ASH Times - American Society of Hypertension

Transcription

ASH
TIMES
San Francisco
FRIDAY | SATURDAY
The American Society of Hypertension, Inc. • 24th Annual Scientific Meeting and Exposition • The San Francisco Marriott • May 6 – May 9, 2009
Meeting Basics
Health-care reform offers challenges,
opportunities for ASH members
Economic crisis has long-term implications for research.
T h e com bi n e d c h a l l e ng e s of
Registration Desk Hours
Friday . . . . . . . . . . . 5:30 a.m. to 6:00 p.m.
Saturday . . . . . . . . . . 5:30 to 10:00 a.m.
Scientific and Technical
Exhibit Hours
Friday . . . . . . . . . . . 9:30 a.m. to 12:45 p.m.
Lunch . . . . . . .
11:45 a.m. to 12:45 p.m.
High Tea . . . . . . . .
2:30 to 3:30 p.m.
ASH Information / CME Desk
Visit the ASH Information / CME Desk in the
Golden Gate Foyer across from the exhibit
hall for information on ASH programs.
health-care reform and economic stress
mean significant changes are ahead for academic medicine.
“It is a remarkable time that we’re in now.
We are living through great change. In the
next five or so years, the underpinnings of
what we’re used to doing are going to be challenged,” said Samuel O. Thier, MD, Professor
of Medicine and Health Care Policy at Harvard Medical School. Dr. Thier presented the
keynote lecture, “Academic Medicine and
the Economy: What Would Darwin Advise?”
at Thursday’s plenary session.
“On the 200th anniversary of Darwin’s
birth, it’s helpful to ask: How would he
think about this change? He had a simple
idea that changed science and even changed
the way that we think about change,” Dr.
Thier said. “Darwin thought that distant
biologic predecessors had evolved on the
basis of external stresses and their ability
to function with those stresses. Those who
were able to cope with those stresses were
successful and evolved, those who were not
became extinct.”
The current progression of science is
unmatched in history, and those in academic
Samuel O. Thier, MD
medical centers must think about how to
move ahead with the science while addressing the challenges of funding and reform.
“It is obvious that we will not be permitted to continue on the present path. We are
going to be making changes in the ways we
organize and deliver care. And since ASH
members are major deliverers of care, and
since you are people who are producing the
new knowledge to improve that care, whatever change is going to happen is going to
Health-care reform, continued on page 2
2009 Annual Scientific
Meeting Corporate Sponsors
The American Society of Hypertension
wishes to acknowledge the following
corporate sponsors for their generous
support of the ASH 24th Annual
Scientific Meeting.
Plenary Session II Friday morning
Boehringer Ingelheim Pharmaceuticals, Inc.
Daiichi Sankyo, Inc.
Merck & Co., Inc.
Novartis Pharmaceuticals Corporation
Sanofi Aventis
8:15 a.m. — Genetic Variations in Human Hypertension.
Daniel T. O’Connor, MD
8:45 a.m. — Salt: From Evidence to Worldwide
Implementation. Graham MacGregor, MD
Don’t miss this Friday morning’s plenary session, which begins at 8:15 a.m. in the Yerba Buena Ballroom – Salon 9. Several
notable speakers will present talks on timely topics in hypertension, including a lecture by cardiovascular specialist Graham
MacGregor, MD.
Visit us at Booth #205
9:15 a.m. — Debate: Do We Need New Risk Factors?
Jay N. Cohn, MD, and William C. Cushman, MD
2
Ash Times • Friday | Saturday • May 8–9 • San Francisco
health-care reform,
continued from page 1
affect you. It’s important for you to underThe other lessons for ASH members
stand that and participate in the discussions are clear.
of how these changes are to come about.
“Reaffirm your ASH mission and values,
Don’t sit on the sidelines and wait for the adhere to them, and make judgments based on
storm to pass — take the opportunity to play them. Review the changes from the perspecan important role in the changes to come,” tive of your mission and what is best for your
he said.
patients. You have to be sure that as you are ana“Darwin saw the importance of exter- lyzing and arguing for what is best at academic
nal factors in survival and extinction. He medical centers going forward, that you keep
thought that successful evolution of species your patients first,” he said. “Understand your
was associated with chance and was largely opportunities and the risks to research and
unplanned. But that’s not always the case,” clinical care and stay involved in the discusDr. Thier said. “Our
sion. Hypertension is
species is one of the Darwin saw the importance of a major public health
few that’s able to anconcern. It is easily
ticipate events and to external factors in survival and diagnosed. It is easily
adjust or even modify extinction. He thought that suc- treated. There is a docthose events. A nd,
umented cost/benefit
therefore, it’s impor- cessful evolution of species was in terms of prevention
tant for us to think associated with chance and was and treatment of heart
about what we’re goattack and stroke. And
largely unplanned. But that’s not there’s also the proming to do.”
Dr. Their noted always the case. Our species is one ise of value added to
t hat N I H f u nd i ng
the healthcare sysis f lat and there has of the few that’s able to anticipate tem by phenotype and
been contraction and events and to adjust or even modify genotype data.
consolidation in big
“A t t he p ol ic y
pharma and in bio- those events. And, therefore, it’s im- level, support pretechnology. This has portant for us to think about what vention, which is one
meant that for acaof your key goa ls.
demic medical cen- we’re going to do.
Support research in
ters it can be risky to
general, you have the
– Samuel O. Thier, MD history of possibilities
invest in people and
in facilities. “Howfor the phenotype and
ever, those that have been willing to take that that is going to give you a lot of information.
risk have had successful recruiting and reten- Lifestyle interventions are a major area of
tion efforts and the changes are going to favor expertise for ASH members. And in the
those who are willing to take some risks and clinical area, educating the public and other
marshal their resources and strategize about health-care professionals is an important part
how they want to go forward,” he said.
of what you do and you need to be organized
The opportunities for ASH members in- to do that.”
clude expanded research. For a number of years,
“We’re in a time of major change. The
academic medical centers have supported their change could be terrific. The science and poacademic mission with the margins generated tential clinical benefits are phenomenal. But
from inpatient and outpatient dollars, but that the economic stresses are going to be major
support is likely to diminish or even disappear. constraints on what you can accomplish,”
So it’s important to think about where funding Dr. Thier concluded. “It’s important to stay
will come from, Dr. Thier said. “I think indus- in the game and to be f lexible. Be sure that
try will be placing more research at academic you know what you want to get done, but
sites. This is going to move the long-term risks understand that you must listen to the arguto your institutions,” he said.
ments in the opposite direction.” l
Board of directors appoints editor
The American Society of Hypertension
Board of Directors recently appointed
Michael Weber, MD, Professor of Medicine
at the State University of New York
Downstate Medical College of Medicine in
Brooklyn, as Editor-in-Chief of The Journal
of Clinical Hypertension — an official
journal of the society.
Dr. Weber’s career has primarily
focused on hypertension and preventive
cardiology. He was one of the founders
of the American Society of Hypertension
and has served as president of the society.
He is a fellow of the American College of
Physicians, American College of Cardiology,
and American Heart Association. Dr. Weber
has served on the Cardiovascular and
Renal Drugs Advisory Board of the Food
and Drug Administration and continues as
a consultant to that agency.
His current research interests focus on
clinical trials of patients with hypertension
and those at high risk of cardiovascular
events or recurrent strokes. He is also
an active participant in trials involving
patients with diabetic and non-diabetic
nephropathy.
Dr. Weber succeeds Marvin Moser, M.D.,
FACP, Clinical Professor of Medicine at Yale
University School of Medicine.
Dr. Moser, who served as Editor-in-Chief
of The Journal of Clinical Hypertension
since its inception in 1999, has chaired
several national committees that
established guidelines for the diagnosis
and treatment of hypertension. He has
received numerous awards from the
International Society of Hypertension, the
National Heart Lung & Blood Institute, the
American Society of Hypertension, and
several medical universities for his research
and treatment efforts in hypertension.
Dr. Moser is the author of more than
500 scientific publications and 11 books
and has lectured extensively in the United
States and abroad. l
Role of hypertension specialist in
research and therapy examined
Lifestyle intervention, pharmacotherapy keys
to pre-diabetes management.
The ASH Annual Scientific meeting
theme, “Health Care 2009: The Role of the
Hypertension Specialist” was highlighted in
presentations by three speakers at Thursday’s
Plenary Session, which was organized around
the meeting’s three concurrent tracks: translational issues in hypertension, therapy of hypertension, and pathobiology of hypertension.
Inflammation and adaptive immunity
Markers of inflammation are commonly
encountered in cardiovascular disease.
“Innate and adaptive immunity are highly
interactive. And there seems to be an interplay
between oxidation and inflammation,” said
David G. Harrison, MD, Chief of Cardiology
at Emory University, who addressed “Roles
of Inflammation and Adaptive Immunity in
Hypertension.”
Dr. Harrison described research indicating
that angiotensin II-induced hypertension leads
to vascular T-cell infiltration. The activated Tcells have a propensity to enter visceral fat.
“Another study indicated that in humans
there is a correlation between BMI and visceral
fat concentration. This seems to be in visceral
fat as opposed to subcutaneous fat. So in humans the accumulation of cells seems to be
concentrated in visceral fat,” he said.
“Research indicates that if you remove
oxidation or if you remove inflammatory cells,
you get a low level of hypertension. It’s a level of
hypertension that as clinicians we would say is
prehypertension,” Dr. Harrison said.
“In a study of people with prehypertension, that prehypertension is stimulating
an inflammatory response,” he said. “If you
treat this inflammation, you can prevent the
development of full hypertension. If you don’t
treat the inflammation, the patient develops a
full-blown, inflammatory response that then
leads to severe hypertension.”
Limitations of outcome trials
In his presentation on “Outcome Trials in
Hypertension: More Limitations that We Used
to Think?” Giuseppe Mancia, MD, Milan,
Italy, described the value and the limitations
of event-based, or morbidity/mortality, randomized trials.
Dr. Mancia described guidelines from the
European Society of Hypertension, which list the
pros and cons of morbidity/mortality trials.
“The guidelines note that randomization
is the safest procedure to avoid bias in the results. In general, the large number of patients
guarantees the power to detect differences in
primary endpoints of clinical importance,” Dr.
Mancia said.
“The guidelines also note the limitations of
morbidity/mortality trials,” he said.
Among the limitations are determining
the applicability to clinical practice, and also
the fact that nonresponders are kept on the
initial treatment, so results are from a mixture
of responders and nonresponders.
Several factors limit the duration of randomized clinical trials, including cost, marketing needs, patency expiration, and the
instability of patients and investigators, Dr.
Mancia said.
“One problem is that trials last four to five
years, and we use this information to make
treatment decisions for patients who may have
life expectancies of 20 years or more,” he said.
“The purpose of the trials is to try to delay
or prevent the progression from a relatively
low-risk condition to a high-risk condition.
Because once a high-risk condition is reached,
it’s almost irreversible,” he said.
Managing pre-diabetes
There are 57 million adults in the United
States with pre-diabetes. The criteria for defining pre-diabetes are impaired fasting glucose,
impaired glucose tolerance, or both.
“There are two models for the progression
from pre-diabetes to type 2 diabetes: low insulin secretion and low insulin resistance,” said
Alan J. Garber, MD, PhD, of Baylor College
of Medicine in Houston, who spoke on “The
Diagnosis and Treatment of the Patient with
Pre-diabetes.”
“The clinical risks and consequences of
not treating pre-diabetes are substantial,” Dr.
Garber said. The microvascular disease risks
include retinopathy, neuropathy, and nephropathy. The cardiovascular risks include heart disease, stroke, and peripheral vascular diseases.
“Lifestyle interventions are generally
effective in preventing or controlling prediabetes,” he said. “To address high-risk cardiovascular factors, pharmacotherapy may also
be necessary.” l
Scientific Poster Presentations
Posters will be displayed in Golden Gate Hall
Friday, May 8
Posters on Display: 9:30 a.m. to 4:00 p.m.
Poster Viewing: 2:30 to 3:30 p.m.
Clinical Trials . . . . . . . . . . . . (P257 – P300)
Epidemiology/Special Populations
. . . . . . . . . . . . . . . . . . . . (P301 – P334)
Neural Hormonal Mechanisms
(Renin; Neural Control; Vasoactive Autacoids)
. . . . . . . . . . . . . . . . . . . . (P335 – P341)
Non-Pharmacological Therapy (Alternative
Medicine; Diet; Physical Activity)
. . . . . . . . . . . . . . . . . . . . (P342 – P348)
Obesity . . . . . . . . . . . . . . . (P349 – P355)
Pediatric Hypertension . . . . . . (P356 – P359)
Preclinical Models/Experimental Hypertension
. . . . . . . . . . . . . . . . . . . . (P360 – P361)
Pregnancy . . . . . . . . . . . . . . . . . . (P362)
Vascular Injury/Inflammation and Remodeling
. . . . . . . . . . . . . . . . . . . . (P363 – P376)
Late-Breaking Posters . . . . . . (LBP1 – LBP14)
Powerful BP efficacy.
For your hypertensive patients.
For your goals.
t 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
t Thiazide diuretics have been reported to cause exacerbation or activation of
systemic lupus erythematosus
t Lithium generally should not be given with thiazides
WARNING: USE IN PREGNANCY
When pregnancy is detected, discontinue AVAPRO or AVALIDE as soon as
possible. 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. [See Warnings and Precautions: Fetal/
Neonatal Morbidity and Mortality.]
Indications
AVAPRO is indicated for the treatment of hypertension. It may be used alone
or in combination with other antihypertensive agents.
AVAPRO is also indicated for the treatment of diabetic nephropathy with an
elevated serum creatinine and proteinuria (>300 mg/day) in patients with type
2 diabetes and hypertension. In this population, AVAPRO reduces the rate of
progression of nephropathy as measured by the occurrence of doubling of serum
creatinine or end-stage renal disease (need for dialysis or renal transplantation).
AVALIDE is indicated for the treatment of hypertension.
AVALIDE may be used in patients whose blood pressure is not adequately
controlled on monotherapy.
AVALIDE may also be used as initial therapy in patients who are likely to need
multiple drugs to achieve their blood pressure goals.
The choice of AVALIDE as initial therapy for hypertension should be based on an
assessment of potential benefits and risks and may be shaped by considerations
such as baseline blood pressure, target goal, and likelihood of achieving goal
compared to monotherapy.
Important Safety Information
t Because of the hydrochlorothiazide component, AVALIDE is contraindicated
in patients with anuria or hypersensitivity to sulfonamide-derived drugs
t In patients with volume or sodium depletion (eg, patients vigorously treated
with diuretics or on dialysis), such depletion should be corrected prior to
administration of AVAPRO or AVALIDE, or a lower initial dose of AVAPRO
(75 mg) should be used, to avoid possible symptomatic hypotension
t Thiazides should be used with caution in patients with severe renal disease
and in patients with impaired hepatic function or progressive liver disease,
since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma
t In placebo-controlled hypertension studies, there were no significant
differences in adverse events (AEs) between AVAPRO and placebo. Adverse
events that occurred in at least 1% of patients treated with AVAPRO and at a
higher incidence vs placebo included diarrhea (3% vs 2%), dyspepsia/heartburn
(2% vs 1%), and fatigue (4% vs 3%)
t Additionally, in a study of hypertensive type 2 diabetic patients with renal
disease (proteinuria ≥900 mg/day), the reported AEs for AVAPRO were similar
to those seen in hypertension studies, with the exception of an increased
incidence of orthostatic symptoms; AVAPRO compared to placebo (both
groups received adjunctive antihypertensives): dizziness (10.2% vs 6.0%),
orthostatic dizziness (5.4% vs 2.7%) and orthostatic hypotension (5.4% vs
3.2%), respectively. In patients with proteinuria, monitor serum potassium
t In placebo-controlled hypertension studies, the most common adverse
experiences reported with AVALIDE that occurred in ≥1% of patients and at
a higher incidence vs placebo included fatigue (7% vs 3%), musculoskeletal
pain (7% vs 5%), dizziness (8% vs 4%), and nausea/vomiting (3% vs 0%). In
a study with AVALIDE used as initial therapy in moderate hypertension, the
most common incidences of pre-specified adverse experiences reported that
occurred in ≥1% of patients were: dizziness (3.0%, 3.8%, and 1.0%), headache
(5.5%, 3.8%, and 4.8%) and hyperkalemia (1.2%, 0%, and 1.0%) in AVALIDE,
AVAPRO, and HCTZ, respectively. In a study with AVALIDE used as initial
therapy in severe hypertension, the most common incidences of pre-specified
adverse experiences reported that occurred in ≥1% were: dizziness (3.6% and
4.0%) and headache (4.3% and 6.6%) in AVALIDE and AVAPRO, respectively
Please see Brief Summary of full Prescribing Information on adjacent pages.
