Data published in the Journal of the American Society of Hypertension
demonstrate that early blockade of angiotensin II reversed vascular
hypertrophy
PARSIPPANY, N.J., June 16 /PRNewswire/ -- A new study published in the
current Journal of the American Society of Hypertension demonstrates that
the hypertension treatment olmesartan medoxomil was effective in reversing
the narrowing of the arteries that occurs in patients with hypertension.
The study, titled VIOS (Vascular Improvement with Olmesartan medoxomil
Study) was a one-year, exploratory study that evaluated the effects of an
angiotensin receptor blocker (olmesartan medoxomil) vs. a beta-blocker
(atenolol) on vascular function and structure in patients with Stage 1
hypertension, independent of the blood pressure lowering effects of these
agents.(1)
In the VIOS trial, olmesartan medoxomil, through early blockade of
angiotensin II, improved the structure abnormalities of resistance arteries
in patients with hypertension as measured by arterial wall to lumen ratio
(W/L), returning arterial architecture to normal levels after one year of
treatment. This protective effect was not seen with the comparator agent in
the study, atenolol.(2) Olmesartan medoxomil is marketed in the United
States by Daiichi Sankyo, Inc., as BENICAR(R). BENICAR and BENICAR HCT(R)
(olmesartan medoxomil/hydrochlorothiazide) are indicated for the treatment
of hypertension. They may be used alone or in combination with other
antihypertensive agents. BENICAR HCT is not indicated for initial therapy.
BENICAR and BENICAR HCT have not been FDA approved for other indications
such as end organ disease or other hypertension related morbidity.
"We believe the VIOS data add to the growing evidence for the role of
angiotensin receptor blockers in preventing or reversing vascular damage at
many stages during this disease process," said Carlos M. Ferrario, M.D.,
one of the study's lead investigators and Professor and Director of
Hypertension and Vascular Research Center, Wake Forest University School of
Medicine.
Angiotensin II has been linked to vascular dysfunction and end-organ
damage, including cardiac hypertrophy and renal injury.(3,4,5) Previous
studies have demonstrated a beneficial effect of ACE inhibitors or other
angiotension II receptor blockers (ARBs) in the reversal of vascular
hypertrophy in hypertensive subjects.(6,7,8,9,10,11,12)
Hypertension is one of the most prevalent conditions in the United
States, affecting one in three Americans.(13) Long-standing, uncontrolled
hypertension can damage the brain, the eyes, the heart and the kidney.(14)
Antihypertensive agents that inhibit the renin-angiotensin system, such as
angiotensin-converting enzyme inhibitors or ARBs, have demonstrated
substantially greater effects on end-organ repair in the kidney and the
heart.(15,16,17,18)
VIOS Study Design
The study was a randomized, controlled, open-label, one-year study. The
primary endpoint of this study was the change in the morphological
characteristics of resistance arteries as determined by differences in the
wall (media)/lumen (W/L) ratio. This parameter was measured using a
pressurized myograph procedure on arteriole biopsy samples obtained from a
sub-group of 49 patients receiving treatment (27 were on olmesartan and 22
were on atenolol) and from 11 normotensive control subjects.(19)
Non-diabetic patients with Stage 1 hypertension (61% male; age 38 to 67
years) were randomized after a 4-week washout period to olmesartan
medoximil 20 to 40 mg or atenolol 50 to 100 mg plus additional agents
(hydrochlorothiazide 12.5-25 mg, amlodipine 5-10 mg, or hydralazine 50-100
mg twice daily) as needed for a goal BP of < 140/90).(20) Stage 1
hypertension is defined by the JNC 7 as systolic blood pressure (SBP) of
140-159 mm Hg or diastolic blood pressure (DBP) of 90-99 mm Hg.(21)
VIOS Study Results
The arteriolar dimensions (W/L Ratios) in the olmesartan medoxomil and
atenolol-based treatment groups were similar prior to drug treatment (14.9%
and 16% respectively) whereas arteries from the normotensive subjects had
significantly smaller W/L ratios (11%). At the end of the study the W/L
ratio in the olmesartan medoxomil-based treatment group was significantly
reduced (from 14.9% to a mean of 11.1%; P<0.01). No significant change was
observed in arteries of atenolol-treated patients (from 16.0% to 15.5%;
P=NS). The difference between olmesartan medoxomil-treated and
atenolol-treated patients at 1 year was significant (11.1% vs. 15.5%;
P<0.001). Blood pressure reductions from baseline occurred within 12 weeks
for both treatments and were statistically significant (P<0.05); blood
pressure reductions were similar between the two treatments for the
remainder of the study.(22)
This study was supported through an unrestricted grant from Daiichi
Sankyo, Inc.
