Hypertension is another name for high blood pressure.

It can lead to severe complications and

increases the risk of heart disease, stroke, and death.

Blood pressure is the force exerted by the blood against the walls of the blood vessels. The
pressure depends on the work being done by the heart and the resistance of the blood vessels.

Medical guidelines define hypertension as a blood pressure higher than 130 over 80 millimeters
of mercury (mmHg), according to guidelines issued by the American Heart Association (AHA)
in November 2017.

Around 85 million people in the United States have high blood pressure.

Hypertension and heart disease are global health concerns. The World Health Organization
(WHO) suggests that the growth of the processed food industry has impacted the amount of salt
in diets worldwide, and that this plays a role in hypertension.

Fast facts on hypertension:

Here are some key points about hypertension. More detail is in the main article.

 Normal blood pressure is 120 over 80 mm of mercury (mmHg), but hypertension is

higher than 130 over 80 mmHg.
 Acute causes of high blood pressure include stress, but it can happen on its own, or it can
result from an underlying condition, such as kidney disease.
 Unmanaged hypertension can lead to a heart attack, stroke, and other problems.
 Lifestyle factors are the best way to address high blood pressure.

Treatment

Regular health checks are the best way to monitor your blood pressure.

While blood pressure is best regulated through the diet before it reaches the stage of
hypertension, there is a range of treatment options.

Lifestyle adjustments are the standard first-line treatment for hypertension.

Regular physical exercise

Doctors recommend that patients with hypertension engage in 30 minutes of moderate-intensity,

dynamic, aerobic exercise. This can include walking, jogging, cycling, or swimming on 5 to 7
days of the week.

Stress reduction
Avoiding stress, or developing strategies for managing unavoidable stress, can help with blood
pressure control.

Using alcohol, drugs, smoking, and unhealthy eating to cope with stress will add to hypertensive
problems. These should be avoided.

Smoking can raise blood pressure. Giving up smoking reduces the risk of hypertension, heart
conditions, and other health issues.

Medications

People with blood pressure higher than 130 over 80 may use medication to treat hypertension.

Drugs are usually started one at a time at a low dose. Side effects associated with
antihypertensive drugs are usually minor.

Eventually, a combination of at least two antihypertensive drugs is usually required.

A range of drug types are available to help lower blood pressure, including:

 diuretics, including thiazides, chlorthalidone, and indapamide

 beta-blockers and alpha-blockers
 calcium-channel blockers
 central agonists
 peripheral adrenergic inhibitor
 vasodilators
 angiotensin-converting enzyme (ACE) inhibitors
 angiotensin receptor blockers

The choice of drug depends on the individual and any other conditions they may have.

Anyone taking antihypertensive medications should be sure to carefully read labels, especially
before taking any over-the-counter (OTC) medications, such as decongestants.

These may interact with medications used to lower blood pressure.

Causes
The cause of hypertension is often not known.

Around 1 in every 20 cases of hypertension is the effect of an underlying condition or

medication.

Chronic kidney disease (CKD) is a common cause of high blood pressure because the kidneys do
not filter out fluid. This fluid excess leads to hypertension.
Risk factors

A number of risk factors increase the chances of having hypertension.

 Age: Hypertension is more common in people aged over 60 years. With age, blood
pressure can increase steadily as the arteries become stiffer and narrower due to plaque
build-up.
 Ethnicity: Some ethnic groups are more prone to hypertension.
 Size and weight: Being overweight or obese is a key risk factor.
 Alcohol and tobacco use: Consuming large amounts of alcohol regularly can increase a
person's blood pressure, as can smoking tobacco.
 Sex: The lifetime risk is the same for males and females, but men are more prone to
hypertension at a younger age. The prevalence tends to be higher in older women.
 Existing health conditions: Cardiovascular disease, diabetes, chronic kidney disease,
and high cholesterol levels can lead to hypertension, especially as people get older.

Other contributing factors include:

 physical inactivity
 a salt-rich diet associated with processed and fatty foods
 low potassium in the diet
 alcohol and tobacco use
 certain diseases and medications

A family history of high blood pressure and poorly managed stress can also contribute.

Below is a 3-D model of hypertension, which is fully interactive.

Explore the model using your mouse pad or touchscreen to understand more about hypertension.

Signs
Blood pressure can be measured by a sphygmomanometer, or blood pressure monitor.

Having high blood pressure for a short time can be a normal response to many situations. Acute
stress and intense exercise, for example, can briefly elevate blood pressure in a healthy person.

For this reason, a diagnosis of hypertension normally requires several readings that show high
blood pressure over time.

The systolic reading of 130 mmHg refers to the pressure as the heart pumps blood around the
body. The diastolic reading of 80 mmHg refers to the pressure as the heart relaxes and refills
with blood.

The AHA 2017 guidelines define the following ranges of blood pressure:
 Systolic (mmHg) Diastolic (mmHg)
Normal blood pressure Less than 120 Less than 80
Elevated Between 120 and 129 Less than 80
Stage 1 hypertension Between 130 and 139 Between 80 and 89
Stage 2 hypertension At least 140 At least 90
Hypertensive crisis Over 180 Over 120

If the reading shows a hypertensive crisis when taking blood pressure, wait 2 or 3 minutes and
then repeat the test.

If the reading is the same or higher, this is a medical emergency.

The person should seek immediate attention at the nearest hospital.

Symptoms
A person with hypertension may not notice any symptoms, and it is often called the "silent
killer." While undetected, it can cause damage to the cardiovascular system and internal organs,
such as the kidneys.

Regularly checking your blood pressure is vital, as there will usually be no symptoms to
make you aware of the condition.

It is maintained that high blood pressure causes sweating, anxiety, sleeping problems, and
blushing. However, in most cases, there will be no symptoms at all.

If blood pressure reaches the level of a hypertensive crisis, a person may experience headaches
and nosebleeds.

Complications

Long-term hypertension can cause complications through atherosclerosis, where the formation of
plaque results in the narrowing of blood vessels. This makes hypertension worse, as the heart
must pump harder to deliver blood to the body.

High blood pressure raises the risk of a number of health problems, including a heart
attack.

Hypertension-related atherosclerosis can lead to:

 heart failure and heart attacks

 an aneurysm, or an abnormal bulge in the wall of an artery that can burst, causing severe
bleeding and, in some cases, death
 kidney failure
  stroke
 amputation
 hypertensive retinopathies in the eye, which can lead to blindness

Regular blood pressure testing can help people avoid the more severe complications.

Diet
Some types of hypertension can be managed through lifestyle and dietary choices, such as
engaging in physical activity, reducing alcohol and tobacco use, and avoiding a high-sodium
diet.

Reducing the amount of salt

Average salt intake is between 9 grams (g) and 12 g per day in most countries around the world.

The WHO recommends reducing intake to under 5 g a day, to help decrease the risk of
hypertension and related health problems.

This can benefit people both with and without hypertension, but those with high blood pressure
will benefit the most.

Moderating alcohol consumption

Moderate to excessive alcohol consumption is linked to raised blood pressure and an increased
risk of stroke.

The American Heart Association (AHA) recommend a maximum of two drinks a day for men,
and one for women.

The following would count as one drink:

 12 ounce (oz.) bottle of beer

 4 oz. of wine
 1.5 oz. of 80-proof spirits
 1 oz. of 100-proof spirits

A healthcare provider can help people who find it difficult to cut back.

Eating more fruit and vegetables and less fat

People who have or who are at risk of high blood pressure are advised to eat as little saturated
and total fat as possible.

Recommended instead are:

  whole-grain, high-fiber foods
 a variety of fruit and vegetables
 beans, pulses, and nuts
 omega-3-rich fish twice a week
 non-tropical vegetable oils, for example, olive oil
 skinless poultry and fish
 low-fat dairy products

It is important to avoid trans-fats, hydrogenated vegetable oils, and animal fats, and to eat
portions of moderate size.