©2009 Bristol-Myers Squibb Sanofi-Synthelabo Partnership
446US08AB04305
4/09
Printed in the USA
AVAPRO® (irbesartan) Tablets
AVALIDE® (irbesartan-hydrochlorothiazide) Tablets
Brief Summary of Prescribing Information. For complete prescribing information consult official package inserts.
When pregnancy is detected, discontinue AVAPRO or AVALIDE as soon as possible. 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. [See Warnings and Precautions: Fetal/Neonatal Morbidity and Mortality.]
INDICATIONS AND USAGE
AVAPRO (irbesartan):
Hypertension
AVAPRO is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
Nephropathy in Type 2 Diabetic Patients
AVAPRO is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with
type 2 diabetes and hypertension. In this population, AVAPRO reduces the rate of progression of nephropathy as measured by the occurrence of
doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see Clinical Pharmocology: Clinical Studies in
AVAPRO Full Prescribing Information].
AVALIDE (irbesartan-hydrochlorothiazide):
AVALIDE® Tablets is indicated for the treatment of hypertension.
AVALIDE may be used in patients whose blood pressure is not adequately controlled on monotherapy.
AVALIDE may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.
The choice of AVALIDE as initial therapy for hypertension should be based on an assessment of potential benefits and risks and may be shaped by
considerations such as baseline blood pressure, target goal, and likelihood of achieving goal compared to monotherapy.
DOSAGE AND ADMINISTRATION [See Dosage and Administration for AVAPRO and AVALIDE (2) in respective Full Prescribing Information Inserts.]
AVAPRO:
Volume- and Salt-Depleted Patients
A lower initial dose of AVAPRO (75 mg) is recommended in patients with depletion of intravascular volume or salt (eg, patients treated vigorously
with diuretics or on hemodialysis) [see Warnings and Precautions: Hypotension in Volume- or Salt-Depleted Patients].
AVALIDE:
General Considerations
Renal impairment. The usual regimens of therapy with AVALIDE may be followed as long as the patient’s creatinine clearance is >30 mL/min. In
patients with more severe renal impairment, loop diuretics are preferred to thiazides, so AVALIDE is not recommended.
CONTRAINDICATIONS
AVAPRO:
L ,'(&:D4@?EC2:?5:42E65:?A2E:6?EDH9@2C69JA6CD6?D:E:G6E@2?J4@>A@?6?E@7E9:DAC@5F4E
AVALIDE:
L ,#!:D4@?EC2:?5:42E65:?A2E:6?EDH9@2C69JA6CD6?D:E:G6E@2?J4@>A@?6?E@7E9:DAC@5F4E
L 642FD6@7E969J5C@49=@C@E9:2K:564@>A@?6?E E9:DAC@5F4E:D4@?EC2:?5:42E65:?A2E:6?EDH:E92?FC:2@C9JA6CD6?D:E:G:EJE@@Eher sulfonamidederived drugs.
WARNINGS AND PRECAUTIONS
Fetal/Neonatal Morbidity and Mortality
AVAPRO:
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women.
Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting-enzyme inhibitors. When
pregnancy is detected, AVAPRO should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with
fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios
has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal
limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.
Mothers whose embryos and fetuses are exposed to an angiotensin Il receptor antagonist only during the first trimester should be so informed.
Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of AVAPRO as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found.
In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be
performed to assess the intraamniotic environment.
If oligohydramnios is observed, AVAPRO should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST),
2?@?DEC6DDE6DE%)* @C3:@A9JD:42=AC@7:=:?8''>2J362AAC@AC:2E656A6?5:?8FA@?E96H66<@7AC68?2?4J '2E:6?ED2?5A9Jsicians should
be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and
hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis
may be required as means of reversing hypotension and/or substituting for disordered renal function.
When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and
650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses
*50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis).
Subcutaneous edema was observed in fetuses at doses *180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these
anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to
15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with
maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase
in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits.
Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.
AVALIDE:
AVALIDE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. In several dozen published
cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension,
neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Similar renal findings occur in reproductive toxicology studies in
rats. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia,
and possibly other adverse reactions that have occurred in adults.
Hypotension in Volume- or Salt-Depleted Patients
AVAPRO:
Excessive reduction of blood pressure was rarely seen (<0.1%) in patients with uncomplicated hypertension. Initiation of antihypertensive
therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients treated vigorously with
diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of AVAPRO, or low starting dose should be
used [see Dosage and Administration in AVAPRO Full Prescribing Information].
If hypotension occurs, 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.
AVALIDE:
Excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with irbesartan alone (<0.1%) or with
irbesartan-hydrochlorothiazide (approximately 1%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with
intravascular volume- or sodium-depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should
be corrected prior to administration of antihypertensive therapy.
If hypotension occurs, 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.
AVALIDE:
Hypersensitivity Reaction
Hydrochlorothiazide
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
Hydrochlorothiazide
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Lithium Interaction
Hydrochlorothiazide
Lithium generally should not be given with thiazides. [See Drug Interactions.]
Electrolyte and Metabolic Imbalances
Irbesartan-Hydrochlorothiazide
In double-blind clinical trials of various doses of irbesartan and hydrochlorothiazide, the incidence of hypertensive patients who developed
hypokalemia (serum potassium <3.5 mEq/L) was 7.5% versus 6.0% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was
<1.0% versus 1.7% for placebo. No patient discontinued due to increases or decreases in serum potassium. On average, the combination of
irbesartan and hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalemic response to
hydrochlorothiazide.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients
receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and
hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral
fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal
disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also
sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability).
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver
disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt
except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics.
Thus latent diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the post sympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known
disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before
carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Hepatic Impairment
Hydrochlorothiazide
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.
Impaired Renal Function
AVAPRO (irbesartan) and AVALIDE (irbesartan-hydrochlorothiazide):
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals.
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart
failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with
acute renal failure and/or death. Irbesartan would be expected to behave similarly. In studies of ACE inhibitors in patients with unilateral or bilateral
C6?2= 2CE6CJ DE6?@D:D :?4C62D6D :? D6CF> 4C62E:?:?6 @C +% 92G6 366? C6A@CE65 *96C6 92D 366? ?@ <?@H? FD6 @7 :C36D2CE2? :? A2E:ents with
unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated.
AVALIDE:
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects
of the drug may develop in patients with impaired renal function.
Information for Patients
Pregnancy
AVAPRO:
Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the reninangiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has
been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
AVALIDE: [See Patient Counseling Information: Pregnancy.]
Drug Interactions
AVAPRO:
No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide,
digoxin, warfarin, and nifedipine.
In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9 substrates/
inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the pharmaco5J?2>:4D@7H2C72C:?H6C6?68=:8:3=6 2D65@? in vitro data, no interaction would be expected with drugs whose metabolism is dependent upon
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In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days had
no effect on the pharmacodynamics of warfarin (prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not
affected by coadministration of nifedipine or hydrochlorothiazide.
AVALIDE: [See Drug Interactions.]
Carcinogenesis, Mutagenesis, Impairment of Fertility
AVAPRO:
No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females,
respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic exposure
to irbesartan (AUC0-24 hour, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans receiving the
maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average
systemic exposure about 21 times that reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to
irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day.
Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward genemutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro -human lymphocyte assay; in vivo -mouse
micronucleus study).
Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses )650 mg/kg/day, the highest dose providing a systemic
exposure to irbesartan (AUC0-24 hour, bound plus unbound) about 5 times that found in humans receiving the maximum recommended dose of
300 mg/day.
AVALIDE: [See Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility.]
Pregnancy
AVAPRO:
Pregnancy Categories C (first trimester) and D (second and third trimesters)
See Warnings and Precautions: Fetal/Neonatal Morbidity and Mortality.
AVALIDE: [See Use in Specific Populations: Pregnancy.]
Nursing Mothers
AVAPRO:
It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in
E96>:=<@7=24E2E:?8C2ED 642FD6@7E96A@E6?E:2=7@C25G6CD667764ED@?E96?FCD:?8:?72?E 2564:D:@?D9@F=536>256H96E96C to discontinue
nursing or discontinue the drug, taking into account the importance of the drug to the mother.
AVALIDE: [See Use in Specific Populations: Nursing Mothers.]
Pediatric Use
AVAPRO:
Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to
16 years.
AVAPRO has not been studied in pediatric patients less than 6 years old.
AVALIDE: [See Use in Specific Populations: Pediatric Use.]
Geriatric Use
AVAPRO:
Of 4925 subjects receiving AVAPRO in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75
years and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity
of some older individuals cannot be ruled out. [See Clinical Pharmacology: Pharmacokinetics, Special Populations, and Clinical Studies in AVAPRO
Full Prescribing Information .]
AVALIDE: [See Use in Specific Populations: Geriatric Use.]
ADVERSE REACTIONS
AVAPRO:
Hypertension
AVAPRO has been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall. This experience includes
1303 patients treated for over 6 months and 407 patients for 1 year or more. Treatment with AVAPRO was well-tolerated, with an incidence of
adverse events similar to placebo. These events generally were mild and transient with no relationship to the dose of AVAPRO.
In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event was required in 3.3% of patients treated with AVAPRO,
versus 4.5% of patients given placebo.
In placebo-controlled clinical trials, the following adverse event experiences reported in at least 1% of patients treated with AVAPRO (n=1965) and
at a higher incidence versus placebo (n=641), excluding those too general to be informative and those not reasonably associated with the use of
drug because they were associated with the condition being treated or are very common in the treated population, include: diarrhea (3% vs 2%),
dyspepsia/heartburn (2% vs 1%), and fatigue (4% vs 3%).
The following adverse events occurred at an incidence of 1% or greater in patients treated with irbesartan, but were at least as frequent or more
frequent in patients receiving placebo: abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza, musculoskeletal
pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality, tachycardia, and urinary tract infection.
Irbesartan use was not associated with an increased incidence of dry cough, as is typically associated with ACE inhibitor use. In placebo-controlled
studies, the incidence of cough in irbesartan-treated patients was 2.8% versus 2.7% in patients receiving placebo.
The incidence of hypotension or orthostatic hypotension was low in irbesartan-treated patients (0.4%), unrelated to dosage, and similar to the
incidence among placebo-treated patients (0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in patients receiving
irbesartan compared with placebo.
In addition, the following potentially important events occurred in less than 1% of the 1965 patients and at least 5 patients (0.3%) receiving
irbesartan in clinical studies, and those less frequent, clinically significant events (listed by body system). It cannot be determined whether these
events were causally related to irbesartan:
Body as a Whole: fever, chills, facial edema, upper extremity edema
Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardio-respiratory
arrest, heart failure, hypertensive crisis
Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria
Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout
Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention
Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis,
muscle weakness
Nervous System: sleep disturbance, numbness, somnolence, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack,
cerebrovascular accident
Renal/Genitourinary: abnormal urination, prostate disorder
Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing
Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis, other eye disturbance, eyelid abnormality, ear abnormality
In clinical studies in patients with hypertension and type 2 diabetic renal disease, the adverse drug experiences were similar to those seen in
patients with hypertension with the exception of an increased incidence of orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic
hypotension) observed in IDNT (proteinuria *900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL). In this trial, orthostatic symptoms
occurred more frequently in the AVAPRO (irbesartan) group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%) than in the
placebo group (dizziness 6.0%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%).
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical
trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
AVALIDE Tablets has been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with
AVALIDE, no adverse events peculiar to this combination drug product have been observed. Adverse events have been limited to those that were
reported previously with irbesartan or hydrochlorothiazide (HCTZ). The overall incidence of adverse events was similar with the combination and
placebo. In general, treatment with AVALIDE was well tolerated. For the most part, adverse events have been mild and transient in nature and have
not required discontinuation of therapy. In controlled clinical trials, discontinuation of AVALIDE therapy due to clinical adverse events was required
in only 3.6%. This incidence was significantly less (p=0.023) than the 6.8% of patients treated with placebo who discontinued therapy.
In these double-blind controlled clinical trials, the following adverse events reported with AVALIDE occurred in *1% of patients, and more often on
the irbesartan-hydrochlorothiazide combination than on placebo, regardless of drug relationship:
Body as a Whole
Chest Pain
Fatigue
Influenza
Cardiovascular
Edema
Tachycardia
Gastrointestinal
Abdominal Pain
Dyspepsia/heartburn
Nausea/vomiting
Immunology
Allergy
Musculoskeletal
Musculoskeletal Pain
Nervous System
Dizziness
Dizziness Orthostatic
Renal/Genitourinary
Abnormality Urination
Irbesartan/HCTZ
(n=898)
(%)
Placebo
(n=236)
(%)
Irbesartan
(n=400)
(%)
HCTZ
(n=380)
(%)
2
7
3
1
3
1
2
4
2
2
3
2
3
1
3
0
2
1
2
1
2
2
3
1
1
0
2
0
2
2
2
0
1
0
1
1
7
5
6
10
8
1
4
0
6
1
5
1
2
1
1
2
The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group: headache, sinus
abnormality, cough, URI, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle cramp.
Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients.
Adverse events in Studies V and VI were similar to those described above in Studies I through IV.
Irbesartan
Other adverse events that have been reported with irbesartan, without regard to causality, are listed below:
Body as a Whole: fever, chills, orthostatic effects, facial edema, upper extremity edema
Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, hypotension, syncope, arrhythmic/conduction
disorder, cardio-respiratory arrest, heart failure, hypertensive crisis
Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria
Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout
Gastrointestinal: diarrhea, constipation, gastroenteritis, flatulence, abdominal distention
Musculoskeletal/Connective Tissue: musculoskeletal trauma, extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain,
joint stiffness, bursitis, muscle weakness
Nervous System: anxiety/nervousness, sleep disturbance, numbness, somnolence, vertigo, emotional disturbance, depression, paresthesia, tremor,
transient ischemic attack, cerebrovascular accident
Renal/Genitourinary: prostate disorder
Respiratory: cough, upper respiratory infection, epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing
Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis
Hydrochlorothiazide
Other adverse events that have been reported with hydrochlorothiazide, without regard to causality, are listed below:
Body as a Whole: weakness
Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation
Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia
Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including
pneumonitis and pulmonary edema, anaphylactic reactions
Metabolic: hyperglycemia, glycosuria, hyperuricemia
Musculoskeletal: muscle spasm
Nervous System/Psychiatric: restlessness
Renal: renal failure, renal dysfunction, interstitial nephritis
Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis
Special Senses: transient blurred vision, xanthopsia
Initial Therapy
In the moderate hypertension Study V (mean SeDBP between 90 and 110 mmHg), the types and incidences of adverse events reported for patients
treated with AVALIDE were similar to the adverse event profile in patients on initial irbesartan or HCTZ monotherapy. There were no reported events
of syncope in the AVALIDE treatment group and there was one reported event in the HCTZ treatment group. The incidences of pre-specified adverse
events on AVALIDE, irbesartan, and HCTZ, respectively, were: 0.9%, 0%, and 0% for hypotension; 3.0%, 3.8%, and 1.0% for dizziness; 5.5%, 3.8%,
and 4.8% for headache; 1.2%, 0%, and 1.0% for hyperkalemia; and 0.9%, 0%, and 0% for hypokalemia. The rates of discontinuation due to adverse
events on AVALIDE, irbesartan alone, and HCTZ alone were 6.7%, 3.8%, and 4.8%.
In the severe hypertension (SeDBP *110 mmHg) Study VI, the overall pattern of adverse events reported through 7 weeks of follow-up was similar
in patients treated with AVALIDE as initial therapy and in patients treated with irbesartan as initial therapy. The incidences of the pre-specified
adverse events on AVALIDE and irbesartan, respectively, were: 0% and 0% for syncope; 0.6% and 0% for hypotension; 3.6% and 4.0% for dizziness;
4.3% and 6.6% for headache; 0.2% and 0% for hyperkalemia; and 0.6% and 0.4% for hypokalemia. The rates of discontinuation due to adverse
events were 2.1% and 2.2%. [See Clinical Studies (14.2) in AVALIDE Full Prescribing Information.]
Post-Marketing Experience
The following have been very rarely reported in post-marketing experience: urticaria; angioedema (involving swelling of the face, lips, pharynx,
and/or tongue); increased liver function tests; jaundice; and hepatitis. Hyperkalemia has been rarely reported.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
The following adverse reactions have been identified during post-approval use of AVALIDE. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction,
(2) frequency of reporting, or (3) strength of causal connection to AVALIDE.
The following have been very rarely reported: urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); and hepatitis.
Hyperkalemia has been rarely reported.
Very rare cases of jaundice have been reported with irbesartan.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Laboratory Abnormalities
AVAPRO:
Hypertension
In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with administration of AVAPRO.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with
essential hypertension treated with AVAPRO alone versus 0.9% on placebo. [See Warnings and Precautions: Impaired Renal Function.]