Ongoing Studies with Olmesartan Medoxomil
Olmestartan medoxomil is currently being reviewed in several outcomes
trials, including the landmark "Randomized Olmesartan And Diabetes
MicroAlbuminuria Prevention Study" or ROADMAP trial. This is a Phase IV
multinational clinical study to investigate the drug's effectiveness in
preventing early stage kidney disease in patients with type 2 diabetes. The
trial is being conducted at 200 sites in 20 countries involving 4,400
patients. Another study, titled "Olmesartan Reducing Incidence of End stage
renal stage in diabetic Nephropathy Trial," or ORIENT, targeting Japanese
and Hong Kong Chinese patients, is investigating the suppressive effects of
the drug against the progression of diabetic nephropathy.
About BENICAR and BENICAR HCT
Angiotensin II is a hormone that interacts with a receptor on arterial
blood vessels, which results in constriction and increasing blood pressure.
In addition, angiotensin II stimulates the release of another hormone that
causes enhanced sodium and chloride (salt) retention, with a resultant
increase in vascular water retention and blood volume that also contributes
to an elevation in blood pressure. BENICAR is a member of the ARB class of
antihypertensive medications that help lower blood pressure by blocking the
angiotensin II receptor on the blood vessels and antagonizing the release
of the hormone which causes salt retention and increased blood volume.
BENICAR HCT combines BENICAR with the diuretic hydrochlorothiazide.
BENICAR and BENICAR HCT are indicated for the treatment of
hypertension. They may be used alone or in combination with other
antihypertensive agents. BENICAR HCT is not indicated for initial therapy.
Important Safety Information
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, BENICAR or
BENICAR HCT should be discontinued as soon as possible. See WARNINGS,
Fetal/Neonatal Morbidity and Mortality in the prescribing information.
Hypotension in Volume- or Salt-Depleted Patients
In patients with an activated renin-angiotensin system, such as volume-
and/or salt-depleted patients (eg, those being treated with high doses of
diuretics), symptomatic hypotension may occur after initiation of treatment
with BENICAR. Treatment should start under close medical supervision. If
hypotension does occur, the patient should be placed in the supine position
and, if necessary, given an intravenous infusion of normal saline. A
transient hypotensive response is not a contraindication to further
treatment, which usually can be continued without difficulty once the blood
pressure has stabilized.
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 results may be expected.
The prescribing information for BENICAR HCT also includes the following
warnings regarding its hydrochlorothiazide component:
BENICAR HCT is not recommended in patients with severe renal impairment
and is contraindicated in patients with anuria or hypersensitivity to other
sulfonamide derived drugs.
Fetal/Neonatal Morbidity and Mortality
Thiazides cross the placental barrier and appear in cord blood. There
is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly
other adverse reactions that have occurred in adults.
Hepatic Impairment
Thiazides should be used with caution in patients with impaired hepatic
function or progressive liver disease, since minor alterations of fluid and
electrolyte balance may precipitate hepatic coma.
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 a history.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or
activation of systemic lupus erythematosus.
Lithium Interaction
Lithium generally should not be given with thiazides.
Adverse Events
-- The withdrawal rates due to adverse events (AEs) were similar with
BENICAR and BENICAR HCT to placebo: BENICAR (2.4% vs 2.7%); BENICAR HCT
(2.0% vs 2.0%)
-- The incidence of AEs with BENICAR and BENICAR HCT was similar to
placebo
-- The only AE that occurred in > 1% of patients treated with BENICAR and
more frequently than placebo was dizziness (3% vs 1%)
-- AEs reported in > 2% of patients taking BENICAR HCT and more frequently
than placebo included nausea (3% vs 0%), hyperuricemia (4% vs 2%),
dizziness (9% vs 2%), and upper respiratory tract infection (7% vs 0%)
Dosing and Administration
-- No initial dosage adjustments are recommended with BENICAR in elderly
or in moderate to marked renal impairment*/hepatic dysfunction
-- In patients with possible depletion of intravascular volume (eg,
patients on diuretics, particularly with impaired renal function),
BENICAR should be initiated under close medical supervision and
consideration given to use of a lower starting dose
-- For BENICAR HCT, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosage range
*Creatinine clearance < 40 mL/min.
Please see full prescribing information for BENICAR and BENICAR HCT.
About Daiichi Sankyo, Inc.
Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is the
U.S. subsidiary of Daiichi Sankyo Co., Ltd., Japan's second largest
pharmaceutical company and a global leader in pharmaceutical innovation
since 1899. The company is dedicated to the discovery, development and
commercialization of innovative medicines that improve the lives of
patients throughout the world.