Managing body weight

Hypertension is closely related to excess body weight, and weight reduction is normally followed
by a fall in blood pressure. A healthy, balanced diet with a calorie intake that matches the
individual's size, sex, and activity level will help.

The DASH diet

The U.S. National Heart Lung and Blood Institute (NHLBI) recommends the DASH diet for
people with high blood pressure. DASH, or "Dietary Approaches to Stop Hypertension," has
been specially designed to help people lower their blood pressure.

It is a flexible and balanced eating plan based on research studies sponsored by the Institute,
which says that the diet:

 lowers high blood pressure

 improves levels of fats in the bloodstream
 reduces the risk of developing cardiovascular disease

There is a cookbook written by the NHLBI called Keep the Beat Recipes with cooking ideas to
help achieve these results.

Some evidence suggests that using probiotic supplements for 8 weeks or more may benefit
people with hypertension.

Types
High blood pressure that is not caused by another condition or disease is called primary or
essential hypertension. If it occurs as a result of another condition, it is called secondary
hypertension.

Primary hypertension can result from multiple factors, including blood plasma volume and
activity of the hormones that regulate of blood volume and pressure. It is also influenced by
environmental factors, such as stress and lack of exercise.
Secondary hypertension has specific causes and is a complication of another problem.

It can result from:

 diabetes, due to both kidney problems and nerve damage

 kidney disease
 pheochromocytoma, a rare cancer of an adrenal gland
 Cushing syndrome, which can be caused by corticosteroid drugs
 congenital adrenal hyperplasia, a disorder of the cortisol-secreting adrenal glands
 hyperthyroidism, or an overactive thyroid gland
 hyperparathyroidism, which affects calcium and phosphorous levels
 pregnancy
 sleep apnea
 obesity
 CKD

https://www.medicalnewstoday.com/articles/150109.php

Does hypertension have symptoms?

Although sometimes hypertension causes nosebleeds, headaches, shortness of breath, or
dizziness, these types of symptoms are nonspecific, and generally only occur if your blood
pressure has increased to a dangerous or life threatening level. In fact:

 most people with hypertension don’t have any signs or symptoms, even when their blood
pressure is extremely high.

What are the risk factors for hypertension?

Although for most people there is no identifiable cause of hypertension, there are known risk
factors that increase the likelihood that you will become hypertensive. Several of these are things
that you can’t do anything about, including:

 Genetics - having family members with hypertension increases the likelihood that you
will too.
 Race - high blood pressure is more common in people with dark skin than in people with
pale skin.1^11start superscript, 1, end superscript
 Age - your blood vessels become more rigid as you age, preventing them from opening as
effectively as when you were younger, which increases peripheral resistance.

Other risk factors are known as modifiable risk factors, because many people can reduce their
blood pressure by changing their diet and lifestyle. The most common risk factors include being
overweight and inactive, eating a high salt diet, and smoking.
Image of modifiable risk factors (obesity, excessive alcohol consumption, smoking, certain
medications, and vitamin D deficiency)

How likely are you to become hypertensive?

If you have high blood pressure, you are certainly not alone. More than one in three adults
worldwide have high blood pressure, and it is credited with contributing to half of all deaths due
to heart disease and stroke.1^11start superscript, 1, end superscript High blood pressure is more
common in men during middle-age, around 45 years, with women catching up after age 65.
Worryingly, children can also become hypertensive for many of the same reasons as adults -
inactivity, unhealthy diet, and obesity. Although it is common in both economically developed
and developing countries and regions, many people in developing countries go undiagnosed, and
miss out on treatment that could significantly reduce cardiovascular problems.

graph showing prevalence of high blood pressure in adults aged 20 and older

Steps you can take to lower your blood pressure

Lifestyle changes can really help to lower your blood pressure. For example, you can work on
eating a healthy diet with lots of fruits and vegetables to take care of any nutritional deficiencies,
and to eat less salt. This, together with reducing high fat, and calorie laden foods can help you
reach and maintain a healthy weight. Another way to lower your blood pressure is to increase the
amount of exercise you do. Routinely exercising not only helps to lower your blood pressure, but
may give you more energy, and is a great way to reduce stress. Finally, reducing or better still
quitting smoking, and limiting your daily amounts of alcohol (2 drinks for men, 1 drink for
women), are also great ways to get your blood pressure heading into the healthy range.
As an adult, it is a good idea to ask your doctor to check your blood pressure one or two times a
year if you think you may be at increased risk for any of the reasons described above. That way,
you will know early on in the course of the disease, and be able to take steps to minimize your
risk for other illnesses.

How do you diagnose and treat hypertension?

Diagnosing hypertension: Blood pressure is usually measured using a pressure cuff or an
electronic device placed on your upper arm. A blood pressure reading is written as two numbers,
representing the maximum pressure in the circulatory system when the heart pumps blood out
(systolic pressure), and the minimum pressure when the heart refills (diastolic pressure). Blood
pressure is measured in millimeters of mercury (mm Hg). Normal resting blood pressure in an
adult is approximately 120 / 80 mm Hg. However, your blood pressure can fluctuate from minute
to minute, and readings are generally higher in the afternoon and lower at night.
Doctors often classify blood pressure into four categories:

 Normal blood pressure - below 120 / 80 mm Hg.

 Prehypertension - 120-139 / 80-89 mm Hg.
  Stage 1 hypertension - 140-159 / 90-99 mm Hg.
 Stage 2 hypertension - 160 / 100 mm Hg or higher.

Both numbers in a blood pressure reading are important, and an increase in either number
(systolic or diastolic pressure) indicates you are hypertensive. It is worth noting that a blood
pressure below 90 / 60 mm Hg is considered outside the normal range, and is known as
hypotension, or low blood pressure.

Treating hypertension
Treatment typically involves lifestyle changes and medications when necessary. If you are
prehypertensive, but otherwise healthy, your doctor is most likely going to encourage lifestyle
changes, such as eating a healthier diet, quitting smoking, getting more exercise, and managing
stress, as a first step to lowering your blood pressure. However, if this doesn’t work, or you are
already hypertensive, you may need medications.
If you are healthy, blood pressure medications are recommended when your blood pressure is
160 / 100 mm Hg or higher, but if you have other cardiovascular risk factors such as
atherosclerosis, diabetes, or obesity, your doctor is likely to recommend medication earlier so as
to protect your kidneys, heart, and other organs from potential damage.3^33start superscript, 3,
end superscript Generally, the treatment goal is to lower blood pressure to less than 140 / 90 mm
Hg in people younger than 60, and less than 150 / 90 in people older than 60.
Many different classes of drugs are used to treat high blood pressure. The most common ones
are:

 Diuretics - these promote the production of urine, which removes excess fluid from the
bloodstream. This reduces the volume of blood in your circulatory system, and your
blood pressure.
 Beta-blockers - these make your heart beat slower and with less force, and your blood
vessels open up. This reduces blood pressure, and improves blood flow.
 Angiotensin-converting enzyme inhibitors, (ACE inhibitors) - these block the action of a
hormone that causes your blood vessels to constrict and that thickens and stiffens the
walls of your blood vessels and heart, as well as triggering the release of another
hormone that increases the amount of sodium and water in your body. Together, this has
the effect of lowering blood pressure.
 Angiotensin II receptor blockers - these affect similar biochemical pathways as ACE
inhibitors, for similar effects.
 Alpha blockers - these block the action of hormones that trigger vasoconstriction of the
smaller arteries and veins, improving blood flow and lowering blood pressure.
 Calcium channel blockers - these relax and widen blood vessels by preventing calcium
from entering heart cells and the muscle cells within the blood vessel walls. This slows
your heart rate and vasodilates your arteries, resulting in lower blood pressure.