Hematologic: Mean decreases in hemoglobin of 0.2 g/dL were observed in 0.2% of patients receiving AVAPRO compared to 0.3% of placebo-treated
patients. Neutropenia (<1000 cells/mm3) occurred at similar frequencies among patients receiving AVAPRO (0.3%) and placebo-treated patients (0.5%).
Hyperkalemia: In IDNT (proteinuria *900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL), the percent of patients with hyperkalemia
(>6 mEq/L) was 18.6% in the AVAPRO group versus 6.0% in the placebo group. Discontinuations due to hyperkalemia in the AVAPRO group were
2.1% versus 0.4% in the placebo group.
AVALIDE:
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of AVALIDE.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3% and 1.1%, respectively,
of patients with essential hypertension treated with AVALIDE alone. No patient discontinued taking AVALIDE due to increased BUN. One patient
discontinued taking AVALIDE due to a minor increase in serum creatinine.
Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated
with AVALIDE alone, one patient was discontinued due to elevated liver enzymes.
Serum Electrolytes: [See Warnings and Precautions.]
DRUG INTERACTIONS
AVAPRO: [See Warnings and Precautions: Drug Interactions.]
AVALIDE:
Irbesartan
No significant drug-drug interactions have been reported with irbesartan. [See Clinical Pharmacology.]
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, Barbiturates, or Narcotics: potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (oral agents and insulin): dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs: additive effect or potentiation.
Cholestyramine and Colestipol Resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of
either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and
43%, respectively.
Corticosteroids, ACTH: intensified electrolyte depletion, particularly hypokalemia.
Pressor Amines (eg, Norepinephrine): possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (eg, Tubocurarine): possible increased responsiveness to the muscle relaxant.
Lithium: should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.
Refer to the package insert for lithium preparations before use of such preparations with AVALIDE. [See Warnings and Precautions.]
Non-steroidal Anti-inflammatory Drugs: in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic,
natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when AVALIDE Tablets and non-steroidal antiinflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
USE IN SPECIFIC POPULATIONS
Pregnancy
AVAPRO: [See Warnings and Precautions: Pregnancy.]
AVALIDE:
Pregnancy Category D. [See Warnings and Precautions.]
AVALIDE contains both irbesartan (an angiotensin II receptor antagonist) and hydrochlorothiazide (a thiazide diuretic). When administered during the
second or third trimester of pregnancy, drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death.
Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and
possibly other adverse reactions that have occurred in adults. AVALIDE can cause fetal harm when administered to a pregnant woman. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Angiotensin II receptor antagonists, like irbesartan, and angiotensin converting enzyme (ACE) inhibitors exert similar effects on the renin-angiotensin
system. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and
neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios was also
reported, presumably from decreased fetal renal function. In this setting, oligohydramnios was associated with fetal limb contractures, craniofacial
deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus were also reported,
although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from
intrauterine drug exposure that has been limited to the first trimester.
When pregnancy occurs in a patient using AVALIDE, the physician should discontinue AVALIDE treatment as soon as possible. The physician should
inform the patient about potential risks to the fetus based on the time of gestational exposure to AVALIDE (first trimester only or later). If exposure
occurs beyond the first trimester, an ultrasound examination should be done.
In rare cases when another antihypertensive agent cannot be used to treat the pregnant patient, serial ultrasound examinations should be performed
to assess the intraamniotic environment. Routine fetal testing with non-stress tests, biophysical profiles, and/or contraction stress tests may be
appropriate based on gestational age and standards of care in the community. If oligohydramnios occurs in these situations, individualized decisions
about continuing or discontinuing AVALIDE treatment and about pregnancy management should be made by the patient, her physician, and experts
in the management of high risk pregnancy. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has
sustained irreversible injury.
Infants with histories of in utero exposure to AVALIDE should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, these
infants may require blood pressure and renal perfusion support. Exchange transfusion or dialysis may be required to reverse hypotension and/or
support decreased renal function.
Irbesartan crosses the placenta in rats and rabbits. In pregnant rats given irbesartan at doses greater than the maximum recommended human dose
(MRHD), fetuses showed increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla. Subcutaneous edema also
occurred in fetuses at doses about 4 times the MRHD (based on body surface area). These anomalies occurred when pregnant rats received
irbesartan through Day 20 of gestation but not when drug was stopped on gestation day 15. The observed effects are believed to be late gestational
effects of the drug. Pregnant rabbits given oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high rate of maternal mortality
and abortion. Surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses [see Nonclinical Toxicology].
Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.
When pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the
MRHD) during their respective periods of major organogenesis, there was no evidence of fetal harm.
A development toxicity study was performed in rats with doses of 50/50 mg/kg/day and 150/150 mg/kg/day irbesartan-hydrochlorothiazide.
Although the high dose combination appeared to be more toxic to the dams than either drug alone, there did not appear to be an increase in toxicity
to the developing embryos.
Nursing Mothers
AVAPRO: [See Warnings and Precautions: Nursing Mothers.]
AVALIDE:
It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in
the milk of lactating rats.
Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to
discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
AVAPRO: [See Warnings and Precautions: Pediatric Use.]
AVALIDE:
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
AVAPRO: [See Warnings and Precautions: Geriatric Use.]
AVALIDE:
Of 1694 patients receiving AVALIDE in controlled clinical studies of hypertension, 264 (15.6%) were 65 years and over, while 45 (2.7%) were 75 years
and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some
older individuals cannot be ruled out. [See Clinical Pharmacology and Clinical Studies (14) in AVALIDE Full Prescribing Information .]
OVERDOSAGE
AVAPRO (irbesartan) and AVALIDE (irbesartan-hydrochlorothiazide):
Irbesartan
No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well tolerated. The most likely
manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. Irbesartan is not
removed by hemodialysis.
To obtain up-to-date information about the treatment of overdosage, a good resource is a certified regional Poison Control Center. Telephone
numbers of certified Poison Control Centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of
multiple-drug interactions, drug-drug interactions, and unusual drug kinetics in the patient.
Laboratory determinations of serum levels of irbesartan are not widely available, and such determinations have, in any event, no established role
in the management of irbesartan overdose.
Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25- and 50-fold the
maximum recommended human dose (300 mg) on a mg/m2 basis, respectively.
AVALIDE:
Hydrochlorothiazide
The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia,
hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac
arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide
is greater than 10 g/kg in both mice and rats.
CLINICAL PHARMACOLOGY
Mechanism of Action
AVAPRO and AVALIDE:
Irbesartan
Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).
Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by
adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth.
Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor.
There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis.
Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500-fold) for the AT1 receptor than for the
AT2 receptor, and no agonist activity.
Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity
and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure.
Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of
blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has
clinical relevance is not known.
AVALIDE:
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of
sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with
consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum
potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse
the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
Pharmacodynamics
AVAPRO and AVALIDE:
Irbesartan
In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions.
Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40%
at 300 mg and 150 mg, respectively).
In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5- to 2-fold rise in angiotensin
II plasma concentration and a 2- to 3-fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan
administration, but serum potassium levels are not significantly affected at recommended doses.
In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow or filtration
fraction. In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol, HDLcholesterol, or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral administration and no uricosuric effect.
AVALIDE:
Hydrochlorothiazide
After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics
AVAPRO and AVALIDE:
Irbesartan
Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and
complete with an average absolute bioavailability of 60% to 80%. Following oral administration of irbesartan, peak plasma concentrations of
irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of irbesartan.
Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.
The terminal elimination half-life of irbesartan averaged 11 to 15 hours. Steady-state concentrations are achieved within 3 days. Limited
accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.
AVALIDE:
Hydrochlorothiazide
When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
Metabolism and Elimination
AVAPRO and AVALIDE:
Irbesartan
Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled irbesartan, more
than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan
glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan’s pharmacologic activity.
Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of 14C-labeled
irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.
In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was
negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism
(1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.
AVALIDE:
Hydrochlorothiazide
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Distribution
AVAPRO and AVALIDE:
Irbesartan
Irbesartan is 90% bound to serum proteins (primarily albumin and 1-acid glycoprotein) with negligible binding to cellular components of blood. The
average volume of distribution is 53 to 93 liters. Total plasma and renal clearances are in the range of 157 to 176 mL/min and 3.0 to 3.5 mL/min,
respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent.
Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in the milk of
lactating rats.
AVALIDE:
Hydrochlorothiazide
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Pediatric
AVAPRO: [See Warnings and Precautions: Pediatric Use.]
AVALIDE:
Irbesartan-hydrochlorothiazide pharmacokinetics have not been investigated in patients <18 years of age.
AVAPRO and AVALIDE:
Gender
No gender-related differences in pharmacokinetics were observed in healthy elderly (age 65 to 80 years) or in healthy young (age 18 to 40 years)
subjects. In studies of hypertensive patients, there was no gender difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan were observed in females (11% to 44%). No gender-related dosage adjustment is necessary.
Geriatric
In elderly subjects (age 65 to 80 years), irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20% to
50% greater than those of young subjects (age 18 to 40 years). No dosage adjustment is necessary in the elderly.
Race
In healthy black subjects, irbesartan AUC values were approximately 25% greater than whites; there were no differences in Cmax values.
Renal Insufficiency
The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by
hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also
volume depleted. [See Warnings: Hypotension in Volume- or Salt-Depleted Patients and Dosage and Administration in AVAPRO Full Prescribing
Information.]
The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by
hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also
volume depleted. [See Warnings and Precautions.]
Hepatic Insufficiency
AVAPRO and AVALIDE:
The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis
of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.
Drug-Drug Interactions
AVAPRO: [See Warnings and Precautions: Drug Interactions.]
AVALIDE:
No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide,
digoxin, warfarin, and nifedipine.
In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9
substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the
pharmacodynamics of warfarin were negligible. Concomitant nifedipine or hydrochlorothiazide had no effect on irbesartan pharmacokinetics. Based
on in vitro data, no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6,
2B6, 2D6, 2E1, or 3A4.
In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days had
no effect on the pharmacodynamics of warfarin (prothrombin time) or the pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were
not affected by coadministration of nifedipine or hydrochlorothiazide.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
AVAPRO: [See Warnings and Precautions: Carcinogenesis, Mutagenesis, Impairment of Fertility.]
AVALIDE:
No carcinogenicity studies have been conducted with the irbesartan-hydrochlorothiazide combination.
Irbesartan-hydrochlorothiazide was not mutagenic in standard in vitro tests (Ames microbial test and Chinese hamster mammaliancell forward gene-mutation assay). Irbesartan-hydrochlorothiazide was negative in tests for induction of chromosomal aberrations (in
vitro—human lymphocyte assay; in vivo—mouse micronucleus study).
The combination of irbesartan and hydrochlorothiazide has not been evaluated in definitive studies of fertility.
Irbesartan
No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females,
respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average
systemic exposure to irbesartan (AUC0-24hours, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure
in humans receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to
females only) provided an average systemic exposure about 21 times that reported for humans at the MRD. For male and female mice,
1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day.
Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell
forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro—human
lymphocyte assay; in vivo—mouse micronucleus study).
Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses )650 mg/kg/day, the highest dose
providing a systemic exposure to irbesartan (AUC0-24hours, bound plus unbound) about 5 times that found in humans receiving the
maximum recommended dose of 300 mg/day.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no
evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in
male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA
1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using
mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait
gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse
Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 g/mL, and in the Aspergillus
nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were
exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
AVAPRO: [See Warnings and Precautions: Fetal/Neonatal Morbidity and Mortality.]
AVALIDE:
When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50, 180, and 650 mg/kg/day),
increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses
*50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area
basis). Subcutaneous edema was observed in fetuses at doses *180 mg/kg/day (about 4 times the MRHD on a body surface area
basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was
limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg
irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the
MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan
was found to cross the placental barrier in rats and rabbits.
PATIENT COUNSELING INFORMATION
AVAPRO: [See Warnings and Precautions: Information for Patients.]
AVALIDE:
Pregnancy
Female patients of childbearing age should be told that use of drugs like AVALIDE during the second or third trimesters of pregnancy can cause
serious problems in the fetus and infant including: low blood pressure, poor development of skull bones, kidney failure, and death. These effects
have not occurred with drug exposure limited to the first trimester. Women using AVALIDE who become pregnant should notify their physician as
soon as possible.
Symptomatic Hypotension
Patients using AVALIDE should be told that they may feel lightheaded, especially during the first days of use. Patients should inform their physician
if they feel lightheaded or faint. If fainting occurs, the patient should stop using AVALIDE and contact the prescribing doctor.
Patients using AVALIDE should be told that getting dehydrated can lower their blood pressure too much and lead to lightheadedness and possible
fainting. Dehydration may occur with excessive sweating, diarrhea, or vomiting and with not drinking enough liquids.
Manufactured by: Bristol-Myers Squibb Company, Princeton, New Jersey 08543 USA
Distributed by: Bristol-Myers Squibb Sanofi-Synthelabo Partnership, New York, New York 10016
Based on
AVAPRO: 1192327A3, 1192328A3
AVALIDE: 1190017A3, 1190018A4
446US08PBS00101
B2-B0002A-11-07
AVAPRO: The power of
proven renal protection to help
slow the progression of nephropathy
in hypertensive patients with
type 2 diabetes.
(see indications statement below).*
When pregnancy is detected, discontinue AVAPRO as
soon as possible. 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. [See Warnings: Fetal/Neonatal
Morbidity and Mortality.]
Indications
AVAPRO (irbesartan) is indicated for the treatment of
hypertension. It may be used alone or in combination with
other antihypertensive agents.
AVAPRO is also indicated for the treatment of diabetic
nephropathy with an elevated serum creatinine and
proteinuria (>300 mg/day) in patients with type 2 diabetes
and hypertension. In this population, AVAPRO reduces the
rate of progression of nephropathy as measured by the
occurrence of doubling of serum creatinine or end-stage
renal disease (need for dialysis or renal transplantation).
Important Safety Information
t In patients with volume or sodium depletion (eg, patients
vigorously treated with diuretics or on dialysis), such
depletion should be corrected prior to administration of
AVAPRO, or a lower initial dose of AVAPRO (75 mg) should
be used, to avoid possible symptomatic hypotension
t In placebo-controlled hypertension studies, there were no
significant differences in adverse events (AEs) between
AVAPRO and placebo. Adverse events that occurred in at least
1% of patients treated with AVAPRO and at a higher incidence
vs placebo included diarrhea (3% vs. 2%), dyspepsia/heartburn
(2% vs 1%) and fatigue (4% vs 3%)
t Additionally, in a study of hypertensive type 2 diabetic
patients with renal disease (proteinuria ≥900 mg/day), the
reported AEs for AVAPRO were similar to those seen in
hypertension studies, with the exception of an increased
incidence of orthostatic symptoms; AVAPRO compared to
placebo (both groups received adjunctive antihypertensives):
dizziness (10.2% vs 6.0%), orthostatic dizziness (5.4% vs 2.7%)
and orthostatic hypotension (5.4% vs 3.2%), respectively. In
patients with proteinuria, monitor serum potassium
Please see Brief Summary of full Prescribing Information on adjacent pages.
©2009 Bristol-Myers Squibb Sanofi-Synthelabo Partnership
446US08AB04305
4/09
Printed in the USA
8
Ash Times • Friday | Saturday • May 8 • San Francisco
ASH publishes position papers for specialists in
clinical hypertension
The American Society of Hyperten-
sion, Inc. recognizes the importance of providing guidance regarding the practicing needs
of designated specialists in clinical hypertension, and other health care providers treating
hypertensive patients. To meet this challenge, the ASH Board of Directors approved
an initiative to establish a Hypertension
Writing Group.
The Hypertension Writing Group is
composed of invited authors and overseen
by a steering committee that reports to the
ASH Board of Directors. The position papers
address topics in hypertension research that a
traditional single guidelines paper would not
cover in depth. As of May 2009, the Society
has published three position papers.
The first paper, “When and How to Use
Self (Home) and Ambulatory Blood Pressure Monitoring,” was written by Thomas G.
Pickering, MD, DPhil, and William B. White,
MD, and was published in the Journal of the
American Society of Hypertension (JASH) 2008:
2(3):119 – 124. (May/June 2008). The paper
was reprinted in the November 2009 issue of
The Journal of Clinical Hypertension (JCH).