The primary focus of Daiichi Sankyo's research and development is
cardiovascular disease, including therapies for dyslipidemia, hypertension,
diabetes, and acute coronary syndrome. The company is also pursuing the
discovery of new medicines in the areas of glucose metabolic disorders,
infectious diseases, cancer, bone and joint diseases, and immune disorders.
For more information, please visit http://www.dsus.com.
1. Smith, Ronalde et al. "Reversal of vascular hypertrophy in
hypertensive patients through blockade of angiotensin II receptors.
J Am Soc Hypertension 2008;2(3);165-172
2. Smith, Ronalde et al. "Reversal of vascular hypertrophy in
hypertensive patients through blockade of angiotensin II receptors.
J Am Soc Hypertension 2008;2(3);165-172
3. Intengan, HD et al. Resistance Artery Mechanics, Structure, and
Extracellular Components in Spontaneously Hypertensive Rats: Effects
of Angiotensin Receptor Antagonism and Converting Enzyme Inhibition.
Circulation 1999;100;2267-75
4. Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial
structure and endothelial dysfunction in human essential hypertension
by the angiotensin receptor antagonist losartan. Circulation
2000;101:1653-9.
5. Schiffrin EL. Vascular and cardiac benefits of angiotensin receptor
blockers. Am J Med 2002;113:409-18.
6. Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial
structure and endothelial dysfunction in human essential hypertension
by the angiotensin receptor antagonist losartan. Circulation 2000;101:
1653-9.
7. Mulvany MJ. Effects of angiotensin-converting enzyme inhibition on
vascular remodeling of resistance vessels in hypertensive patients.
Metabolism 1998;47(12 suppl1):S20-3
8. Schiffrin EL, Park JB, Pu Q. Effect of crossing over hypertensive
patients from a beta-blocker to an angiotensin receptor antagonist on
resistance artery structure and on endothelial function. J Hypertens
2002;20:71-8
9. Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany MJ.
Effect of antihypertensive treatment on small arteries of patients
with previously untreated essential hypertension. Hypertension 1995;
25:474-81
10. Schiffrin EL, Deng LY, Larochelle P. Effects of a beta-blocker or a
converting enzyme inhibitor on resistance arteries in essential
hypertension. Hypertension 1994;23:83-91
11. Schiffrin EL, Deng LY. Structure and function of resistance arteries
of hypertensive patients treated with a beta-blocker or a calcium
channel antagonist. J Hypertens 1996;14:1247-55
12. Schiffrin EL. Remodeling of resistance arteries in essential
hypertension and effects of antihypertensive
treatment. Am J Hypertens 2004;17:1192-200
13. http://www.americanheart.org/presenter.jhtml?identifier=4621 Site
accessed 4/18/2008
14. High Blood Pressure; Why Should I Care.
http://www.americanheart.org/presenter.jhtml?identifier=2129 Site
accessed 6/3/2008
15. Lewis, EJ. The Role of Angiotensin II Receptor Blockers in Preventing
the Progression of Renal Disease in Patients with Type 2 Diabetes. Am
J Hypertension 2002;15;123S-8S
16. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal
and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med 2001;345:861-9.
17. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular
hypertrophy in hypertensive patients. A metaanalysis of 109 treatment
studies. Am J Hypertens 1992;5:95-110.
18. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity
and mortality in the Losartan Intervention For Endpoint Reduction in
Hypertension Study (LIFE): a randomized trial against atenolol. Lancet
2002;359:995-1003.
19. Smith, Ronalde et al. "Reversal of vascular hypertrophy in
hypertensive patients through blockade of angiotensin II receptors.
J Am Soc Hypertension 2008;2(3);165-172
20. Smith, Ronalde et al. "Reversal of vascular hypertrophy in
hypertensive patients through blockade of angiotensin II receptors.
J Am Soc Hypertension 2008;2(3);165-172
21. JNC 7 = The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation and Treatment of High Blood Pressure
(JNC 7), which issued new guidelines in 2003 for hypertension
prevention and management.
22. Smith, Ronalde et al. "Reversal of vascular hypertrophy in
hypertensive patients through blockade of angiotensin II receptors.
J Am Soc Hypertension 2008;2(3);165-172
For more information, please contact:
Kimberly Wix Rich Salem
Daiichi Sankyo, Inc. Daiichi Sankyo, Inc.
Office: 973 695 8338 Office: 973 695 8330
Cell: 908 656 5447 Cell: 973 563 1086
kwix@dsus.com rsalem@dsus.com
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SOURCE Daiichi Sankyo, Inc.
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http://www.dsus.com
CONTACT:
Kimberly Wix, Office, +1-973-695-8338, Cell,
+1-908-656-5447, kwix@dsus.com; or Rich Salem, Office,
+1-973-695-8330, Cell, +1-973-563-1086, rsalem@dsus.com, both of
Daiichi Sankyo, Inc.
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