Diuretics are often recommended as the first line of therapy for most people who have high
blood pressure, and no other medical conditions. If you do have a medical condition, then your
doctor may choose a medication from one of the other drug classes to suit your individual needs.
For example, if you have diabetes, your doctor may prescribe an ACE inhibitor rather than a
diuretic, as diuretics sometimes interfere with blood sugar levels. The good thing is that if one
drug doesn’t work, there are plenty more to choose from. And, if your blood pressure is
extremely high, your doctor may prescribe combinations of two or more medications to bring it
under control.
After you start antihypertensive medication, your doctor will want to follow your blood pressure
regularly for a few months to make sure you reach your treatment goal. You may also need blood
tests to check the health of your kidneys, which are sometimes affected as a side effect of blood
pressure medicine.

Consider the following:

People with vitamin D deficiency tend to have higher blood pressure than average. Why do you
think this is? Vitamin D inhibits the secretion and activity of a hormone that triggers a cascade of
hormonal activity that ultimately increases blood pressure, by constricting blood vessels
throughout your body, and stimulating reabsorption of sodium and water, which increases blood
volume, and also raises blood pressure. One possible mechanism is that a vitamin D deficiency
leads to increased renin secretion.

https://www.khanacademy.org/science/health-and-medicine/circulatory-system-
diseases/hypertension/a/what-is-hypertension

Overview
High blood pressure is a common condition in which the long-term force of the blood against
your artery walls is high enough that it may eventually cause health problems, such as heart
disease.

Blood pressure is determined both by the amount of blood your heart pumps and the amount of
resistance to blood flow in your arteries. The more blood your heart pumps and the narrower
your arteries, the higher your blood pressure.

You can have high blood pressure (hypertension) for years without any symptoms. Even without
symptoms, damage to blood vessels and your heart continues and can be detected. Uncontrolled
high blood pressure increases your risk of serious health problems, including heart attack and
stroke.

High blood pressure generally develops over many years, and it affects nearly everyone
eventually. Fortunately, high blood pressure can be easily detected. And once you know you
have high blood pressure, you can work with your doctor to control it.

Symptoms
Most people with high blood pressure have no signs or symptoms, even if blood pressure
readings reach dangerously high levels.
A few people with high blood pressure may have headaches, shortness of breath or nosebleeds,
but these signs and symptoms aren't specific and usually don't occur until high blood pressure
has reached a severe or life-threatening stage.

When to see a doctor

You'll likely have your blood pressure taken as part of a routine doctor's appointment.

Ask your doctor for a blood pressure reading at least every two years starting at age 18. If you're
age 40 or older, or you're 18 to 39 with a high risk of high blood pressure, ask your doctor for a
blood pressure reading every year.

Blood pressure generally should be checked in both arms to determine if there's a difference. It's
important to use an appropriate-sized arm cuff.

Your doctor will likely recommend more frequent readings if you've already been diagnosed
with high blood pressure or have other risk factors for cardiovascular disease. Children age 3 and
older will usually have blood pressure measured as a part of their yearly checkups.

If you don't regularly see your doctor, you may be able to get a free blood pressure screening at a
health resource fair or other locations in your community. You can also find machines in some
stores that will measure your blood pressure for free.

Public blood pressure machines, such as those found in pharmacies, may provide helpful
information about your blood pressure, but they may have some limitations. The accuracy of
these machines depends on several factors, such as a correct cuff size and proper use of the
machines. Ask your doctor for advice on using public blood pressure machines.

Request an Appointment at Mayo Clinic

Causes
There are two types of high blood pressure.

Primary (essential) hypertension

For most adults, there's no identifiable cause of high blood pressure. This type of high blood
pressure, called primary (essential) hypertension, tends to develop gradually over many years.

Secondary hypertension

Some people have high blood pressure caused by an underlying condition. This type of high
blood pressure, called secondary hypertension, tends to appear suddenly and cause higher blood
pressure than does primary hypertension. Various conditions and medications can lead to
secondary hypertension, including:
  Obstructive sleep apnea
 Kidney problems
 Adrenal gland tumors
 Thyroid problems
 Certain defects you're born with (congenital) in blood vessels
 Certain medications, such as birth control pills, cold remedies, decongestants, over-the-
counter pain relievers and some prescription drugs
 Illegal drugs, such as cocaine and amphetamines

Risk factors
High blood pressure has many risk factors, including:

 Age. The risk of high blood pressure increases as you age. Until about age 64, high blood
pressure is more common in men. Women are more likely to develop high blood pressure
after age 65.
 Race. High blood pressure is particularly common among people of African heritage,
often developing at an earlier age than it does in whites. Serious complications, such as
stroke, heart attack and kidney failure, also are more common in people of African
heritage.
 Family history. High blood pressure tends to run in families.
 Being overweight or obese. The more you weigh the more blood you need to supply
oxygen and nutrients to your tissues. As the volume of blood circulated through your
blood vessels increases, so does the pressure on your artery walls.
 Not being physically active. People who are inactive tend to have higher heart rates. The
higher your heart rate, the harder your heart must work with each contraction and the
stronger the force on your arteries. Lack of physical activity also increases the risk of
being overweight.
 Using tobacco. Not only does smoking or chewing tobacco immediately raise your blood
pressure temporarily, but the chemicals in tobacco can damage the lining of your artery
walls. This can cause your arteries to narrow and increase your risk of heart disease.
Secondhand smoke also can increase your heart disease risk.
 Too much salt (sodium) in your diet. Too much sodium in your diet can cause your
body to retain fluid, which increases blood pressure.
 Too little potassium in your diet. Potassium helps balance the amount of sodium in
your cells. If you don't get enough potassium in your diet or retain enough potassium, you
may accumulate too much sodium in your blood.
 Drinking too much alcohol. Over time, heavy drinking can damage your heart. Having
more than one drink a day for women and more than two drinks a day for men may affect
your blood pressure.

If you drink alcohol, do so in moderation. For healthy adults, that means up to one drink a
day for women and two drinks a day for men. One drink equals 12 ounces of beer, 5
ounces of wine or 1.5 ounces of 80-proof liquor.
  Stress. High levels of stress can lead to a temporary increase in blood pressure. If you try
to relax by eating more, using tobacco or drinking alcohol, you may only increase
problems with high blood pressure.
 Certain chronic conditions. Certain chronic conditions also may increase your risk of
high blood pressure, such as kidney disease, diabetes and sleep apnea.

Sometimes pregnancy contributes to high blood pressure, as well.

Although high blood pressure is most common in adults, children may be at risk, too. For some
children, high blood pressure is caused by problems with the kidneys or heart. But for a growing
number of kids, poor lifestyle habits, such as an unhealthy diet, obesity and lack of exercise,
contribute to high blood pressure.

Complications
The excessive pressure on your artery walls caused by high blood pressure can damage your
blood vessels, as well as organs in your body. The higher your blood pressure and the longer it
goes uncontrolled, the greater the damage.

Uncontrolled high blood pressure can lead to complications including:

 Heart attack or stroke. High blood pressure can cause hardening and thickening of the
arteries (atherosclerosis), which can lead to a heart attack, stroke or other complications.
 Aneurysm. Increased blood pressure can cause your blood vessels to weaken and bulge,
forming an aneurysm. If an aneurysm ruptures, it can be life-threatening.
 Heart failure. To pump blood against the higher pressure in your vessels, the heart has to
work harder. This causes the walls of the heart's pumping chamber to thicken (left
ventricular hypertrophy). Eventually, the thickened muscle may have a hard time
pumping enough blood to meet your body's needs, which can lead to heart failure.
 Weakened and narrowed blood vessels in your kidneys. This can prevent these organs
from functioning normally.
 Thickened, narrowed or torn blood vessels in the eyes. This can result in vision loss.
 Metabolic syndrome. This syndrome is a cluster of disorders of your body's metabolism,
including increased waist circumference; high triglycerides; low high-density lipoprotein
(HDL) cholesterol, the "good" cholesterol; high blood pressure and high insulin levels.
These conditions make you more likely to develop diabetes, heart disease and stroke.
 Trouble with memory or understanding. Uncontrolled high blood pressure may also
affect your ability to think, remember and learn. Trouble with memory or understanding
concepts is more common in people with high blood pressure.
 Dementia. Narrowed or blocked arteries can limit blood flow to the brain, leading to a
certain type of dementia (vascular dementia). A stroke that interrupts blood flow to the
brain also can cause vascular dementia.

https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/symptoms-causes/syc-20373410
Hypertension
From Wikipedia, the free encyclopedia

This article is about arterial hypertension. For other forms of hypertension, see Hypertension
(disambiguation).