This position paper focuses on the importance of out-of-office blood pressure (BP)
measurement for the clinical management of
patients with hypertension and its complications. Studies have supported direct and independent associations of cardiovascular risk
with ambulatory BP and inverse associations
This position paper updates concepts on
with the degree of BP reduction from day to hypertension management in patients with
night. Self-monitoring of the BP (or home BP diabetes. It focuses on clinical outcomes litmonitoring) also has advantages in evaluating erature published within the past three years
patients with hypertension, especially those and incorporates these observations into
already on drug
modifications of
treatment, but less
established guideis known about its While neither ABPM nor self-BP monitor- lines. W hile the
relation to future ing are mandatory for the routine diag- fundamentals of
c a rd io v a s c u l a r
t reat ment a nd
events. Data de- nosis of hypertension, these modalities goal blood presrived from ambula- can enhance the ability for identification s u r e s r e m a i n
tory BP monitoring
u ncha nged, ap(ABPM) allow the of white-coat and masked hypertension proaches to speidentification of and evaluate the extent of BP control in cif ic patient-rehigh-risk patients,
lated issues have
independent from patients on drug therapy.
changed. This upthe BP obtained
date focuses on
in the clinic or office setting. While neither questions such as what to do when a patient
ABPM nor self-BP monitoring are manda- has an elevated potassium level when therapy
tory for the routine diagnosis of hypertension, is initiated and whether combinations of
these modalities can enhance the ability for agents that block the renin-angiotensin
identification of white-coat and masked hyper- system still be used. In addition, there are
tension and evaluate the extent of BP control updates from trials, just published and in
in patients on drug therapy.
press, that focus on related management
The second ASH position paper on “Treat- issues influencing cardiovascular outcomes
ment of Hypertension in Patients with Diabetes: in persons with diabetes. Last, an updated
An Update” was written by George L. Bakris, MD, algorithm is provided that incorporates many
and James R. Sowers, MD, and was published in of the new findings and is suggested as a startThe Journal of Clinical Hypertension 2008: 10(9): ing point to achieve blood pressure goals.
707 – 713. (October 2008). It was reprinted in the
The third position paper on “HypertenMarch/April 2009 issue of JASH.
sion in Pregnancy” was written by Marshall
Lindheimer, MD; Sandra Taler, MD; and
Gary Cunningham, MD. It was published
in the Journal of the American Society of
Hypertension 2008: 2(6): 484 – 494. (November/December 2008) and reprinted in
the April 2009 issue of JCH.
This position paper summarizes the
clinical spectrum of hypertension in pregnancy, focusing on preeclampsia. Recent
research breakthroughs relating to etiology are brief ly reviewed. Topics include
classification of the different forms of
hypertension during pregnancy, status of
the tests available to predict preeclampsia,
and strategies to prevent preeclampsia
and to manage this serious disease. The
use of antihy pertensive drugs in pregnancy and the prevention and treatment
of the convulsive phase of preeclampsia,
eclampsia, with intravenous MgSO4 is
also highlighted.
The impact of the position papers has
been substantial. Press conferences were organized around the first two papers, which
resulted in significant media coverage.
A fourth paper on “Dietary Approaches
to Lower Blood Pressure” written by Lawrence J. Appel, MD, MPH, will be published
in the July issue of JCH.
A series of papers on the “Pharmacologic Therapy of Hypertension” will be
published in the Fall of 2009. l
New Research
Late-breaking trials session features study
of hypertension in NFL players
A Late-Br eaking Clinical Trials
and New Research session this afternoon will
include a talk on Cardiovascular Risk Factors
in Active National Football League Players by
Robert A. Vogel, MD, who is Professor of
Medicine at the University of Maryland School
of Medicine in Baltimore and Co-Chair of the
NFL subcommittee on cardiovascular health.
His 30-minute address begins at 3:30 p.m.
today, Friday, May 8, in Yerba Buena Ballroom
— Salon 9.
Dr. Vogel will present preliminary information on the results of research he has done into
the cardiovascular health of active and retired
NFL players, concentrating on hypertension.
“We have early evidence that active NFL
players have elevated blood pressure that is
approximately 10 to 15 mmHg higher than
an age-adjusted population. Their blood pressure is mostly in the pre-hypertension range,
averaging about 130 mmHg systolic,” he said.
“The reasons are hypothetical at this point, but
they certainly may include strength training,
high salt intake, and the use of NSAIDs. These
are the kinds of things we are looking at in an
ongoing study focused on the causes.”
Professional football players differ from an
age-matched population in a number of ways.
They are generally 75 pounds heavier than average and usually about five inches taller than
most men their age.
“Interestingly, they don’t have a lot of
body fat. In fact, they have less body fat than
a 75-pound lighter American man of the same
age,” Dr. Vogel said. “If you look at their cardiovascular risk factors, they do better than
average in several things. They have lower
blood sugar, they don’t smoke, their lipids are
relatively equivalent, but their blood pressure is
higher. We are trying to find out why. We don’t
really know yet.”
However, retired NFL players have cardiovascular risks roughly equivalent to an age-
However, retired NFL players have
cardiovascular risks roughly equivalent to an age-adjusted, sizeadjusted population. A former NFL
player who weighs 300 pounds
will have the cardiovascular health
of a 300-pound non-athlete, so
eventually, their size catches up
with them.
– Robert A. Vogel, MD
adjusted, size-adjusted population. A former
NFL player who weighs 300 pounds will have
the cardiovascular health of a 300-pound nonathlete, so eventually, their size catches up with
them, he said.
“In active players, there appears to be a
balancing effect of physical activity. They may
be 75 pounds heavier than average, but they
are very physically active. It’s the old debate of
fat vs. fit, and most active players are fit from
a cardiovascular point of view, certainly in
comparison with an average 25-year-old man,”
Dr. Vogel said. “Being so fit balances out the effect of weight. However, in retirement from the
game, they are no longer as physically active.”
Dr. Vogel and his colleagues began their
research in 2004 under sponsorship of an NFL
charity fund to promote and monitor cardiovascular health among players.
“In screening for cardiovascular health,
we do not just measure blood pressure.
We do very sophisticated tests, especially
in the retired players, including CT scans,
coronary calcium scans, carotid ultrasound for
plaque and intima-media thickness, echocardiograms, and C-reactive protein testing.
I think this type of screening is indicative of
where medicine is going in the future, toward
a more robust way of looking for cardiovascular
disease beyond blood pressure and cholesterol levels,” he said. “The number one cause of
death in the United States is cardiovascular disease, and yet we don’t screen
for it. We check blood pressu re, but
w e d o n’t c h e c k f o r h e a r t d i s e a s e .
We have screening tests for colon cancer,
breast cancer, and prostate cancer that
look for the disease itself and not just the
risk factors.”
Dr. Vogel hopes that hypertension specialists who attend his talk will learn that it’s
important to look for cardiovascular disease
beyond the risk factors. “I believe that carotid
screening, coronary screening, and other sophisticated tests need to be made part and
parcel of our efforts to prevent heart disease,”
he said. l
Meet-the-Expert
Sessions
These sessions will provide an opportunity for interaction and consultation
with professionals who have expertise in a
specific area. Attendees will be admitted
on a first-come, first-served basis.
Friday, May 8 – 11:45 a.m. to 12:45 p.m.
Uric Acid
Takahiko Nakagawa, MD, Aurora, CO
Yerba Buena Ballroom — Salon 1
Headaches
Dara G. Jamieson, MD, New York, NY
Hypertension in Children and Adolescents
Bonita Falkner, MD, Philadelphia, PA
Sleep Apnea
Virend K. Somers, MD, DPhil, Rochester, MN
Nutraceuticals
Matthew Sorrentino, MD, Chicago, IL
y
Save the Date y
ASH 25th Annual Scientific Meeting
May 1-4, 2010 • New York, New York
10
Exhibition Map
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San Francisco • May 8–9 • Friday | Saturday • Ash Times
11
Exhibitors
AtCor Medical
One Pierce Place, Suite 295E
Itasca, IL 60143
Phone: 630-228-8871
Fax: 630-228-8872
www.atcormedical.com
211
AtCor Medical’s SphygmoCor® systems, featured in more
than 400 published studies, are the global gold standard
for noninvasive central blood pressure/arterial stiffness
assessment. Major studies have found:
• Elevated central pressure is a superior independent
predictor of cardiovascular risk
• 70 percent of patients with high normal blood pressure
had central pressures equivalent with those of patients
with stage 1 hypertension
• Patients with central pulse pressure ≥ 50mmHg are at
significantly higher risk for cardiovascular events.
Boehringer Ingelheim
Pharmaceuticals, Inc
202
900 Ridgebury Road,
Ridgefield, CT 06877
Phone: 203-798-9988
Fax: 203-791-6234
us.boehringer-ingelheim.com
Boehringer Ingelheim Pharmaceuticals, Inc., the U.S.
subsidiary of Boehringer Ingelheim in Germany, operates
globally in 47 countries with about 39,800 employees.
The company is committed to researching, developing,
manufacturing, and marketing novel products of high
therapeutic value for human and veterinary medicine.
BpTRU Medical Devices
Unit 1, 1850 Hartley Avenue
Coquitlam, BC V3K 7A1
Phone: 604-540-7887
Fax: 604-540-7875
www.BpTRU.com
514
6175 Nancy Ridge Drive
San Diego, CA 92121
Phone: 858-535-0202
Fax: 858-535-9622
www.cardiodynamics.com
316
In minutes, BioZ ICG (Impedance Cardiography) technology
provides noninvasive hemodynamic parameters, including
cardiac output and fluid status, for patients with heart
failure, dyspnea, and resistant hypertension. ICG is a
Medicare-covered test used in more than 5 million patient
applications to assist physicians select and optimize
cardiovascular medications including ACEs, BBs, and
diuretics.
Cardiology Career Network
9100 E. Panorama Drive, Suite 200
Englewood, CO 80112
Phone: 888-884-8242
Fax: 800-595-2929
www.cardiologycareernetwork.com
214
The Cardiology Career Network is a member of
HEALTHeCAREERS Network, an onTargetjobs, Inc.,
company. The online portal offers recruitment, advertising,
and career opportunities paired with enhanced, industryspecific access to thousands of cardiology job seekers,
top employers, and partnerships with multiple cardiology
associations.
CVRx Inc.
9201 West Broadway Avenue, Suite 650
Minneapolis, MN 55445
Phone: 763-416-2840
Fax: 763-416-2841
www.cvrx.com
516
CVRx, Inc. has developed an implantable device for the
treatment of hypertension in patients who cannot control
their blood pressure with medications and lifestyle
modifications. The Rheos™ Barorefliex Hypertension
Therapy™ System is an investigational device and currently
is in clinical trials in the United States and Europe.
Daiichi Sankyo
Two Hilton Court
Parsippany, NJ 07054
Phone: 973-359-6300
Fax: 973-630-2891
www.dsus.com
205A
1644 Laurel Street
Chico, CA 95928
Phone: 530-892-9086
Fax: 530-892-9086
www.DataDancer.com
308
Elsevier is proud to publish the Journal of the American
Society of Hypertension, the official journal of the
American Society of Hypertension. Please stop by our
booth to view the latest issue of the journal and browse
our other books and journals in the field of hypertension.
Forest Pharmaceuticals, Inc.
13600 Shoreline Drive
St. Louis, MO 63045
Phone: 800-678-1605
Fax: 314-493-7450
www.frx.com
205
Forest Pharmaceuticals, Inc., welcomes you to San
Francisco! We invite you to visit our exhibit where our
professional representatives will welcome the opportunity
to discuss and answer any questions regarding our
product Bystolic ® (nebivolol ) tablets.
Please visit our website at www.bystolic.com.
Gilead Sciences Inc.
333 Lakeside Drive
Foster city, CA 94404
Phone: 650-574-3000
Fax: 650-578-9264
www.gilead.com
218
Gilead Sciences is a biopharmaceutical company that
discovers, develops, and commercializes therapeutics to
advance the care of patients suffering from life-threatening
diseases worldwide.
Three Franklin Plaza
1600 Vine Street
Philadelphia, PA 19101
Phone: 800-366-8900
www.gsk.com
306
GlaxoSmithKline is a leading research-based
pharmaceutical company with a powerful combination
of skills to discover and deliver innovative medicines. We
offer a number of programs to support effective health
management strategies and improve patient care. Please
visit our exhibit to learn more about our products.
HemoCue, Inc.
40 Empire Drive
Lake Forest, CA 92630
Phone: 800-881-1611
Fax: 949-859-3066
www.hemocue.com
314
HemoCue is a world leader in point-of-caring testing.
The name HemoCue has long been synonymous
with precision, accuracy, and reliability. HemnoCue’s
leading point-of-care analyzers, for the measurement of
hemoglobin and glucose in whole blood and albumin
in urine, allow any health-care professional the ability to
obtain lab quality results anytime, anywhere.
HoMedics, Inc. 3000 Pontiac Trail
Commerce Township, MI 48390
Phone: 248-863-3000
Fax: 248-863-3103
www.homedics.com
216
HoMedics innovative technologies and advanced features
give consumers the tools needed to proactively and
effectively manage their health. Our line of blood pressure
monitors feature clinically proven accuracy with Smart
Measure ® technology, Supersize Digits ® for easy reading,
simplified user interface for ease of use, standard and
large size cuffs to fit most arms, dual user memory and a
5-year warranty.
International Society of Hypertension
201 Bewicke Avenue, Suite 206
North Vancouver, British Columbia V7M 3M7
Phone: 604-984-6455
Fax: 604-984-6434
www.VancouverHypertension2010.com
304
The International Society of Hypertension invites you to
participate in the 23rd Scientific Meeting, which takes
place September 26 to 30, 2010, in Vancouver, British
Columbia, Canada. The scientific program will include
keynote presentations, industry and investigator initiated
symposia, oral and poster presentations, public forums,
an exhibition, and of course a diverse social program
highlighting Vancouver and the surrounding area.
International Society on
Hypertension in Blacks, Inc.
510
157 Summit View Drive
Please visit Daiichi Sankyo, Inc., marketer of
Azor™ (amlodipine and olmesartan medoxomil), Benicar®
(olmesartan medoxomil), and Benicar® HCT® (olmesartan
medoxomil-hydrochlorothiazide).
Data Dancer Medical Systems
1600 JFK Blvd., Suite 1800
Phone: 215-239-3491
Fax: 215-239-3494
www.elsevierhealth.com
GlaxoSmithKline
BpTRU Medical Devices is the Canadian inventor and
manufacturer of the BpTRU automated blood pressure
device.
This is a precision instrument that delivers remarkable
accuracy with reliable and reproducible readings. By
discarding the first reading and averaging the remaining
five it reduces “white coat hypertension.” These proven
patented technologies help to consistently identify and
manage hypertension.
CardioDynamics — The ICG Company
Elsevier 504
Data Dancer offers innovative blood pressure software
that pairs patients with physicians in the diagnosis and
treatment process. Data Dancer organizes home blood
pressure results providing performance feedback that
is easy to understand, comprehensive and essential in
achieving treatment goals. Our software products (Limbo,
Tango, and Salsa) are designed to track established
treatments, assess the quality of home measurements,
and to provide treatment performance across multiple trial
treatments.
McDonough, GA 30253
Phone: 404-880-0343
Fax: 404-880-0347
www.ishib.org
Founded in 1986, the International Society on
Hypertension in Blacks, Inc. is a non-profit organization
of health-care professions and leaders in cardiovascular
disease and related disorders. Our mission is to improve
the health and life expectancy of ethnic minorities
and eliminate racial and ethnic health disparities in
cardiovascular disease through professional and public
education, targeted clinical research, and facilitation of
the delivery of higher quality cardiovascular health care.
We host an annual conference, membership, and other
programs.
International Society For Vascular Health 312
87 Rue de l’Assomption,
75016 Paris France.
Phone: 331-5574-6669
Fax: 331-5574-6665
[email protected]
www.isvh.net
The International Society for Vascular Health (ISVH) is a
not-for-profit charity established under French law in 1901.
The society aims to be a catalyst for clinical cooperation
between health-care professionals in disciplines such as
cardiovascular therapy, thrombosis, nephrology, lipidology,
and a broad spectrum of others to actively promote
worldwide vascular health. The society’s President and
Editor-in-Chief of the its journal Vascular Health & Risk
Management is Pr Roland Asmar of the Cardiovascular
Institute in Paris.
Kent Scientific Corporation
1116 Litchfield Street
Torrington, CT 06790
Phone: 888-572-8887
Fax: 860-626-1172
www.kentscientific.com
212
Kent Scientific Corporation serves medical and research
scientists as a worldwide provider of integrated solutions
for pre-clinical research and drug discovery advancement.
As the world leader in non-invasive blood pressure
products for mice and rats, we enable our customers to
achieve results that are fast, consistent, and exceedingly
accurate. Customers can rely on our informative web site
to purchase research products with confidence.
Lippincott, Williams & Wilkins
530 Walnut Street, Suite 8W
Phone: 916-425-1254
Fax: 800-882-9237
www.LW W.com
213
Lippincott, Williams & Wilkins offers specialized
publications and software for physicians, nurses,
students, and specialized clinicians. Products include
drug guides, medical journals, nursing journals, medical
textbooks, and medical PDA software. LWW publishes the
journal Hypertension, the Journal of the American Heart
Association, and The Journal of Hypertension, the official
journal of the International Society of Hypertension and
the European Society of Hypertension.
Merck & Co., Inc.
