4621. Accessed March 29, 2010.

(7) McInnes, GT et al. How Important is Optimal BP Control? Clinical Therapeutics, Vol 26, Supplement 1, 2004, Pages A3-A11.

SOURCE Daiichi Sankyo, Inc.