Hypertension

Arterial hypertension, high blood

Synonyms
pressure

Automated arm blood pressure meter showing arterial

hypertension (shown a systolic blood pressure
158 mmHg, diastolic blood pressure 99 mmHg and heart
rate of 80 beats per minute)

Specialty Cardiology

Symptoms None[1]

Coronary artery disease, stroke, heart

failure, peripheral vascular disease,
Complications
vision loss, chronic kidney disease,
dementia[2][3][4]

Usually lifestyle and genetic

Causes
factors[5][6]

Excess salt, excess body weight,

Risk factors
smoking, alcohol[1][5]
 Resting blood pressure
Diagnostic method
130/90 or 140/90 mmHg[5][7]

Treatment Lifestyle changes, medications[8]

Frequency 16–37% globally[5]

Deaths 9.4 million / 18% (2010)[9]

Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical
condition in which the blood pressure in the arteries is persistently elevated.[10] High blood
pressure usually does not cause symptoms.[1] Long-term high blood pressure, however, is a major
risk factor for coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular
disease, vision loss, chronic kidney disease, and dementia.[2][3][4][11]

High blood pressure is classified as either primary (essential) high blood pressure or secondary
high blood pressure.[5] About 90–95% of cases are primary, defined as high blood pressure due
to nonspecific lifestyle and genetic factors.[5][6] Lifestyle factors that increase the risk include
excess salt in the diet, excess body weight, smoking, and alcohol use.[1][5] The remaining 5–10%
of cases are categorized as secondary high blood pressure, defined as high blood pressure due to
an identifiable cause, such as chronic kidney disease, narrowing of the kidney arteries, an
endocrine disorder, or the use of birth control pills.[5]

Blood pressure is expressed by two measurements, the systolic and diastolic pressures, which are
the maximum and minimum pressures, respectively.[1] For most adults, normal blood pressure at
rest is within the range of 100–130 millimeters mercury (mmHg) systolic and 60–80 mmHg
diastolic.[7][12] For most adults, high blood pressure is present if the resting blood pressure is
persistently at or above 130/90 or 140/90 mmHg.[5][7] Different numbers apply to children.[13]
Ambulatory blood pressure monitoring over a 24-hour period appears more accurate than office-
based blood pressure measurement.[5][10]

Lifestyle changes and medications can lower blood pressure and decrease the risk of health
complications.[8] Lifestyle changes include weight loss, decreased salt intake, physical exercise,
and a healthy diet.[5] If lifestyle changes are not sufficient then blood pressure medications are
used.[8] Up to three medications can control blood pressure in 90% of people.[5] The treatment of
moderately high arterial blood pressure (defined as >160/100 mmHg) with medications is
associated with an improved life expectancy.[14] The effect of treatment of blood pressure
between 130/80 mmHg and 160/100 mmHg is less clear, with some reviews finding
benefit[7][15][16] and others finding unclear benefit.[17][18][19] High blood pressure affects between
16 and 37% of the population globally.[5] In 2010 hypertension was believed to have been a
factor in 18% of all deaths (9.4 million globally).[9]

Signs and symptoms

Hypertension is rarely accompanied by symptoms, and its identification is usually through
screening, or when seeking healthcare for an unrelated problem. Some with high blood pressure
report headaches (particularly at the back of the head and in the morning), as well as
lightheadedness, vertigo, tinnitus (buzzing or hissing in the ears), altered vision or fainting
episodes.[20] These symptoms, however, might be related to associated anxiety rather than the
high blood pressure itself.[21]

On physical examination, hypertension may be associated with the presence of changes in the
optic fundus seen by ophthalmoscopy.[22] The severity of the changes typical of hypertensive
retinopathy is graded from I–IV; grades I and II may be difficult to differentiate.[22] The severity
of the retinopathy correlates roughly with the duration or the severity of the hypertension.[20]

Secondary hypertension

Main article: Secondary hypertension

Hypertension with certain specific additional signs and symptoms may suggest secondary
hypertension, i.e. hypertension due to an identifiable cause. For example, Cushing's syndrome
frequently causes truncal obesity, glucose intolerance, moon face, a hump of fat behind the
neck/shoulder (referred to as a buffalo hump), and purple abdominal stretch marks.[23]
Hyperthyroidism frequently causes weight loss with increased appetite, fast heart rate, bulging
eyes, and tremor. Renal artery stenosis (RAS) may be associated with a localized abdominal
bruit to the left or right of the midline (unilateral RAS), or in both locations (bilateral RAS).
Coarctation of the aorta frequently causes a decreased blood pressure in the lower extremities
relative to the arms, or delayed or absent femoral arterial pulses. Pheochromocytoma may cause
abrupt ("paroxysmal") episodes of hypertension accompanied by headache, palpitations, pale
appearance, and excessive sweating.[23]

Hypertensive crisis

Main article: Hypertensive crisis

Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 110) is
referred to as a hypertensive crisis. Hypertensive crisis is categorized as either hypertensive
urgency or hypertensive emergency, according to the absence or presence of end organ damage,
respectively.[24][25]

In hypertensive urgency, there is no evidence of end organ damage resulting from the elevated
blood pressure. In these cases, oral medications are used to lower the BP gradually over 24 to 48
hours.[26]

In hypertensive emergency, there is evidence of direct damage to one or more organs.[27][28] The
most affected organs include the brain, kidney, heart and lungs, producing symptoms which may
include confusion, drowsiness, chest pain and breathlessness.[26] In hypertensive emergency, the
blood pressure must be reduced more rapidly to stop ongoing organ damage,[26] however, there is
a lack of randomized controlled trial evidence for this approach.[28]
Pregnancy

Main articles: Gestational hypertension and Pre-eclampsia

Hypertension occurs in approximately 8–10% of pregnancies.[23] Two blood pressure

measurements six hours apart of greater than 140/90 mm Hg is diagnostic of hypertension in
pregnancy.[29] High blood pressure in pregnancy can be classified as pre-existing hypertension,
gestational hypertension, or pre-eclampsia.[30]

Pre-eclampsia is a serious condition of the second half of pregnancy and following delivery
characterised by increased blood pressure and the presence of protein in the urine.[23] It occurs in
about 5% of pregnancies and is responsible for approximately 16% of all maternal deaths
globally.[23] Pre-eclampsia also doubles the risk of death of the baby around the time of birth.[23]
Usually there are no symptoms in pre-eclampsia and it is detected by routine screening. When
symptoms of pre-eclampsia occur the most common are headache, visual disturbance (often
"flashing lights"), vomiting, pain over the stomach, and swelling. Pre-eclampsia can occasionally
progress to a life-threatening condition called eclampsia, which is a hypertensive emergency and
has several serious complications including vision loss, brain swelling, seizures, kidney failure,
pulmonary edema, and disseminated intravascular coagulation (a blood clotting disorder).[23][31]

In contrast, gestational hypertension is defined as new-onset hypertension during pregnancy

without protein in the urine.[30]

Children

Failure to thrive, seizures, irritability, lack of energy, and difficulty in breathing[32] can be
associated with hypertension in newborns and young infants. In older infants and children,
hypertension can cause headache, unexplained irritability, fatigue, failure to thrive, blurred
vision, nosebleeds, and facial paralysis.[32][33]