351 N. Sumneytown Pike
North Wales, PA 19454
Phone: 267-305-5000
Fax: 267-305-1266
www.merck.com
101
Merck & Co., Inc. is a global research-driven
pharmaceutical company dedicated to putting patients
first. Established in 1891, Merck discovers, develops,
manufactures, and markets vaccines and medicines to
address unmet medical needs.
Microlife Medical Home Solutions, Inc.
2801 Youngfield Street, Suite 241
Golden, CO 80401
Phone: 800-968-1378
Fax: 303-274-2244
www.MiMHS.com
506
Microlife Medical Home Solutions Inc. is dedicated to
meeting the needs of physicians and their busy practices.
Our tools and solutions offer a systematic and evidencebased method for assessment, diagnosis, and treatment
of hypertension and obesity. Microlife is committed to
providing physicians with the means to implement new
modes of patient-centered care that are efficient, effective,
and profitable.
National Kidney Foundation
30 East 33rd Street
New York, NY 10016
Phone: 212-889-2210
Fax: 212-889-2310
www.kidney.org
508
How many of your patients with diabetes, hypertension
and cardiovascular disease have undiagnosed chronic
kidney disease? One in nine U.S. adults has chronic kidney
disease. Early detection can help prevent progression to
kidney failure. Visit booth 508 to learn how your patients
and clinicians can benefit from the National Kidney
Foundation’s educational tools, resources, and screening
programs.
Nature Publishing Group
75 Varick Street, 9th f loor
New York, New York 10013-1917
Phone: 212-726-9200
www.natureny.com
318
Nature Publishing Group brings leading scientific and
medical research to your desktop. The NPG portfolio
combines the continued excellence of Nature, its
associated research and review journals, and more than
45 leading academic and society journals in the life,
physical, and clinical sciences. Visit booth 318 for
sample copies.
NicOx
Les Tasissounieres
1681 Route des Dolines — Bat HB4 BP 313
06 906 Sophia Antipolis Ledex France
Phone: 33 (0) 497 245300
Fax: 33(0) 497 245399
[email protected]
www.nicox.com
310
NicOx is a pharmaceutical company committed to
developing nitric oxide–donating drugs that address
important unmet medical needs and targeting the
therapeutic areas of inflammatory and cardiometabolic
diseases. NicOx is maximizing the value of its broad
product portfolio through in-house development of drug
candidates and partnerships with major pharmaceutical
companies.
Novartis Pharmaceuticals
Corporation
One Health Plaza
East Hanover, NJ 07936
Phone: 862-778-1899
Fax: 973-781-5488
www.novartis.com
402/502
Novartis Pharmaceuticals is dedicated to discovering,
developing, manufacturing, and marketing prescription
drugs that meet our customers’ medical needs and
improve their quality of life. Please visit the Novartis exhibit
where our sales representatives will be available to discuss
our products.
Omron Healthcare
1200 Lakeside Drive
Bannockburn, IL 60015
Phone: 800-323-1482
Fax: 800-637-6763
www.omronhealthcare.com
406
Omron Healthcare, Inc., in Bannockburn, IL, is the North
and South American sales and marketing office of
Omron Healthcare Group, a leading manufacturer and
distributor of blood pressure monitors for home use.
Omron Heathcare offers innovative products and medical
devices for use in sites ranging from hospitals to the home
in the blood pressure monitoring, fitness diagnostics,
thermometry, and respiratory categories.
sanofi–aventis U.S.
55 Corporate Drive
Bridgewater, New Jersey 08807
Phone: 908-981-5000
Fax: 908-981-7851
www.sanofi-aventis.com
208
Sanofi-aventis U.S. is an affiliate of sanofi-aventis, a leading
global pharmaceutical company that discovers, develops,
and distributes therapeutic solutions to improve the lives
of everyone. Sanofi-aventis is listed in Paris (EURONEXT:
SAN) and in New York (NYSE: SNY).
statMAP
4920 W. Cypress St., Ste 110
Tampa, FL 33607
Phone: 813-289-5555
Fax: 813-289-5454
www.statmap.com
211A
Introducing statMAP — a revolutionary new class of blood
pressure device, statMAP’s small size combined with its
hospital grade accuracy and reliability make it unique. Easy
to use, statMAP, electronically measures systolic, diastolic,
mean arterial pressure and heart rate in seconds. Battery
operation makes it useful practically everywhere. Call
(800) 231-6370 or visit www.cardiocommand.com.
Tiba Medical, Inc.
2701 NW Vaughn Street, Suite 470
Portland, Oregon 97210
Phone: 503-222-1500
Fax: 503-222-3324
Phone: 800-985-TIBA
www.tibamedical.com
515
Our advanced Ambulo 2400 24-hour ambulatory blood
pressure monitoring systems provide for better diagnosis
and management of your hypertensive patients. Accurate,
validated, and reliable systems complete with four
cuffs, built-in actigraphy, and Windows-based software.
Purchase, lease, and short-term rental options are
available. Great service and support for your clinic. We
also specialize in supporting the stringent requirements of
clinical trials (Phase I through Phase IV) including unique
features for PK/PD studies.
W.A. Baum Co., Inc.
620 Oak Street
Copiague, NY 11726
Phone: 631-226-3940
Fax: 631-226-3969
www.wabaum.com
410
The Baum Company manufactures a complete line of
mercury-gravity and aneroid clinical sphygmomanometers
equipped with calibrated V-Lok inflation systems.
Additionally, we offer stethoscopes, a full line of latex and
non-latex replacement parts, decorated and disposable
cuffs and cuffs designed for use with automated NIPB
monitors. Baum products are sold through an international
network of medical/surgical supply dealers.
Wiley-Blackwell
350 Main Street
Malden, MA 02148
Phone:
Fax: 781-338-8212
www.wiley-blackwell.com
302
781-388-8200
Wiley publishes an enormous range of top quality
consumer, professional, educational, and research
material. Wiley-Blackwell, the scientific, technical,
medical and scholarly publishing business of John Wiley
& Sons, is the leading society publisher and offers peerreviewed primary research and evidence-based medicine
across 1,250 online journals, books, reference works,
and databases.
Zona Health
11770 W President Drive, Suite H
Boise, ID 83713
Phone: 208-322-9399
Fax: 208-322-9483
www.zona.com
105
Zona Plus™ is an innovative handheld device clinically
proven to significantly reduce high blood pressure for
more than 93 percent of users by using the device just
12 minutes a day. The Zona Plus focuses on shifting the
vagal tone from sympathetic to parasympathetic and
improving endothelial dysfunction by improving nitric
oxide production. Clinical trials support the effectiveness
of Zona Plus for improving these indicators.
12
Role of salt in blood pressure often misunderstood
A series of talks this morning will look at potential causes as well as management strategies
for salt-sensitive hypertension.
While ingestion of salt clearly
plays a role in hypertension, there are many
variables and emerging findings suggest
new treatments on the horizon. Hypertension specialists will hear about interesting
developments and theories regarding salt
sensitivity during the session, “Salt-Sensitive
Hypertension,” which takes place from 10:00
to 11:30 a.m., Saturday, May 9, in Yerba Buena
Ballroom — Salon 7.
Renal medulla defects may
play a role
Structures within the renal medulla of the
kidney are critically important for the control
of sodium in water excretion. Defects in the
tubular and vascular elements within the renal
medulla, particularly the renal endothelin
system, can lead to salt-sensitive hypertension,
said David Pollock, MD, Regents Professor,
Medical College of Georgia.
Dr. Pollock, who will be presenting “Is the
cause in the renal medulla?” said it’s clear that
Americans consume far too much salt, and that
at least 60 percent to 70 percent of people with
hypertension are salt-sensitive.
Research shows that an imbalance between endothelin A and B receptors may be
at the root of salt-sensitive hypertension. The
endothelin A receptor system contributes to
elevating blood pressure by direct constriction
of arteries and veins.
“In a healthy person, the kidney senses
your salt intake and will excrete it to keep your
pressure normal. Our hypothesis is that people
who have a defect in the renal medullary function, in particular, the endothelin B receptor
pathway, are not able to eliminate enough salt
and water and they retain f luid, becoming
hypertensive,” Dr. Pollock said.
Additionally, endothelin antagonists
already on the market for pulmonary hyper-
Featuring the Latest in Hypertension
Visit Nature Publishing Group at Booth #318 for your
FREE Sample Copies of:
AJH
EDITORIALS
1
AJH Joins the Nature Family
Michael H. Alderman
2
Publisher’s Note
Joy Moore
3
Blood Pressure Variability: The Challenge of Variation
Tom P. Marshall
5
Plasma Renin Activity for Predicting Antihypertensive Drug
Efficacy
Jon D. Blumenfeld
NEWS AND VIEWS
HIGHLIGHTS
7
The renin-angiotensin system and treatment of
hypertension | Albuminuria is common and reversible |
Improved diastolic function by central sympathetic inhibition
COMMENTARIES
8
The Metabolic Syndrome as a Prohypertensive State
Giuseppe Mulè and Giovanni Cerasola
9
Ventricular Repolarization in Hypertension:
Beyond Bazett
Claudio Passino and Michele Emdin
ONLINE ISSN:1348-4214
PRINT ISSN:0916-9636
nature publishing group | volume 21 | number 1 | january 2008
www.nature.com/ajh
35
41
47
54
61
ORIGINAL CONTRIBUTIONS
BRIEF COMMUNICATIONS
Pretreatment Plasma Renin Activity Levels Correlate With
the Blood Pressure Response to Telmisartan in Essential
Hypertension
Junichi Minami, Toshihiko Ishimitsu and Hiroaki Matsuoka
14 Carryover Effects After Cessation of Drug Treatment:
Trophies or Dreams?
Thomas Lumley, Kenneth M. Rice and Bruce M. Psaty
ARTICLES
EPIDEMIOLOGY
17 Relationship Between the Metabolic Syndrome and
the Development of Hypertension in the Hong Kong
Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2)
Bernard M.Y. Cheung, Nelson M.S. Wat, Y. B. Man, Sidney Tam,
C. H. Cheng, Gabriel M. Leung, Jean Woo, Edward D. Janus, C. P. Lau,
T. H. Lam and Karen S.L. Lam
23 Hydroxyhydroquinone Interferes With the Chlorogenic
Acid-induced Restoration of Endothelial Function in
Spontaneously Hypertensive Rats
Atsushi Suzuki, Akihiko Fujii, Hiroko Jokura, Ichiro Tokimitsu,
Tadashi Hase and Ikuo Saito
28 Upregulation of Endothelial and Inducible Nitric Oxide
Synthase Expression by Reactive Oxygen Species
Junhui Zhen, Hua Lu, Xiu Q. Wang, Nosratola D. Vaziri and
Xin J. Zhou
Hypertension
Research
American Journal
of Hypertension
10
67
72
78
85
Official Journal of the
Japanese Society of Hypertension
Volume ?? Number ?
BP MEASUREMENT
Inverse Relationship Between Ambulatory Arterial Stiffness
Index and Glomerular Filtration Rate in Arterial Hypertension
Giuseppe Mulè, Santina Cottone, Paola Cusimano, Francesca
Incalcaterra, Maria Giandalia, Miriam Costanzo, Emilio Nardi,
Alessandro Palermo, Calogero Geraci, Renato Costa
and Giovanni Cerasola
Changing Relationship Between Home and Office Blood
Pressure With Increasing Age in Children: The Arsakeion
School Study
George S. Stergiou, Vayia C. Rarra and Nikolaos G. Yiannes
HEART
Recent Ventricular Repolarization Markers in Resistant
Hypertension: Are They Different from the Traditional QT
Interval?
Gil F. Salles, Claudia R.L. Cardoso, Sharon M. Leocadio and
Elizabeth S. Muxfeldt
Improvement of Cardiac Diastolic Function by Long-term
Centrally Mediated Sympathetic Inhibition in One-Kidney,
One-Clip Hypertensive Rabbits
Isabelle L. Signolet, Pascal P. Bousquet and Laurent J.P. Monassier
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
Predictors of Blood Pressure Response to the Angiotensin
Receptor Blocker Candesartan in Essential Hypertension
Vincent J. Canzanello, Evelyn Baranco-Pryor, Frederic
Rahbari-Oskoui, Gary L. Schwartz, Eric Boerwinkle,
Stephen T. Turner and Arlene B. Chapman
Ascorbic Acid Decreases the Binding Affinity of the AT1
Receptor for Angiotensin II
Patrice C. Leclerc, Christophe D. Proulx, Guillaume Arguin,
Simon Bélanger, Fernand Gobeil Jr, Emanuel Escher, Richard Leduc
and Gaétan Guillemette
Effects of an ARB on Endothelial Progenitor Cell Function and
Cardiovascular Oxidation in Hypertension
Yi Yu, Noboru Fukuda, En-Hui Yao, Taro Matsumoto,
Naohiko Kobayashi, Ryo Suzuki, Yoshiko Tahira, Takahiro Ueno
and Koichi Matsumoto
THERAPEUTICS
Calcium Channel Blockers Suppress Cytokine-induced
Activation of Human Neutrophils
Etsuko Shima, Masataka Katsube, Takayuki Kato, Maki Kitagawa,
Fumihiko Hato, Masayuki Hino, Tatsuji Takahashi, Hisakazu Fujita
and Seiichi Kitagawa
DIAGNOSTICS
Blood Pressure Variability Causes Spurious Identification of
Hypertension in Clinical Studies: A Computer Simulation Study
Martin J. Turner and Johan M. van Schalkwyk
January 2009
EDITORIAL COMMENT
Hypoxia-Induced Cardiac Remodeling in Sleep Apnea
Syndrome: Involvement of the Renin-AngiotensinAldosterone System
1147
Yoshikazu MIWA and Toshiyuki SASAGURI
ORIGINAL ARTICLES
Aortic Pulse Wave Velocity and Carotid-Femoral Pulse
Wave Velocity: Similarities and Discrepancies
1151
Piotr PODOLEC, Grzegorz KOPEC
Relationship between Oxidative Stress and Essential
Hypertension
1159
Ramón RODRIGO, Hernán PRAT, Walter PASSALACQUA
Joint Impact of Smoking and Hypertension on
Cardiovascular Disease and All-Cause Mortality in Japan:
NIPPON DATA80, a 19-Year Follow-Up
1169
Atsushi HOZAWA, Tomonori OKAMURA, Yoshitaka MURAKAMI
Telmisartan Treatment Decreases Visceral Fat
Accumulation and Improves Serum Levels of Adiponectin
and Vascular Inflammation Markers in Japanese
Hypertensive Patients
1205
Daisuke CHUJO, Kunimasa YAGI, Akimichi ASANO
Independent Determinants of Second Derivative of
the Finger Photoplethysmogram among Various
Cardiovascular Risk Factors in Middle-Aged Men
1211
Toshiaki OTSUKA, Tomoyuki KAWADA, Masao KATSUMATA
Angiotensin II Receptor Blocker Reduces Oxidative
Stress and Attenuates Hypoxia-Induced Left Ventricular
1219
Remodeling in Apolipoprotein E−Knockout Mice
Chika YAMASHITA, Tetsuya HAYASHI
Inhibition of Vascular Angiotensin-Converting Enzyme by
Telmisartan via the Peroxisome Proliferator−Activated
1231
Receptor a Agonistic Property in Rats
Shinji TAKAI, Denan JIN, Maki KIMURA
C-Reactive Protein, Left Ventricular Mass Index, and Risk
of Cardiovascular Disease in Essential Hypertension 1177
Yoshio IWASHIMA, Takeshi HORIO
Gene Polymorphism of Myospryn (CardiomyopathyAssociated 5) Is Associated with Left Ventricular Wall
Thickness in Patients with Hypertension
1239
Hironori NAKAGAMI, Yasushi KIKUCHI
Renal Protective Effect in Hypertensive Patients:
The High Doses of Angiotensin II Receptor Blocker
(HARB) Study
Mitsuru OHISHI, Takashi TAKAGI
Angiotensin-Converting Enzyme Inhibitor
Suppresses Activation of Calcineurin in Renovascular
Hypertensive Rats
1247
Hongzhuan SHENG, Jianhua ZHU
1187
www.nature.com/jhh
www.nature.com/hr
Functional Polymorphism of the Myeloperoxidase Gene
in Hypertensive Nephrosclerosis Dialysis Patients 1193
Kent DOI, Eisei NOIRI, Rui MAEDA
Systemic Distribution of Salusin Expression in the Rat
1255
Noriko SUZUKI, Masayoshi SHICHIRI
Effects of Short-Term Hypocaloric Diet on SympathoVagal Interaction Assessed by Spectral Analysis of Heart
Rate and Blood Pressure Variability during Stress Tests
in Obese Hypertensive Patients
1199
Terunao ASHIDA, Chikako ONO and Takao SUGIYAMA
CASE REPORT
Obesity, adiposity, and
hypertension
Plasma visfatin levels in
hypertension
Endothelial activation
and microalbuminuria in
hypertension
Torsades de Pointes: A Rare Complication of an ExtraAdrenal Pheochromocytoma
1263
Heiko METHE, Martin HINTERSEER
CONTINUED ON NEXT PAGE
www.nature.com/ajh
www.nature.com/hr
www.nature.com/jhh
Nature Publishing Group is proud to publish three journals spanning the breadth
of hypertension – the American Journal of Hypertension, Hypertension Research
and Journal of Human Hypertension. Each of these journals offers unique features
as well as the latest research covering:
• molecular biology
• neurophysiology
• cardiology
• epidemiology
• endocrinology
• clinical and experimental hypertension
• nephrology
• cardiovascular biology.
tension may be causing problems, he said. “By
giving the blocker, you may be blocking some
of the good effects of the endothelin system.”