Causes
Primary hypertension

Main article: Essential hypertension

Hypertension results from a complex interaction of genes and environmental factors. Numerous
common genetic variants with small effects on blood pressure have been identified[34] as well as
some rare genetic variants with large effects on blood pressure.[35] Also, genome-wide
association studies (GWAS) have identified 35 genetic loci related to blood pressure; 12 of these
genetic loci influencing blood pressure were newly found.[36] Sentinel SNP for each new genetic
loci identified has shown an association with DNA methylation at multiple nearby Cpg sites.
These sentinel SNP are located within genes related to vascular smooth muscle and renal
function. DNA methylation might affect in some way linking common genetic variation to
multiple phenotypes even though mechanisms underlying these associations are not understood.
Single variant test performed in this study for the 35 sentinel SNP (known and new) showed that
genetic variants singly or in aggregate contribute to risk of clinical phenotypes related to high
blood pressure.[36]

Blood pressure rises with aging and the risk of becoming hypertensive in later life is
considerable.[37] Several environmental factors influence blood pressure. High salt intake raises
the blood pressure in salt sensitive individuals; lack of exercise, obesity, and depression[38] can
play a role in individual cases. The possible role of other factors such as caffeine
consumption,[39] and vitamin D deficiency[40] are less clear. Insulin resistance, which is common
in obesity and is a component of syndrome X (or the metabolic syndrome), is also thought to
contribute to hypertension.[41] One review suggests that sugar may play an important role in
hypertension and salt is just an innocent bystander.[42]

Events in early life, such as low birth weight, maternal smoking, and lack of breastfeeding may
be risk factors for adult essential hypertension, although the mechanisms linking these exposures
to adult hypertension remain unclear.[43] An increased rate of high blood urea has been found in
untreated people with hypertensive in comparison with people with normal blood pressure,
although it is uncertain whether the former plays a causal role or is subsidiary to poor kidney
function.[44] Average blood pressure may be higher in the winter than in the summer.[45]

Secondary hypertension

Main article: Secondary hypertension

Secondary hypertension results from an identifiable cause. Kidney disease is the most common
secondary cause of hypertension.[23] Hypertension can also be caused by endocrine conditions,
such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or
hyperaldosteronism, renal artery stenosis (from atherosclerosis or fibromuscular dysplasia),
hyperparathyroidism, and pheochromocytoma.[23][46] Other causes of secondary hypertension
include obesity, sleep apnea, pregnancy, coarctation of the aorta, excessive eating of liquorice,
excessive drinking of alcohol, and certain prescription medicines, herbal remedies, and illegal
drugs such as cocaine and methamphetamine.[23][47] Arsenic exposure through drinking water has
been shown to correlate with elevated blood pressure.[48][49]

Pathophysiology
Main article: Pathophysiology of hypertension
Determinants of mean arterial pressure

Illustration depicting the effects of high blood pressure

In most people with established essential hypertension, increased resistance to blood flow (total
peripheral resistance) accounts for the high pressure while cardiac output remains normal.[50]
There is evidence that some younger people with prehypertension or 'borderline hypertension'
have high cardiac output, an elevated heart rate and normal peripheral resistance, termed
hyperkinetic borderline hypertension.[51] These individuals develop the typical features of
established essential hypertension in later life as their cardiac output falls and peripheral
resistance rises with age.[51] Whether this pattern is typical of all people who ultimately develop
hypertension is disputed.[52] The increased peripheral resistance in established hypertension is
mainly attributable to structural narrowing of small arteries and arterioles,[53] although a
reduction in the number or density of capillaries may also contribute.[54]

It is not clear whether or not vasoconstriction of arteriolar blood vessels plays a role in
hypertension.[55] Hypertension is also associated with decreased peripheral venous compliance[56]
which may increase venous return, increase cardiac preload and, ultimately, cause diastolic
dysfunction.

Pulse pressure (the difference between systolic and diastolic blood pressure) is frequently
increased in older people with hypertension. This can mean that systolic pressure is abnormally
high, but diastolic pressure may be normal or low a condition termed isolated systolic
hypertension.[57] The high pulse pressure in elderly people with hypertension or isolated systolic
hypertension is explained by increased arterial stiffness, which typically accompanies aging and
may be exacerbated by high blood pressure.[58]

Many mechanisms have been proposed to account for the rise in peripheral resistance in
hypertension. Most evidence implicates either disturbances in the kidneys' salt and water
handling (particularly abnormalities in the intrarenal renin–angiotensin system)[59] or
abnormalities of the sympathetic nervous system.[60] These mechanisms are not mutually
exclusive and it is likely that both contribute to some extent in most cases of essential
hypertension. It has also been suggested that endothelial dysfunction and vascular inflammation
may also contribute to increased peripheral resistance and vascular damage in hypertension.[61][62]
Interleukin 17 has garnered interest for its role in increasing the production of several other
immune system chemical signals thought to be involved in hypertension such as tumor necrosis
factor alpha, interleukin 1, interleukin 6, and interleukin 8.[63]

Consumption of excessive sodium and/or insufficient potassium leads to excessive intracellular

sodium, which contracts vascular smooth muscle, restricting blood flow and so increases blood
pressure.[64][65]

Diagnosis
Typical tests performed
System Tests
Kidney Microscopic urinalysis, protein in the urine, BUN and/or creatinine
Endocrine Serum sodium, potassium, calcium, TSH
Metabolic Fasting blood glucose, HDL, LDL, and total cholesterol, triglycerides
Other Hematocrit, electrocardiogram, and chest radiograph
Sources: Harrison's Principles of Internal Medicine[66] and others[67][68][69][70][71]

Hypertension is diagnosed on the basis of a persistently high resting blood pressure.

Traditionally, the National Institute of Clinical Excellence recommends three separate resting
sphygmomanometer measurements at monthly intervals.[72][73] The American Heart Association
recommends at least three resting measurements on at least two separate health care visits.[74]

For an accurate diagnosis of hypertension to be made, it is essential for proper blood pressure
measurement technique to be used.[75] Improper measurement of blood pressure is common and
can change the blood pressure reading by up to 10 mmHg, which can lead to misdiagnosis and
misclassification of hypertension.[75] Correct blood pressure measurement technique involves
several steps. Proper blood pressure measurement requires the person whose blood pressure is
being measured to sit quietly for at least five minutes which is then followed by application of a
properly fitted blood pressure cuff to a bare upper arm.[75] The person should be seated with their
back supported, feet flat on the floor, and with their legs uncrossed.[75] The person whose blood
pressure is being measured should avoid talking or moving during this process.[75] The arm being
measured should be supported on a flat surface at the level of the heart.[75] Blood pressure
measurement should be done in a quiet room so the medical professional checking the blood
pressure can hear the Korotkoff sounds while listening to the brachial artery with a stethoscope
for accurate blood pressure measurements.[75][76] The blood pressure cuff should be deflated
slowly (2-3 mmHg per second) while listening for the Korotkoff sounds.[76] The bladder should
be emptied before a person's blood pressure is measured since this can increase blood pressure
by up to 15/10 mmHg.[75] Multiple blood pressure readings (at least two) spaced 1–2 minutes
apart should be obtained to ensure accuracy.[76] Ambulatory blood pressure monitoring over 12
to 24 hours is the most accurate method to confirm the diagnosis.[77]
An exception to this is those with very high blood pressure readings especially when there is
poor organ function.[73] Initial assessment of the hypertensive people should include a complete
history and physical examination. With the availability of 24-hour ambulatory blood pressure
monitors and home blood pressure machines, the importance of not wrongly diagnosing those
who have white coat hypertension has led to a change in protocols. In the United Kingdom,
current best practice is to follow up a single raised clinic reading with ambulatory measurement,
or less ideally with home blood pressure monitoring over the course of 7 days.[73] The United
States Preventive Services Task Force also recommends getting measurements outside of the
healthcare environment.[78] Pseudohypertension in the elderly or noncompressibility artery
syndrome may also require consideration. This condition is believed to be due to calcification of
the arteries resulting in abnormally high blood pressure readings with a blood pressure cuff while
intra arterial measurements of blood pressure are normal.[79] Orthostatic hypertension is when
blood pressure increases upon standing.[80]

Once the diagnosis of hypertension has been made, healthcare providers should attempt to
identify the underlying cause based on risk factors and other symptoms, if present. Secondary
hypertension is more common in preadolescent children, with most cases caused by kidney
disease. Primary or essential hypertension is more common in adolescents and has multiple risk
factors, including obesity and a family history of hypertension.[81] Laboratory tests can also be
performed to identify possible causes of secondary hypertension, and to determine whether
hypertension has caused damage to the heart, eyes, and kidneys. Additional tests for diabetes and
high cholesterol levels are usually performed because these conditions are additional risk factors
for the development of heart disease and may require treatment.[6]

Serum creatinine is measured to assess for the presence of kidney disease, which can be either
the cause or the result of hypertension. Serum creatinine alone may overestimate glomerular
filtration rate and recent guidelines advocate the use of predictive equations such as the
Modification of Diet in Renal Disease (MDRD) formula to estimate glomerular filtration rate
(eGFR).[27] eGFR can also provide a baseline measurement of kidney function that can be used to
monitor for side effects of certain anti-hypertensive drugs on kidney function. Additionally,
testing of urine samples for protein is used as a secondary indicator of kidney disease.
Electrocardiogram (EKG/ECG) testing is done to check for evidence that the heart is under strain
from high blood pressure. It may also show whether there is thickening of the heart muscle (left
ventricular hypertrophy) or whether the heart has experienced a prior minor disturbance such as a
silent heart attack. A chest X-ray or an echocardiogram may also be performed to look for signs
of heart enlargement or damage to the heart.[23]

Adults

Classification in adults (Persons with systolic and diastolic in different categories are assigned
to the higher category.[7])
Category Systolic, mmHg Diastolic, mmHg
Hypotension < 90 < 60
[7]
90–119 60–79[7]
Normal
 90–129[82] 60–84[82]
120–129[7] 60–79[7]
Prehypertension
(high normal, elevated[7])
130–139[82][83] 85–89[82][83]
130-139[7] 80-89[7]
Stage 1 hypertension
140–159[82] 90–99[82]
>140[7] >90[7]
Stage 2 hypertension
160–179[82] 100–109[82]
Hypertensive crises ≥ 180[7] ≥ 120[7]
Isolated systolic hypertension ≥ 160[7] < 90 to 110[7]

In people aged 18 years or older hypertension is defined as either a systolic or a diastolic blood
pressure measurement consistently higher than an accepted normal value (this is above 129 or
139 mmHg systolic, 89 mmHg diastolic depending on the guideline).[5][7] Other thresholds are
used (135 mmHg systolic or 85 mmHg diastolic) if measurements are derived from 24-hour
ambulatory or home monitoring.[73] Recent international hypertension guidelines have also
created categories below the hypertensive range to indicate a continuum of risk with higher
blood pressures in the normal range. The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7) published in
2003[27] uses the term prehypertension for blood pressure in the range 120–139 mmHg systolic or
80–89 mmHg diastolic, while European Society of Hypertension Guidelines (2007)[84] and
British Hypertension Society (BHS) IV (2004)[85] use optimal, normal and high normal
categories to subdivide pressures below 140 mmHg systolic and 90 mmHg diastolic.
Hypertension is also sub-classified: JNC7 distinguishes hypertension stage I, hypertension stage
II, and isolated systolic hypertension. Isolated systolic hypertension refers to elevated systolic
pressure with normal diastolic pressure and is common in the elderly.[27] The ESH-ESC
Guidelines (2007)[84] and BHS IV (2004)[85] additionally define a third stage (stage III
hypertension) for people with systolic blood pressure exceeding 179 mmHg or a diastolic
pressure over 109 mmHg. Hypertension is classified as "resistant" if medications do not reduce
blood pressure to normal levels.[27] In November 2017, the American Heart Association and
American College of Cardiology published a joint guideline which updates the recommendations
of the JNC7 report.[86]

Children

Hypertension occurs in around 0.2 to 3% of newborns; however, blood pressure is not measured
routinely in healthy newborns.[33] Hypertension is more common in high risk newborns. A
variety of factors, such as gestational age, postconceptional age and birth weight needs to be
taken into account when deciding if a blood pressure is normal in a newborn.[33]

Hypertension defined as elevated blood pressure over several visits affects 1% to 5% of children
and adolescents and is associated with long term risks of ill-health.[87] Blood pressure rises with
age in childhood and, in children, hypertension is defined as an average systolic or diastolic
blood pressure on three or more occasions equal or higher than the 95th percentile appropriate
for the sex, age and height of the child. High blood pressure must be confirmed on repeated visits
however before characterizing a child as having hypertension.[87] Prehypertension in children has
been defined as average systolic or diastolic blood pressure that is greater than or equal to the
90th percentile, but less than the 95th percentile.[87] In adolescents, it has been proposed that
hypertension and pre-hypertension are diagnosed and classified using the same criteria as in
adults.[87]

The value of routine screening for hypertension in children over the age of 3 years is
debated.[88][89] In 2004 the National High Blood Pressure Education Program recommended that
children aged 3 years and older have blood pressure measurement at least once at every health
care visit[87] and the National Heart, Lung, and Blood Institute and American Academy of
Pediatrics made a similar recommendation.[90] However, the American Academy of Family
Physicians[91] supports the view of the U.S. Preventive Services Task Force that the available
evidence is insufficient to determine the balance of benefits and harms of screening for
hypertension in children and adolescents who do not have symptoms.[92]

Prevention
Much of the disease burden of high blood pressure is experienced by people who are not labeled
as hypertensive.[85] Consequently, population strategies are required to reduce the consequences
of high blood pressure and reduce the need for antihypertensive medications. Lifestyle changes
are recommended to lower blood pressure, before starting medications. The 2004 British
Hypertension Society guidelines[85] proposed lifestyle changes consistent with those outlined by
the US National High BP Education Program in 2002[93] for the primary prevention of
hypertension:

 maintain normal body weight for adults (e.g. body mass index 20–25 kg/m2)
 reduce dietary sodium intake to <100 mmol/ day (<6 g of sodium chloride or <2.4 g of
sodium per day)
 engage in regular aerobic physical activity such as brisk walking (≥30 min per day, most
days of the week)
 limit alcohol consumption to no more than 3 units/day in men and no more than 2
units/day in women
 consume a diet rich in fruit and vegetables (e.g. at least five portions per day);

Effective lifestyle modification may lower blood pressure as much as an individual

antihypertensive medication. Combinations of two or more lifestyle modifications can achieve
even better results.[85] There is considerable evidence that reducing dietary salt intake lowers
blood pressure, but whether this translates into a reduction in mortality and cardiovascular
disease remains uncertain.[94] Estimated sodium intake ≥6g/day and <3g/day are both associated
with high risk of death or major cardiovascular disease, but the association between high sodium
intake and adverse outcomes is only observed in people with hypertension.[95] Consequently, in
the absence of results from randomized controlled trials, the wisdom of reducing levels of dietary
salt intake below 3g/day has been questioned.[94]
Management
Main article: Management of hypertension

According to one review published in 2003, reduction of the blood pressure by 5 mmHg can
decrease the risk of stroke by 34%, of ischemic heart disease by 21%, and reduce the likelihood
of dementia, heart failure, and mortality from cardiovascular disease.[96]

Target blood pressure

See also: Comparison of international blood pressure guidelines

Various expert groups have produced guidelines regarding how low the blood pressure target
should be when a person is treated for hypertension. These groups recommend a target below the
range 140–160 / 90–100 mmHg for the general population.[13][97][98][99][100][101] Controversy exists
regarding the appropriate targets for certain subgroups, including the elderly, people with
diabetes, and people with kidney disease.[102]

Many expert groups recommend a slightly higher target of 150/90 mmHg for those over
somewhere between 60 and 80 years of age.[97][98][99][103] The JNC-8 and American College of
Physicians recommend the target of 150/90 mmHg for those over 60 years of age,[13][104] but
some experts within these groups disagree with this recommendation.[105] Some expert groups
have also recommended slightly lower targets in those with diabetes[97] or chronic kidney disease
with protein loss in the urine,[106] but others recommend the same target as for the general
population.[13][102] The issue of what is the best target and whether targets should differ for high
risk individuals is unresolved,[107] but current best evidence supports more intensive blood
pressure lowering than advocated in some guidelines.[108]

Lifestyle modifications

The first line of treatment for hypertension is lifestyle changes, including dietary changes,
physical exercise, and weight loss. Though these have all been recommended in scientific
advisories,[109] a Cochrane systematic review found no evidence for effects of weight loss diets
on death, long-term complications or adverse events in persons with hypertension.[110] The
review did find a decrease in blood pressure.[110] Their potential effectiveness is similar to and at
times exceeds a single medication.[12] If hypertension is high enough to justify immediate use of
medications, lifestyle changes are still recommended in conjunction with medication.