Advances offer new treatment
techniques
Renovascular disease is one of the most
common causes of secondary hypertension,
said Stephen Textor, MD, Professor of Medicine and Vice Chair of the Division of Nephrology and Hypertension at the Mayo Clinic.
Dr. Textor’s will present “A Clinical Case in
Renovascular Hypertension.”
“It’s a bit of a controversial area right
now because anti-hypertensive drug therapy
has proven good, but at the same time there
have been a lot of advances in techniques for
opening up blood vessels like angioplasty and
stenting,” Dr. Textor said. “The controversy is
over when and where to use each of those. It’s
hard to know if opening up those blood vessels
really adds much benefit for most patients.”
Dr. Textor will discuss which situations
call for moving ahead with therapy, and which
don’t. He expects the question-and-answer
portion of the talk to yield fruitful discussion.
“We will look at when to move ahead with
renal vascular therapy and when to rely on
anti-hypertensive drug therapy — and when
not to,” he said. “We’re living in a time when
the trial results are ambiguous. Some think
we’re doing too many procedures. Because
of these questions hypertension specialists
are really going to have to weigh in on the
individual cases.”
Elderly benefit from treatment
Doctors should not be reluctant to treat
people over 80 to get their blood pressure
down, said William J. Elliott, MD, PhD,
Yakima, Wash.
Along with Gary Mitchell, MD, Norwood,
Mass., Dr. Elliott will discuss a patient case history and the overlap of salt-sensitive hypertension with systolic hypertension in the elderly,
particularly those over 80 years in age.
The HYVET study abstract in the May 1,
2008, New England Journal of Medicine showed
that patients above 80 benefit from treatment,
Dr. Elliott said.
“As people become older they become
more salt-sensitive and their arteries stiffen
and the systolic blood pressure goes up and
diastolic blood pressure goes down. People
used to think that’s okay (as a normal part of
aging) and therefore not worth treating, but
now it’s known that lowering blood pressure
is beneficial,” he said.
“In the olden days, people over 80 would
argue with me that it doesn’t pay to take
medication to reduce blood pressure. People
are still stuck with the idea that because their
diastolic blood pressure is below 90 mmHg,
that they’re okay. They’re wrong,” he said.
“Systolic blood pressure is not something to
be dismissed.”
Racial differences offer clues
For many years it’s been widely formulated the mechanism by which salt causes
the pressor effect is through the kidney, but
the true mechanism has never really been established, said Curtis Morris, MD, Professor
of Medicine, Pediatrics and Radiology at the
University of California, San Francisco.
Salt, continued on next page
13
Vascular Health
Speakers to address clinical relevancy
Vascular stiffness and inf lammation rosis. “We looked at why people with COPD diastolic pressure. If clinicians do a more
may be underlying risk factors for hyper- had stiff aortas and found that they had aortic detailed analysis, they can obtain much more
tension and cardiovascular disease. In the calcification. We also looked at people with information about the risk of cardiovascular
first part of Saturday afternoon’s session on osteoporosis and found that they
morbidity and mortality. I will
“Arterial Evaluation: Clinically Relevant?” were at high cardiovascular risk
focus mainly on people with
which takes place from 4:00 to 5:30 p.m. as well because when calcium
pre-hypertension or normotenin Yerba Buena Ballroom — Salon 8, two comes out of their bones, it goes
sion. I will address the issue of
speakers will assess the role of vascular into their arteries. So there is a
whether arterial elasticity or
health in hypertension and the various ways link between osteoporosis and
stiffness can provide extended
of evaluating vascular health. The session is vascular complications,” he said.
information beyond arterial
co-sponsored by ASH and the International “People with osteoporosis may
blood pressure measurement
Society for Vascular Health.
well be hypertensive and may
for the prediction of cardiovasJohn R. Cockcroft, MD, Professor of well have systolic hypertension,
cular events as well the developCardiology at the Wales Heart Research which can be difficult to treat.
ment of hypertension in these
Institute, Cardiff, UK, will examine the role So clinicians should consider Daniel Duprez, MD, PhD people,” Dr. Duprez said.
of vascular health in chronic obstructive pul- people with osteoporosis at high
He will discuss carotid femmonary disease (COPD) and osteoporosis risk for cardiovascular events.
oral pulse-wave velocity as one method of
and how these conditions are
“It’s been suggested that assessing cardiovascular disease risk. This
related to hypertension.
statins have effects beyond measurement assesses the difference in time
“COPD is actually a vascucholesterol reduction, and one from when the waveform from the heart
lar disease, and a lot of people
of those effects is to reduce reaches the carotid and the femoral artery.
with COPD die of cardiovasinf lammation. It’s also been
He will also describe a method to analyze
cular disease. Smoking doesn’t
show n that statins improve the blood pressure curve or waveform at
explain all the mortality risk.
bone density. Statins may be the level of the radial artery and a method
One indication that COPD is a
the ideal drug for people with to measure cross-sectional compliance or
vascular disease is that people
COPD and osteoporosis.”
distensibility.
with COPD have inf lammation
Daniel Duprez, MD, PhD,
“Changes in arterial elasticity should be
outside the lungs, or systemic
Professor of Medicine, Donald detected as early as possible to prevent the
inf lammation, which may dam- John R. Cockcroft, MD
and Patricia Garofalo Chair in development of hypertension and cardioage the arteries. I will show data
Preventive Cardiology, Direc- vascular disease. These changes will help us
demonstrating that people with COPD have tor of the Lipid Clinic, Director of Research predict who will develop arterial hypertenincreased arterial stiffness and evidence of of the Rasmussen Center for Cardiovascular sion and, in the future, help us determine
arterial damage,” Dr. Cockcroft said. “When Disease Prevention, and Associate Director when to start treatment to maintain vascular
clinicians see patients with COPD, they of the Cardiovascular Clinical Trial Center health,” Dr. Duprez said.
should check the patients’ cardiovascular at the University of Minnesota, MinneThe second part of this program will
risk factors and treat those risk factors. I apolis, will present an overview of different feature a debate of the question, “Are the Difwill show some data that clinicians should methods of evaluating arterial stiffness or ferent Vascular Effects of Antihypertensives
even consider giving statins to people with elasticity, including pulse-wave velocity Clinically Relevant?” Arguing the pro side
COPD”
measurements.
is Gary F. Mitchell, MD, Norwood, Mass.,
Dr. Cockcroft will also describe his re“Blood pressure measurements only and debating the con is James D. Cameron,
search linking arterial stiffness with osteopo- assess two extreme points — systolic and MBBS, MD, Melbourne, Australia. l
Awards to be presented at final
plenary session
Don’t miss Saturday’s Awards Plenary Session, which begins at 8:15 a.m. in the
Yerba Buena Ballroom – Salon 9. Several honor lectures will be presented, including
the Robert Tigerstedt Award Lecture and the Young Scholars Awards.
8:15 a.m. — Welcome and Introduction
8:20 a.m. — Robert Tigerstedt Award
Lecture: Angiotensin Type-2 (AT2)
Receptors: Understanding Their Role in
Cardiovascular and Renal Function.
Robert M. Carey, MD
Young Scholars Award Lectures
8:50 a.m. — Aldosterone Signaling
through Cholesterol-Rich Domains:
Implications in Hypertension.
Glaucia E. Callera, PhD
9: 07 a.m. — Identification of Genetic
Susceptibility to Hypertension and
the Metabolic Syndrome in the Lyon
Hypertensive Rat. Anne E. Kwitek, PhD
9: 24 a.m. — Renal Heme Oxygenase
and Hypertension. David E. Stec, PhD
9:41 a.m.
Presentation of the First Marvin Moser
Clinical Hypertension Award to Domenic
A. Sica, MD.
9:45 a.m.
Announcement of ASH 2009 Young
Investigator-in-Training Abstract
Competition Award Recipients.
Featured Posters
Friday, May 8, 2009
Posters on Display: 9:30 a.m. to 4:00 p.m.
Poster Viewing: 2:30 to 3:30 p.m.
P-308: Hypertension Treatment and Control
among 28 Physician Practices across the
US: Results of the Hypertension: Assessment
of Treatment To Target (HATT) Study
Daniel A. Belletti, Jenifer L. Wogen, Christopher
Zacker
P-359: Successful Treatment of Acute
Hypertension in Children with Isradipine
Yosuke Miyashita, Do Peterson, Joseph Flynn
Audio recordings
available as
CD-ROM, MP3
Audio recordings on CD-ROM
(including select speaker presentations
as PDFs) from the scientific sessions and
satellite symposia will be for sale through
AVMG in the Mission Street Tunnel.
You may also download the individual
sessions in MP3 format to your computer
post-conference. Visit our e-commerce
store at www.ash-us.org. l
Satellite Symposia
The latest information on new
concepts, treatments, devices, and
techniques will be examined during
industry-supported satellite symposia.
All symposia take place in the Yerba
Buena Ballroom Salon 7 at the San
Francisco Marriott.
Friday, May 8
5:30 – 8:00 a.m.
Antihypertensive Combinations
for Blood Pressure and Beyond: A
Moderated Debate
Chair: William J. Elliott MD, PhD
Supported by an educational grant from
Daiichi Sankyo Inc.
5:30 – 8:00 p.m.
Defining Resistant Hypertension and
New Therapeutic Pathways
Chair: Henry R. Black, MD
Gilead Sciences Medical Affairs.
saturday, May 9
5:30 – 8:00 a.m.
Improving Cardiovascular Risk Factor
Management in Community-Based
Practices: Prototypical Challenges
and Practical Solutions
Chair: Brent M. Egan, MD
Merck & Co., Inc.
SALT,
continued from page 12
For unknown reasons, salt-sensitivity is
particularly frequent and severe in AfricanAmericans, even in those who are not hypertensive when not ingesting excessive amounts
of salt.
Dr. Morris, whose speech is entitled
“What Causes Salt-Sensitive Hypertension?
Renal Salt Retention or Increased Peripheral
Resistance?” has looked at racial differences
in salt-sensitive hypertension.
In recent studies of such normotensive
African-American conducted by Dr. Morris
and his colleagues, said he they were surprised
to fund that in those who were salt-resistant,
blood pressure and systemic vascular resistance actually decreased substantially during
the first three days of salt-loading — an apparently normal response. It appeared that
the failure of this response to occur in the
salt-sensitive subjects, in combination with a
normal increase in cardiac output, accounted
for their initial increase in blood pressure in
response to salt loading.
“In the African Americans we studied, you
can’t invoke a kidney abnormality that causes a
positive salt balance as the reason for why the
blood pressure went up,” he said.
For some time it was assumed that both sodium and chloride were needed to make blood
pressure rise, but it was found that sodium
citrate would not make the blood pressure rise.
Yet the studies were not performed on African
Americans until Dr. Morris’ research.
During his talk, Dr. Morris will share further details of his research as he discusses potential causes of salt-sensitive hypertension. l
14
Obesity
Panel to discuss BP management in this population
clude physical activity, meditation, and pro“Blood Pressure Management in the Obese gressive muscle relaxation,” Dr. Foreyt said.
Person” will feature a panel of experts “Psychological factors can have a significant
discussing various aspects of dealing with effect on blood pressure in obese patients.
hypertension in this population, including My talk will provide attendees with insights
the psychological considerations, surgery into potential strategies that their patients
for obesity, and the management of resistant can learn to help manage the psychological
hypertension.
aspects of high blood pressure.”
The session will take place
Bruce M. Wolfe, MD, Profesfrom 10:00 to 11:30 a.m., Satsor of Surgery at Oregon Health
urday, May 9, in Yerba Buena
& Science University, Portland,
Ballroom — Salon 8.
will acquaint attendees with the
John P. Foreyt, PhD, Profesreasons for performing surgery
sor of Medicine and Director
for obese people with hypertenof the Behavioral Medicine
sion and other co-morbidities.
Research Center at Baylor Col“I will talk about the incilege of Medicine in Houston,
dence of severe obesity, the
will examine the psychological
incidence of complications or
side of this issue, focusing on
co-morbidities of obesity inthe psychological factors afcluding hypertension, the genfecting blood pressure in obese
eral criteria for surgery, and the
individuals and how health-care John P. Foreyt, PhD
choices for surgical treatment,”
professionals can help patients
Dr. Wolfe said.
manage these psychological factors.
The primary choice for surgery is gastric
“I plan to discuss behavioral strategies, bypass followed by adjustable gastric bandincluding strategies to raise patients’ aware- ing. Infrequently done is biliopancreatic
ness of their lifestyle factors affecting their diversion. And the latest innovation is sleeve
blood pressure and specific problem-solving gastrectomy. “Sleeve gastrectomy is the
strategies that can be used to help them man- stomach part of biliopancreatic diversion
age their blood pressure. These strategies in- with duodenal switch,” he said. “Resolution
Satur day mor n ing’s session on
of hypertension just by weight loss is vari“Obesity is strongly associated with
able and incomplete, and the benefits may be difficult-to-control hypertension and an
somewhat temporary. Hypertension is usually increased need for a number of medications
not the only co-morbidity of obeto control hypertension. The
sity, and the information we have
underlying reasons for that
is that bariatric surgery improves
are multiple,” Dr. Calhoun
survival over the long term for
said. “My particular research
the obese population.”
interest has been in aldosterone
What is not know is whether
excess as an underlying cause
obesity is as big a survival risk if
of resistant hypertension. My
the patient’s hypertension is well
colleagues and I have found this
treated at all times using modern
to be particularly true of obese
pharmacology.
patients. In our experience,
“The prevalence of obesity
blocking aldosterone can be an
and hypertension together is
effective treatment for resistant
high, and the relative risk of David A. Calhoun, MD
hypertension, especially in
death is raised by obesity itself.
obese patients.”
Treating hypertension alone will most likely
He said he also believes resistant hyhelp some patients but not enough because of pertension in obese people may be related
other co-morbidities. Severe obesity is a life- to increased salt sensitivity. Another asthreatening condition with or without hyper- sociated feature of obesity is sleep apnea,
tension, and surgery is an effective treatment which contributes to difficulty in treating
that is acceptably safe,” Dr. Wolfe said.
hypertension.
David A. Calhoun, MD, Professor of
“Therapy for resistant hypertension
Medicine in the Vascular Biology and Hyper- in these patients includes effective use
tension Program at the University of Alabama of diuretics and aldosterone antagonists
at Birmingham, will highlight the association and eva luating and treating sleep apbetween obesity and resistant hypertension nea. I will also emphasize dietary reco
and discuss the management of resistant mendations, especially salt restriction,”
hypertension in obese individuals.
Dr. Calhoun said. l
Sex hormones affect multiple
mechanisms related to blood pressure
Dur ing y ester day’s session “Sex
Hormones and Blood Pressure,” two experts on
hormones and hypertension looked at the roles
testosterone and estrogen play in regulating
blood pressure as well as other cardiovascular
concerns.
Cardiologist and
hypertension specialist L. Michael Prisant, MD, Professor
of Medicine at the
Medical College of
Georgia in Augusta,
looked at the affects
of testosterone during his talk “Endoge- L. Michael Prisant,
nous and Exogenous MD
Testosterone and Blood Pressure.”
Dr. Prisant reviewed the body of evidence
available from animal and human studies regarding testosterone’s effects on blood pressure.
“Animal studies show that testosterone
increases blood pressure,” he said.
In the animal studies he discussed, Dr.
Prisant demonstrated that there are a number
of mechanisms through which testosterone
affects blood pressure. In humans, however,
the evidence is limited.
Dr. Prisant did review a few studies, including a trial in which patients with low testosterone levels were given the hormone.
“Testosterone does appear to lower blood
pressure if given acutely,” he said. “And chronic
testosterone administration does not appear to
increase blood pressure.”
Other human studies on testosterone do
not directly examine its role in blood pressure but seek to answer questions about the
hormone’s affect on other cardiovascular
concerns such as myocardial ischemia, anginal
threshold, ejection fraction, and exercise capacity, for example.
“There seems to be an inverse relationship between testosterone, ejection fraction,
exercise capacity, etc.,” Dr. Prisant said. “The
lower the testosterone, the higher the blood
pressure.”