Dietary changes shown to reduce blood pressure include diets with low sodium,[111][112][113] the
DASH diet,[114] vegetarian diets,[115] and green tea consumption.[116][117][118][119]

Increasing dietary potassium has a potential benefit for lowering the risk of hypertension.[120][121]
The 2015 Dietary Guidelines Advisory Committee (DGAC) stated that potassium is one of the
shortfall nutrients which is under-consumed in the United States.[122]
Physical exercise regimens which are shown to reduce blood pressure include isometric
resistance exercise, aerobic exercise, resistance exercise, and device-guided breathing.[123]

Stress reduction techniques such as biofeedback or transcendental meditation may be considered

as an add-on to other treatments to reduce hypertension, but do not have evidence for preventing
cardiovascular disease on their own.[123][124][125] Self-monitoring and appointment reminders
might support the use of other strategies to improve blood pressure control, but need further
evaluation.[126]

Medications

Several classes of medications, collectively referred to as antihypertensive medications, are

available for treating hypertension.

First-line medications for hypertension include thiazide-diuretics, calcium channel blockers,

angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.[13] These
medications may be used alone or in combination (ACE inhibitors and ARBs are not
recommended for use in combination); the latter option may serve to minimize counter-
regulatory mechanisms that act to revert blood pressure values to pre-treatment levels.[13][127]
Previously beta-blockers were thought to have similar beneficial effects when used as first-line
therapy for hypertension. However, a Cochrane review that included 13 trials found that the
effects of beta-blockers are inferior to that of other antihypertensive medications.[128] Most
people require more than one medication to control their hypertension.[109] Medications for blood
pressure control should implemented by a stepped care approach when target levels are not
reached.[126]

Resistant hypertension

Resistant hypertension is defined as high blood pressure that remains above a target level, in
spite of being prescribed three or more antihypertensive drugs simultaneously with different
mechanisms of action.[129] Failing to take the prescribed drugs, is an important cause of resistant
hypertension.[130] Resistant hypertension may also result from chronically high activity of the
autonomic nervous system, an effect known as "neurogenic hypertension".[131] Electrical
therapies that stimulate the baroreflex are being studied as an option for lowering blood pressure
in people in this situation.[132]

Epidemiology

Map of the prevalence of hypertension in adult men in 2014.[133]

Disability-adjusted life year for hypertensive heart disease per 100,000 inhabitants in 2004.[134]
no data 660-770
<110 770-880
110-220 880-990
220-330 990-1100
330-440 1100–1600
440-550 >1600
550-660

Adults

As of 2014, approximately one billion adults or ~22% of the population of the world have
hypertension.[135] It is slightly more frequent in men,[135] in those of low socioeconomic status,[6]
and it becomes more common with age.[6] It is common in high, medium, and low income
countries.[135][136] In 2004 rates of high blood pressure were highest in Africa, (30% for both
sexes) and lowest in the Americas (18% for both sexes). Rates also vary markedly within regions
with rates as low as 3.4% (men) and 6.8% (women) in rural India and as high as 68.9% (men)
and 72.5% (women) in Poland.[137] Rates in 2016 rates in Africa were about 45%.[138]

In Europe hypertension occurs in about 30-45% of people as of 2013.[12] In 1995 it was estimated
that 43 million people (24% of the population) in the United States had hypertension or were
taking antihypertensive medication.[139] By 2004 this had increased to 29%[140][141] and further to
32% (76 million US adults) by 2017.[7] In 2017, with the change in definitions for hypertension,
46% of people in the United States are affected.[7] African-American adults in the United States
have among the highest rates of hypertension in the world at 44%.[142] It is also more common in
Filipino Americans and less common in US whites and Mexican Americans.[6][143]

Children

Rates of high blood pressure in children and adolescents have increased in the last 20 years in the
United States.[144] Childhood hypertension, particularly in pre-adolescents, is more often
secondary to an underlying disorder than in adults. Kidney disease is the most common
secondary cause of hypertension in children and adolescents. Nevertheless, primary or essential
hypertension accounts for most cases.[145]

Outcomes
Main article: Complications of hypertension
Diagram illustrating the main complications of persistent high blood pressure

Hypertension is the most important preventable risk factor for premature death worldwide.[146] It
increases the risk of ischemic heart disease,[147] strokes,[23] peripheral vascular disease,[148] and
other cardiovascular diseases, including heart failure, aortic aneurysms, diffuse atherosclerosis,
chronic kidney disease, atrial fibrillation, and pulmonary embolism.[11][23] Hypertension is also a
risk factor for cognitive impairment and dementia.[23] Other complications include hypertensive
retinopathy and hypertensive nephropathy.[27]

History
Main article: History of hypertension

Image of veins from Harvey's Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus

Measurement

Modern understanding of the cardiovascular system began with the work of physician William
Harvey (1578–1657), who described the circulation of blood in his book "De motu cordis". The
English clergyman Stephen Hales made the first published measurement of blood pressure in
1733.[149][150] However, hypertension as a clinical entity came into its own with the invention of
the cuff-based sphygmomanometer by Scipione Riva-Rocci in 1896.[151] This allowed easy
measurement of systolic pressure in the clinic. In 1905, Nikolai Korotkoff improved the
technique by describing the Korotkoff sounds that are heard when the artery is ausculated with a
stethoscope while the sphygmomanometer cuff is deflated.[150] This permitted systolic and
diastolic pressure to be measured.

Identification

The symptoms similar to symptoms of patients with hypertensive crisis are discussed in
medieval Persian medical texts in the chapter of "fullness disease".[152] The symptoms include
headache, heaviness in the head, sluggish movements, general redness and warm to touch feel of
the body, prominent, distended and tense vessels, fullness of the pulse, distension of the skin,
coloured and dense urine, loss of appetite, weak eyesight, impairment of thinking, yawning,
drowsiness, vascular rupture, and hemorrhagic stroke.[153] Fullness disease was presumed to be
due to an excessive amount of blood within the blood vessels.

Descriptions of hypertension as a disease came among others from Thomas Young in 1808 and
especially Richard Bright in 1836.[149] The first report of elevated blood pressure in a person
without evidence of kidney disease was made by Frederick Akbar Mahomed (1849–1884).[154]

Treatment

Historically the treatment for what was called the "hard pulse disease" consisted in reducing the
quantity of blood by bloodletting or the application of leeches.[149] This was advocated by The
Yellow Emperor of China, Cornelius Celsus, Galen, and Hippocrates.[149] The therapeutic
approach for the treatment of hard pulse disease included changes in lifestyle (staying away from
anger and sexual intercourse) and dietary program for patients (avoiding the consumption of
wine, meat, and pastries, reducing the volume of food in a meal, maintaining a low-energy diet
and the dietary usage of spinach and vinegar).