Following Dr. Prisant’s presentation, the
session switched focus to estrogen. Noted
researcher Jane F. Reckelhoff, PhD, Professor
of Physiology at the University of Mississippi
Medical Center in Jackson, took to the stage
to present “What the Hypertension Specialist
Should Know about Estrogens and Menopause.”
Dr. Reckelhoff reviewed well-known results from past studies of hormone replacement
in post-menopausal woman, which suggested
that such therapy not only failed to offer protection, but that it increased risk.
The Women’s Health Initiative, for example, showed increased risks for cardiovascular
disease, stroke, pulmonary embolism, and
breast cancer. However, it also showed reduced
risk of colorectal cancer, endometrial cancer,
and hip fracture.
Dr. Reckelhoff said that since these studies, most clinicians have stopped prescribing
hormone replacement therapy except in cases
where symptoms were severe enough to interfere with a woman’s daily life.
However, she said, new findings suggest there’s
more to consider regarding hormone replacement
therapy and cardiovascular protection.
Dr. Reckehoff reviewed animal studies
looking at the effects of estrogen. She said
studies show estrogen downgrades reninangiotensin system activity and offers antiinflammatory and mild antioxidant properties
among other benefits.
Other studies of women following estrogen
loss show increased salt sensitivity, increased
body weight, increased sedentary behaviors,
increased insulin resistance, and increased
prevalence of type 2 diabetes.
“Estradiol should offer protection,” Dr. Reckelhoff said. “So why did we get the results we did?”
One possibility she suggested is that in
studies like the Women’s Health Initiative,
therapy was started too long following the
onset of menopause. Two new studies are looking at hormone replacement therapy in
women who had their
last period less than
three years before
starting therapy.
“Another problem is that you can’t
separate menopause
f rom ag i ng ,” Dr.
Jane F. Reckelhoff, PhD
Reckelhoff said. “If
you give hormone replacement therapy to
young women who have not been long without
estrogen, they do just fine.”
Another possibility, she said, is that scientists are looking at it the wrong way. It’s possible, she said, that women may have a negative
reaction to testosterone — which increases
with age in women.
“A lack of testosterone in men may contribute to cardiovascular disease,” she said. “But in
women, maybe the opposite is true.” l
2009 ASH Elections
Treasurer
Franz H. Messerli, MD
Directors-at-Large, ASH Board of Directors:
John D. Bisognano, MD, PhD
Daniel Levy, MD
Robert A. Phillips, MD, PhD
William B. White, MD
Chair, CME Committee
Robert A. Phillips, MD, PhD
Committee Members, CME Committee
Jerry G. Back, MD
Ali G. Gharavi, MD
Michael A. Moore, MD
James A. Underberg, MD
Allan B. Schwartz, MD
Chair, Membership Committee
Daniel T. Lackland, DrPh
Committee Member, Membership Committee
William J. Elliott, MD, PhD
Committee Members, 2010 Nominating
Committee
F. Wilford Germino, MD
Richard H. Grimm, Jr., MD
Shawna D. Nesbitt, MD
Christopher S. Wilcox, MD, PhD
Committee Members, Public Policy &
Advocacy Committee
Jordan R. Asher, MD
Donald J. DiPette, MD
John M. Flack, MD
Jackson T. Wright, Jr. MD, PhD
Chair, Publications Committee
L. Gabriel Navar, PhD
Committee Member, Publications Committee
Suzanne Oparil, MD
15
Session looks at hypertension management in
special populations
Populations around the world differ dividuals using appropriate therapies,” Dr.
in their risk for hypertension and their Margolis said.
response to anti-hypertension medication.
Few studies have focused on BP control
Saturday morning’s session on Management in Hispanics, and ALLHAT provides an
of Hypertension in Special Populations will excellent source of data. She said the study
bring together physicians with expertise in demonstrates that BP control in Hispanic pamanaging hypertension in Hispanic, South tients is an achievable goal and should thereAsian, East Asian, and African American fore be declared a public health priority.
populations. The session will take place
“The low rate of BP control in Hispanfrom 10:00 to 11:30 a.m. in Yerba
Buena Ballroom — Salons 9.
Karen Margolis, MD, MPH,
Hypertension is as prominent in South
Senior Clinical Investigator with
Asian populations as it is in Caucasians,
HealthPartners Research Foundation, Minneapolis, and Asand it may occur even more frequently in
sociate Professor of Medicine at
South Asians. In addition, the treatment
the University of Minnesota, will
review information about blood
approaches may be different for South
pressure control in Hispanic
Asians because there have not been
participants from the ALLHAT
(A ntihy pertensive and Lipidlarge studies looking at the differential
Lowering Treatment to Prevent
effect of various anti-hypertension drugs
Heart Attack Trial) study, which
had the largest number of Hisin these patients.
panic participants of any hypertension trial.
– Prakash C. Deedwania, MD
“I will discuss trends in national data on BP control in Hispanics and other racial and ethnic
groups as well as the possible reasons why ics in the United States does not appear to
BP control in Hispanic people has lagged be the result of biological factors. BP can be
behind other groups. The ALLHAT results controlled in more than two-thirds of Hissuggest that BP is equally easily controlled panics using inexpensive, commonly availin Hispanics as in non-Hispanic white in- able generic medications. Hispanic patients
ASH launches education initiative
Last month ASH President Henry
R. Black, MD, announced the launch
of a new educational initiative in
hypertension and related cardiovascular
disease — the ASH Hypertension
Accreditation Program — to enhance
the level of education of health
care providers, pharmaceutical sales
representatives, medical journalists,
and other disseminators of healthcare information. While this rigorous
academic program will be tailored to
meet the educational needs of each of
the intended target groups, it is designed
to improve all participants’ understanding
of hypertension and related cardiovascular
disease, improve the flow of information
and create partnerships between healthcare providers who seek to improve
patient outcomes. The ASH Hypertension Accreditation
Program is based on the Society’s
Clinical Hypertension Review Course,
which emphasizes state-of-the-art
scientific principles and evidencebased clinical practice. The content of
the Program focuses on epidemiology,
pathophysiology, treatment, clinical
trials, and includes patient case
presentations — which fully enhances
and expands the ASH educational
mission. Daiichi Sankyo, Inc., which
collaborated with ASH on the training
concept, will be the first pharmaceutical
company to have its sales force enrolled
for the ASH Hypertension Accreditation
Program.
In developing the ASH
Hypertension Accreditation Program,
Dr. Black and Curriculum Committee
members Jan N. Basile, M.D., Joseph
L. Izzo, Jr., M.D., and Committee
Chairman Robert A. Phillips, M.D.,
Ph.D., worked with Thornton Medical
Communications, an independent
medical education company, to adapt
the Clinical Hypertension Review
Course for sales representatives.
The curriculum content focuses on
the science on which hypertension
and cardiovascular disease is based
and will examine mechanisms that
regulate blood flow, pathways to heart
disease and organ involvement, as well
as social and economic disparities that
affect diagnosis, treatment, control,
and compliance.
Beginning in June 2009, ASH
will begin the Accreditation
Program. ASH will train more than
700 Daiichi Sankyo, Inc. sales team
members in the first year of the
program and intends to offer the
program to representatives of other
pharmaceutical companies thereafter.
To achieve accreditation, sales
representatives will be required to
complete approximately 10 hours of
home study before the live course, 13
hours of intense classroom training
during 2.5 days, six hours of homework
during the training program, and pass
a 1.5 hour written exam administered
by ASH.
may need to make additional efforts to make myocardial infarction,” Dr. Deedwania said.
sure they have adequate knowledge about “A very common coexisting condition in
hypertension, access to care and affordable South Asians with hypertension is diabetes.
medications, and good doctor-patient com- Diabetes is up to four times more frequent
munication,” Dr. Margolis said.
in South Asians compared with Caucasians.
Prakash C. Deedwania, MD, Professor of South Asians who have both hypertension
Medicine at the University of California, San and diabetes are at significantly greater risk
Francisco, School of Medicine, and Chief of of myocardial infarction and other complicaCardiology with the VA Central California tions related to MI.”
Health Care System and the UCSF Program
Gordon Fong, MD, PhD, Director of
at Fresno, will examine the treatment of hy- Cardiology Services at the University of
pertension in South Asian populations.
California San Francisco Medical Center,
“Hypertension is as prominent in South will discuss the prevalence of hypertension,
Asian populations as it is in
clinical trials of hypertension,
Caucasians, and it may occur
and specific treatment issues in
even more frequently in South
East Asian populations.
Asians. In addition, the treatMorbidity and mortality rement approaches may be diflated to hypertension are higher
ferent for South Asians because
in East Asian populations than
there have not been large studies
in whites, and early identificalooking at the differential effect
tion and treatment with antiof various anti-hypertension
hypertension medications are
drugs in these patients,” Dr.
particularly important. Since
Deedwania said.
20 04, China has embarked
He said South Asian patients Prakash C. Deedwania, MD on an early vascular disease
have a low tolerance for very
de t e c t ion pro g r a m t o t r y
high doses of calcium channel blockers, to pre vent c a rd iov a sc u l a r e vent s i n
therefore clinicians need to modify the doses hypertensive patients.
in these individuals.
Finally, Shawna D. Nesbitt, MD, MS, As“I will talk about the increasing prob- sociate Professor of Internal Medicine at the
lem of hypertension associated with other University of Texas Southwestern Medical
cardiovascular risk factors that many South Center at Dallas, will talk about the manageAsians have, which puts them at significantly ment of hypertension in African American
higher risk of coronary artery disease and populations. l
ASH Specialist Program Inc., Board
of Directors establish Association
of Hypertension Specialists
These are perilous times, particularly
in the arena of health care. Although
hypertension remains the most important
cardiovascular problem facing the U.S.
population, those who are most expert in
dealing with this problem — designated
specialists in clinical hypertension — have
no place at the negotiating table.
To meet this challenge, the Board of
Directors of the ASH Specialists Program
Inc., in collaboration with the ASH Board
of Directors established the Association of
Hypertension Specialists (AHS) as a Special
Interest Group within ASH.
The AHS will serve as an advocacy
group dedicated to promoting increased
recognition for expertise in the diagnosis
and treatment of hypertension and
providing increased resources for the
care of patients with hypertension. The
inaugural session of the Association of
Hypertension Specialists took place on
Wednesday, May 06, at the ASH Annual
Scientific Meeting.
The initial goals of the Association of
Hypertension Specialists:
To obtain a medical specialty code
description from AMA and CMS to identify
a hypertension specialist.
In collaboration with ASH, negotiate
with CMS to recognize a higher level of
service, and thus reimbursement, when a
hypertension specialist sees patients with
hypertension.
To advocate for legislation to provide
increased support for patients with
hypertension, e.g. home blood pressure
recorders.
To establish a CPT code for
cardiovascular risk assessments that
hypertension specialists could perform.
To establish at the national and
local level credentialing criteria for
technology related to hypertension —
e.g. ambulatory blood pressure recording
and interpretation, measures of vascular
compliance, and estimation of central
blood pressure.
To meet with members of the
medical insurance industry to negotiate
and promote recognition and increased
reimbursement for hypertension specialists.
To host forums during the annual
meeting of the American Society of
Hypertension, and at other meetings, to
learn of ways to improve the practice of
the hypertension specialists, including the
incorporation of new technology.
To devise brief presentations for use
by national and local speakers when
presenting to policy makers — i.e.
government, insurance industry, hospital
staffs, etc.
Since no group has taken up the role of
acting as an advocate for the hypertension
specialists that deal with this major U.S.
health care issue, the AHS will fill this
vacuum.
16
Therapy Session
Headaches can have multiple causes in hypertensive
patients, speaker says
Headaches are a common, almost
Preeclampsia and eclampsia both occur
universal complaint from patients, yet in the period around delivery — either bepeople with headaches do not always get the fore, during, or up to six weeks after delivery.
treatment they need. During the session on Eclampsia is preeclampsia with seizures.
Resistant Hypertension
Both have symptoms of
Friday morning from
headaches, elevated blood
10:00 to 11:30 a.m. in Yepressure, brisk musclerba Buena Ballroom —
stretch reflexes, and proSalon 8, Dara G.
teinuria, she said.
Jamieson, MD, Associ“PR ES is a neuroate Professor of Clinical
logic disorder that inNeurology at Weill Corcludes elevated blood
nell Medical College in
pressure and characterNew York, will explain
istic changes on MR I
“What the Hypertension
in the posterior par t
Specialist Should Know
of the brain as well as
About Headaches.”
headaches. Clinicians
“ I t ’s a m y t h t o
need to treat the pathink that headaches in
tient’s hypertension first
hy pertensive patients
and then the other signs
are caused only by high
of the neurologic synblood pressure. Elevated Dara G. Jamieson, MD
drome will improve. In
blood pressure is rarely
addition to headaches,
the cause of their headaches. Most patients patients usually present with confusion, vihave either tension-type headaches or mi- sual changes, and seizures. One of the major
graines,” Dr. Jamieson said. “However, some causes, but not the only cause of PRES is
specific types of headaches can be related unexpectedly elevated blood pressure,” Dr.
to acutely elevated blood pressure. These Jamieson said. “People with PRES are quite
hypertension-related headaches are most sick and need to be hospitalized. If left unoften seen in the setting of preeclampsia and treated, PRES can be life threatening. Their
eclampsia with pregnancy and posterior re- blood pressure needs to be brought down as
versible encephalopathy syndrome (PRES), quickly and effectively as possible.”
which may be associated with acute blood
She said tension-type headaches are
pressure elevation among other causes.”
the most common types of headaches, and
migraines are the most common types of also need to avoid triggers in their diets, such
headaches that bring individuals to a doc- as cheap red wine, processed meats, or smelly
tor’s attention. People with tension-type cheeses,” she said.
headaches generally take over-the-counter
Migraine pain is generally unresponsive
medications and don’t seek a doctor’s help, to over-the-counter medications, such as
Dr. Jamieson said.
aspirin, acetaminophen, or ibuprofen.
“People with migraine headaches have
“Most patients with migraines comrelatively severe pain that is sharp or stab- monly require triptan medications, such
bing or throbas sumatriptan.
bi ng. Feel i ng
Many patients
pressure is more People with migraine headaches have who have frecom mon w ith relatively severe pain that is sharp or stab- quent disabling
tension-t y pe
migraine headheadaches. Pain bing or throbbing. Feeling pressure is more aches need to
with nausea or common with tension-type headaches. be given a presen sit iv it y to
ventive medicamovement or Pain with nausea or sensitivity to move- tion to decrease
light or sound ment or light or sound or smell is more the frequenc y
or smell is more
a nd sever it y
com mon w ith common with migraine headaches.
of these headmigraine headaches. Patients
– Dara G. Jamieson, MD w ith f requent
aches,” she
said.
migraines and
About 30
hy pe r ten s ion
million Americans have chronic, disabling might require a preventative medication
migraines. These headaches are poorly that also lowers blood pressure, such as a
recognized, and only about half of these calcium channel blocker or propranolol,”
individuals are diagnosed and treated for Dr. Jamieson said. “Hypertension specialmigraine.
ists should know that they should not give
“In general, the treatment for migraines triptans to patients with chronic, untreated
is lifestyle adjustment in terms of daily ex- hypertension. They need to manage the
ercise, getting enough sleep, not skipping patient’s blood pressure first before giving
meals, avoiding dehydration, and trying to the patient a triptan for acute treatment
avoid stress. People with chronic migraines of migraine.” l
Pathobiology Session
Expert to explore the role of uric acid in hypertension, renal disease
H y pe rur ic e m i a h a s l ong be e n
considered a biologically inert marker of
hypertension, renal disease, and cardiovascular events, but new research is emerging
to suggest that elevated uric acid levels may
play a role in the pathogenetics of these
conditions.
During Friday morning’s Pathobiology
Session on Genetic Insight into Hypertension, which takes place from 10:00 to 11:30
a.m. in Yerba Buena Ballroom — Salon
7, Takahiko Nakagawa, MD, will address
“What the Hypertension Specialist Should
Know About Uric Acid” and describe his
and other investigators’ findings about the
potential pathologic role of hyperuricemia.
Dr. Nakagawa is Associate Professor of
Medicine in the Division of Renal Disease
and Hypertension at the University of Colorado — Denver.
“Our animal data and recent epidemiologic studies suggest that uric acid has
a pathologic role in hypertension, renal
disease, and the metabolic syndrome. Since
hyperuricemia is often observed in patients,
it might be important for hypertension specialists to know these experimental and clinical data,” Dr. Nakagawa said. “My colleagues
and I have done a number of studies with animal models to demonstrate the causal role of
uric acid in the development of hypertension,
renal disease, and the metabolic syndrome.
We and others have also performed clinical
studies and demonstrated that lowering uric
acid with allopurinol prevented the development of hypertension and renal disease.”
may be caused by its ability to inhibit endothelial function. In animals given a highfructose diet, allopurinol was able to lower
serum uric acid levels and prevent or reverse
My message is that hyperuricemia might have a causal
role in the development of hypertension, renal disease,
and metabolic syndrome. While our studies are not
yet meant for the clinic, it is important for clinicians to
know about studies related to the pathogenesis of disease states. I will provide evidence that uric acid may
have a role in hypertension. In the future, uric acid could
become a novel target for treatment.
– Takahiko Nakagawa, MD
In his research, Dr. Nakagawa has suggested a causal role for uric acid in fructoseinduced metabolic syndrome, noting that
the worldwide epidemic of the metabolic
syndrome, including hypertension, correlates with elevations in serum uric acid
levels as well as a marked increase in total
fructose intake in the form of table sugar and
high-fructose corn syrup.
His animal data provide evidence that
uric acid’s role in the metabolic syndrome
features of the metabolic syndrome.
Studies of experimental models of hyperuricemia have found that elevated uric
acid levels result in the development of
hypertension, Dr. Nakagawa said. Hyperuricemia in animals reduces nitric oxide
levels and activates the renin-angiotensin
system, which leads to uric acid-mediated
renal microvascular disease.
“Studies of new-onset essential hypertension in adolescents have reported an eleva-
tion of uric acid in 90 percent of hypertensive
subjects vs. zero percent of controls, and the
relationship of uric acid with hypertension
was linear and dramatic. In preliminary
studies, the lowering of uric acid resulted
in the normalization of blood pressure in
four of five hy pertensive adolescents,”
he said.
Dr. Nakagawa’s experimental animal
studies have also suggested that uric acid
may be a mediator of renal disease and its
progression. Hyperuricemia accelerates
renal disease progression in animal models
through a mechanism linked to high blood
pressure and COX-2-mediated, thromboxane-induced vascular disease, he said.
“My message is that hy peruricemia
might have a causal role in the development of hypertension, renal disease, and
metabolic syndrome. While our studies are
not yet meant for the clinic, it is important
for clinicians to know about studies related
to the pathogenesis of disease states. I will
provide evidence that uric acid may have a
role in hypertension. In the future, uric acid
could become a novel target for treatment,”
Dr. Nakagawa said. “It is evident that more
studies on the role of uric acid in cardiovascular and renal disease are required. In
particular, studies identifying the conditions
under which uric acid may be beneficial vs.
deleterious are critical.” l
e
or
m h
n ot
ar bo
Le at
5A
20
Powerful efficacy in the overall population
In the COACH pivotal trial
AZOR 10/40 mg consistently provided significant reductions in mean SBP vs baseline
across many patient types1
Elderly patients have decreased clearance of
amlodipine with a resulting increase of AUC of
approximately 40% to 60%, and a lower initial
dose may be required
Mean changes in SBP at Week 8 with AZOR 10/40 mg1
0
Stage 1
hypertension
(n=33)
Stage 2
hypertension
(n=128)
Severe
hypertension
(n=28)
With diabetes
(n=24)
r65 yrs
(n=33)
African American
(n=34)
Obese
(n=100)
30
–10
mm Hg
–20
mm Hg
–20
–30
–30
–33
–40
–50
–29
–34
mean SBP reduction
in the overall
population*2
–30
–41
A randomized, multicenter, double-blind, placebo-controlled factorial
study (N=1940). Patients were randomized for 8 weeks of double-blind
treatment. Mean baseline BP was 167/102 mm Hg for placebo in the
overall population and 166/102 mm Hg for AZOR 10/40 mg in the
overall population. Mean baseline SBP for AZOR 10/40 mg was
147 mm Hg in patients with Stage 1 hypertension (defined as:
SBP 140–159 mm Hg or DBP 90–99 mm Hg), 171 mm Hg in
patients with Stage 2 hypertension (defined as: SBP ≥160 mm Hg
or DBP ≥100 mm Hg), 192 mm Hg in patients with severe hypertension
(defined as: SBP ≥180 mm Hg), 171 mm Hg in patients with diabetes,
180 mm Hg in patients ≥65 years old, 168 mm Hg in African American
patients, and 166 mm Hg in obese patients (BMI ≥30 kg/m2). Mean
baseline SBP for placebo was 149 mm Hg in patients with Stage 1
hypertension, 170 mm Hg in patients with Stage 2 hypertension,
191 mm Hg in patients with severe hypertension, 176 mm Hg in
patients with diabetes, 179 mm Hg in patients ≥65 years old,
168 mm Hg in African American patients, and 166 mm Hg in obese
patients. Severe hypertension results presented are derived from
a post hoc subanalysis of the pivotal trial. All other subgroup
analyses were prespecified.1,2
P<0.0001 vs baseline.
*Mean SBP reduction with AZOR 10/40 mg (placebo: 5 mm Hg).
Mean BP baseline was 164/102 mm Hg in the overall population.2
Mean reductions in SBP with placebo were 2 mm Hg in patients with Stage 1 hypertension, 5 mm Hg in patients with Stage 2 hypertension, and 15 mm Hg in
patients with severe hypertension. Mean reductions in SBP with placebo were 15 mm Hg in patients with diabetes, 8 mm Hg in elderly patients, 4 mm Hg in
African American patients, and 5 mm Hg in obese patients.1
Decrease pill burden with one convenient tablet, once a day, and just one co-pay3,4
AZOR is available in 4 combinations of amlodipine and olmesartan medoxomil
Amlodipine 5 mg
AZOR 5/20 mg
AZOR 5/40 mg
Amlodipine 10 mg
AZOR 10/20 mg
AZOR 10/40 mg
Actual size of tablets.
Depiction of
BP reduction
based on overall
population results with
AZOR 10/40 mg in the
COACH pivotal trial
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.
Please see following pages for important safety information and brief summary of prescribing information for AZOR.
References: 1. Data on file. Daiichi Sankyo, Inc. 2. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind,
placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30:587-604. 3. Taylor AA. Combination drug treatment of hypertension: have we come full circle? Curr Cardiol Rep. 2004;6:421-426. 4. Dezii CM. A retrospective study
of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000;9(suppl 9):2-6.
www.AZOR.com
©2009 Daiichi Sankyo, Inc.
DSAZ09000398
Important safety information and study description
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.
Brief Summary – See package insert for full prescribing information.
AZOR™
(amlodipine and olmesartan medoxomil) tablets
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, drugs that act directly on the reninangiotensin 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 (5.1)].
1 INDICATIONS AND USAGE
AZOR™ is indicated for the treatment of hypertension, alone or with other antihypertensive agents. This fixed
combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION
in the full prescribing information).
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
The adverse reactions of AZOR™ are generally related to those of each of its components.
5.1 Fetal/Neonatal Morbidity and Mortality
Olmesartan medoxomil. Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal
morbidity and death when administered to pregnant women. There have been several dozen cases reported in
the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is
detected, AZOR™ should be discontinued as soon as possible. During the second and third trimesters of pregnancy, these drugs have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably
resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb
contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth
retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine
drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an
angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients
become pregnant, physicians should have the patient discontinue the use of AZOR™ as soon as possible. Rarely
(probably less often than once in every thousand pregnancies), no alternative to a drug acting on the reninangiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards
to their fetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, AZOR™ should be discontinued unless it is considered life-saving for the
mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydram nios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure
to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia.
If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange
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.
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% of patients treated with AZOR and more frequently than placebo
was edema. The placebo-subtracted incidence was 5.7% (5/20 mg),
6.2% (5/40 mg), 13.3% (10/20 mg), and 11.2% (10/40 mg). The
edema incidence for placebo was 12.3%.
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.
AZOR COACH pivotal trial—study description
A randomized, multicenter, double-blind, placebo-controlled factorial
study (N=1940) to evaluate the efficacy and safety of AZOR across
a range of doses and compared with monotherapy components.
Patients were randomized to one of 12 treatment arms for 8 weeks
of double-blind treatment with placebo, amlodipine monotherapy
(5 or 10 mg/day), olmesartan medoxomil monotherapy (10, 20, or
40 mg/day), or amlodipine/olmesartan medoxomil combination
therapy (all possible combinations). Patients were not titrated to
different doses.
Primary endpoint: mean change from baseline in trough SeDBP at
Week 8, using the last observation carried forward (LOCF) for patients
who did not complete the protocol. Secondary endpoint was a mean
change from baseline in trough SeSBP at Week 8 (LOCF).
Mean baseline seated BP was 162–167/101–102 mm Hg.
transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered
renal function. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant
rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a
mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher
doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses r1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal
hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the
renal pelvis were observed at doses r8 mg/kg/day. The no observed effect dose for developmental toxicity in
rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
5.2 Hypotension in Volume- or Salt-Depleted Patients
Olmesartan medoxomil. Symptomatic hypotension may occur after initiation of treatment with olmesartan
medoxomil. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients
(e.g., those being treated with high doses of diuretics) may be particularly vulnerable. Treatment with AZOR™
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.
5.3 Vasodilation
Amlodipine. 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.
5.4 Patients with 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. The mechanism of this effect has not been elucidated.
5.5 Patients with Congestive Heart Failure
Amlodipine. In general, calcium channel blockers should be used with caution in patients with heart failure.
Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III
or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with
a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by
life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure).
Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based
on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.
5.6 Patients with Impaired Renal Function
Olmesartan medoxomil. Changes in renal function may be anticipated in susceptible individuals treated with
olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose
renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe
congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or
death. Similar effects may occur in patients treated with AZOR™ due to the olmesartan medoxomil component [See
Clinical Pharmacology (12.3) in the full prescribing information]. 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.
5.7 Patients with Hepatic Impairment
Amlodipine. 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.
5.8 Laboratory Tests
AZOR™. There was a greater decrease in hemoglobin and hematocrit in the combination product compared to
either component. Other laboratory changes can usually be attributed to either monotherapy component.
Amlodipine. In post-marketing experience, hepatic enzyme elevations have been reported (6.2). Olmesartan
medoxomil. In post-marketing experience, increased blood creatinine levels and hyperkalemia have been
reported.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not
reflect the rates observed in practice. AZOR™. The data described below reflect exposure to AZOR™ in more
than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for
1 year. AZOR™ was studied in one placebo-controlled factorial trial (see Section 14.1 in the full prescribing information). The population had a mean age of 54 years and included approximately 55% males. Seventy-one
percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once
daily. The overall incidence of adverse reactions on therapy with AZOR™ was similar to that seen with corresponding doses of the individual components of AZOR™, and to placebo. The reported adverse reactions were
generally mild and seldom led to discontinuation of treatment (2.6% for AZOR™ and 6.8% for placebo).
Edema. Edema is a known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil. The
placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest
with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan
medoxomil was added to the 10 mg amlodipine dose.
Placebo-Subtracted Incidence of Edema during the Double-Blind Treatment Period
Amlodipine
Placebo
0%*
0.7%
24.5%
Placebo
5 mg
10 mg
Olmesartan Medoxomil
20 mg
(-2.4%)
5.7%
13.3%
40 mg
6.2%
6.2%
11.2%
*12.3%=actual placebo incidence
Across all treatment groups, the frequency of edema was generally higher in women than men, as has been
observed in previous studies of amlodipine. Adverse reactions seen at lower rates during the double-blind period
also occurred in the patients treated with AZOR™ at about the same or greater incidence as in patients receiving
placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and
nocturia. The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine
plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled
period.
Amlodipine. Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical
trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients
and about 1% of placebo-treated patients. The most common side effects were headache and edema. The incidence (%) of dose-related side effects was as follows:
Adverse Event
Edema
Dizziness
Flushing
Palpitation
Placebo
N=520
0.6
1.5
0.0
0.6
2.5 mg
N=275
1.8
1.1
0.7
0.7
5.0 mg
N=296
3.0
3.4
1.4
1.4
10.0 mg
N=268
10.8
3.4
2.6
4.5
For several adverse experiences that appear to be drug- and dose-related, there was a greater incidence in
women than men associated with amlodipine treatment as shown in the following table:
Adverse Event
Edema
Flushing
Palpitation
Somnolence
Placebo
Male=%
(N=914)
1.4
0.3
0.9
0.8
Amlodipine
Female=%
(N=336)
5.1
0.9
0.9
0.3
Male=%
(N=1218)
5.6
1.5
1.4
1.3
Female=%
(N=512)
14.6
4.5
3.3
1.6
Olmesartan medoxomil. Olmesartan medoxomil has been evaluated for safety in more than 3825
patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience
included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with
olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo.
Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil. The overall frequency of adverse events was not dose-related. Analysis of gender, age, and race groups demonstrated no
differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse
events in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan
medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse event that
occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence in olmesartan
medoxomil treated patients vs. placebo was dizziness (3% vs 1%).
6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of the individual components of
AZOR™. Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is
uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported
in association with use of amlodipine.
Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:
Body as a Whole: asthenia, angioedema. Gastrointestinal: vomiting. Musculoskeletal: rhabdomyolysis. Urogenital System: acute renal failure. Skin and Appendages: alopecia, pruritus, urticaria.
7 DRUG INTERACTIONS
7.1 Drug Interactions with AZOR™
The pharmacokinetics of amlodipine and olmesartan medoxomil are not altered when the drugs are co-administered.
No drug interaction studies have been conducted with AZOR™ and other drugs, although studies have been conducted with the individual amlodipine and olmesartan medoxomil components of AZOR™, as described below,
and no significant drug interactions have been observed.
7.2 Drug Interactions with Amlodipine
In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin,
warfarin, and indomethacin.
Effect of Other Agents on Amlodipine
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg
in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. Maalox® (antacid):
Co-administration of the antacid Maalox® with a single dose of amlodipine had no significant effect on the
pharmacokinetics of amlodipine. Sildenafil: A single 100 mg dose of sildenafil in subjects with essential
hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil
were used in combination, each agent independently exerted its own blood pressure lowering effect.
Effect of Amlodipine on Other Agents
Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted
in no significant change in the steady state pharmacokinetic parameters of atorvastatin. Digoxin:
Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance
in normal volunteers.
Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol. Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin
prothrombin response time.
AZOR™ (amlodipine and olmesartan medoxomil) tablets
In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensinconverting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal antiinflammatory drugs, antibiotics, and oral hypoglycemic drugs.
7.3 Drug Interactions with Olmesartan Medoxomil
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered
with digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan medoxomil was not significantly
altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan medoxomil is not metabolized by
the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit,
induce, or are metabolized by those enzymes are not expected.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Olmesartan medoxomil. Pregnancy Categories C (first trimester) and D (second and third trimesters). [See
Warnings and Precautions (5.1)]
Amlodipine. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about
10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their
respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg). However, litter size
was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased
(about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days
before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the
gestational period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether the amlodipine or olmesartan medoxomil components of AZOR™ are excreted in human
milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for
adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue
the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of AZOR™ in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of subjects in the double-blind clinical study of AZOR™, 20% (384/1940) were 65 years of
age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were
observed between subjects 65 years of age or older and younger subjects.
8.6 Hepatic Impairment
There are no studies of AZOR™ in patients with hepatic insufficiency, but both amlodipine and olmesartan
medoxomil show moderate increases in exposure in patients with hepatic impairment. Use caution when administering AZOR™ to patients with severe hepatic impairment.
8.7 Renal Impairment
There are no studies of AZOR™ in patients with renal impairment.
8.8 Black Patients
Of the total number of subjects in the double-blind clinical study of AZOR™, 25% (481/1940) were black patients.
AZOR™ was effective in treating black patients (usually a low-renin population), and the magnitude of blood
pressure reduction in black patients approached that observed for non-black patients.
10 OVERDOSAGE
There is no information on overdosage with AZOR™ in humans.
17 PATIENT COUNSELING INFORMATION
Physicians should instruct female patients of childbearing age about the consequences of second and third
trimester exposure to drugs that act on the renin-angiotensin system and they should be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first
trimester. These patients should be informed to report pregnancies to their physicians as soon as possible. [See
Warnings and Precautions (5.1)].
Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054
Manufactured by Daiichi Sankyo Europe GmbH, Germany
Copyright © Daiichi Sankyo, Inc. 2007. All rights reserved.
P1801701-B
5A
20
Power plus
tolerability
e
or
m h
n ot
ar bo
Le at
Cut hypertension with AZOR
AZOR provides powerful efficacy plus proven tolerability
in the overall population of the COACH pivotal trial2
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.
AZOR is indicated for the treatment of hypertension, alone or with other
antihypertensive agents.
AZOR is not indicated for the initial therapy of hypertension.
Please see preceding pages for important safety information
and brief summary of prescribing information for AZOR.
Depiction of
BP reduction
based on overall
population results with
AZOR 10/40 mg in the
COACH pivotal trial
(placebo: 5 mm Hg)

ASH Times - American Society of Hypertension

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