In the 19th and 20th centuries, before effective pharmacological treatment for hypertension
became possible, three treatment modalities were used, all with numerous side-effects: strict
sodium restriction (for example the rice diet[149]), sympathectomy (surgical ablation of parts of
the sympathetic nervous system), and pyrogen therapy (injection of substances that caused a
fever, indirectly reducing blood pressure).[149][155]

The first chemical for hypertension, sodium thiocyanate, was used in 1900 but had many side
effects and was unpopular.[149] Several other agents were developed after the Second World War,
the most popular and reasonably effective of which were tetramethylammonium chloride,
hexamethonium, hydralazine, and reserpine (derived from the medicinal plant Rauwolfia
serpentina). None of these were well tolerated.[156][157] A major breakthrough was achieved with
the discovery of the first well-tolerated orally available agents. The first was chlorothiazide, the
first thiazide diuretic and developed from the antibiotic sulfanilamide, which became available in
1958.[149][158] Subsequently, beta blockers, calcium channel blockers, angiotensin converting
enzyme (ACE) inhibitors, angiotensin receptor blockers, and renin inhibitors were developed as
antihypertensive agents.[155]

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The Hypertension Danger Zone

You have stage 1 high blood pressure if your systolic reading is between 130 and 139 or your
diastolic is between 80 and 89. A reading of 140 or higher systolic or 90 or greater diastolic is
stage 2 hypertension. You may not have symptoms. If your systolic is over 180 or your diastolic
is above over 120, you may be having a hypertensive crisis, which can lead to a stroke, heart
attack, or kidney damage. Rest for a few minutes and take your blood pressure again. If it's still
that high, call 911. Symptoms include a severe headache, anxiety, and nosebleeds. You might
feel short of breath or pass out.

Who Gets High Blood Pressure?

Up to age 45, men are more likely to have high blood pressure than women. Things even up as
we grow older, and by 65 it's more common in women. You're more likely to get it if a close
family member has it. It's also widespread among people with diabetes. But in most cases, the
cause isn't known. Sometimes, kidney or adrenal gland disease can bring it on.

https://www.webmd.com/hypertension-high-blood-pressure/ss/slideshow-hypertension-overview
6 / 27

Race Plays a Role

African-Americans are more likely to get hypertension -- and at a younger age. Genetic research
suggests they're more sensitive to salt. Diet and excess weight make a difference, too.

6 / 27
Say No to Sodium
Or at least watch how much you get. This building block of salt causes your body to retain fluid.
That puts a greater burden on your heart and boosts your blood pressure. Aim for less than 1,500
milligrams of sodium per day. You'll need to check nutrition labels and menus carefully.
Processed foods make up the bulk of our sodium intake. Canned soups and lunch meats are
prime suspects.

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Get a Handle on Stress

It can make your blood pressure spike, but there's no proof stress keeps it high long-term. To
manage it, stay away from unhealthy things like poor diet, alcohol use, and smoking. All are
linked to high blood pressure and heart disease.
6 / 27

Drop Those Extra Pounds

They put a strain on your heart and raise your odds of having high blood pressure. That's why
diets designed to lower blood pressure also aim to control calories. You'll cut out fatty foods and
extra sugars, while adding fruits, vegetables, lean protein, and fiber. Even a 10-pound weight
loss can make a difference.

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Cut Back on Booze
Too much alcohol can boost your blood pressure. Limit drinks to no more than two a day for
men, or one for women. How much is that?

 12 ounces of beer
 4 ounces of wine
 1.5 ounces of 80-proof spirits
 1 ounce of 100-proof spirits

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Caffeine Is OK
It can make you jittery, so does caffeine also raise your blood pressure? It might for a little while,
but there's no link between caffeine and hypertension. You can safely drink one or two cups of
coffee a day.
6 / 27

Moms-to-Be Can Get It

Gestational hypertension can affect women who've never had high blood pressure before. It
happens in the second half of pregnancy. Without treatment, it may lead to a serious condition
called preeclampsia. This limits blood and oxygen flow to your baby and can affect your kidneys
and brain. After delivery, your blood pressure should return to its normal level.

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Medication Might Bring It On
Cold and flu medicines with decongestants are one of several classes of medication that can raise
blood pressure. Others include NSAID pain relievers, steroids, diet pills, birth control pills, and
some antidepressants. If you have high blood pressure, ask your doctor if any drugs or
supplements you're taking could affect your readings.

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Your Doctor Can Cause It

You may have a high reading only in the doctor's office. This is probably due to nerves. You
might have one only every now and then. This could mean you're more likely to get high blood
pressure later. For a more accurate reading, take your blood pressure at home, chart the results,
and share them with your doctor. Bring your home monitor in so the doctor can check the device
and your technique.
6 / 27

It Can Affect Kids

It's more often a problem for older people, but children can also have high blood pressure.
What's normal varies based on a child’s age, height, and sex. Your doctor will need to tell you if
there's a concern. Children are more likely to get it if they're overweight, have a family history of
the illness, or are African-American.

6 / 27
Try the DASH Diet
You may be able to lower your blood pressure by eating better. The DASH Diet -- Dietary
Approaches to Stop Hypertension -- calls for more fruits, vegetables, whole-grain foods, low-fat
dairy, fish, poultry, and nuts. Steer clear of red meat, saturated fats, and sweets. Cutting back on
sodium in your diet can also help.

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Get More Exercise

Regular activity helps lower blood pressure. Adults should get about 150 minutes of moderate-
intensity exercise every week. That could include gardening, walking briskly, bicycling, or other
aerobic exercise. Add in some muscle strengthening at least 2 days a week. Target all your major
muscle groups.
6 / 27

Diuretics Get Rid of Extra Water

Also called water pills, they're often the first choice if diet and exercise changes aren't enough.
They help your body shed excess sodium and water to lower blood pressure. That means you'll
pee more often. Some diuretics may lower the amount of potassium in your body. You might
notice more muscle weakness, leg cramps, and fatigue. Others can boost blood sugar in people
with diabetes. Erectile dysfunction is a less common side effect.
6 / 27

Beta-Blockers Slow Things Down

These drugs slow your heart rate, which means your ticker doesn't have to work as hard. They're
also used to treat other heart conditions, like an abnormal heart rate, or arrhythmia. Your doctor
may prescribe them along with other medications. Side effects can include insomnia, dizziness,
fatigue, cold hands and feet, and erectile dysfunction.

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ACE Inhibitors Open Things Up

These meds lower your body's supply of angiotensin II -- a substance that makes blood vessels
contract and narrow. The result is more relaxed, open (dilated) arteries, as well as lower blood
pressure and less effort for your heart. Side effects can include a dry cough, skin rash, dizziness,
and high potassium levels. Don’t get pregnant while taking one of these drugs.
6 / 27

ARBs Keep the Flow Going

Instead of lowering your supply of angiotensin II, these drugs block receptors for angiotensin.
It's like placing a shield over a lock. This blockade prevents the chemical's artery-tightening
effects and lowers your blood pressure. ARBs can take several weeks to become fully effective.
Possible side effects include dizziness, muscle cramps, insomnia, and high potassium levels.
Don’t get pregnant while taking this medication.
6 / 27

Calcium Channel Blockers Slow the Beat

Calcium causes stronger heart contractions. These medications slow its movement into the cells
of your heart and blood vessels. That eases your heartbeat and relaxes your blood vessels. These
meds can cause dizziness, heart palpitations, swollen ankles, and constipation. Take them with
food or milk. Avoid grapefruit juice and alcohol because of possible interactions.

6 / 27

Other Medications Can Help

Vasodilators, alpha blockers, and central agonists also relax blood vessels. Side effects can
include dizziness, a fast heartbeat or heart palpitations, headaches, or diarrhea. Your doctor may
suggest them if other blood pressure medications don't work well enough or if you have another
condition.
6 / 27

Complementary Therapies Are an Option

Meditation can lower blood pressure by putting your body into a state of deep rest. Yoga, tai chi,
and deep breathing also help. Pair these relaxation techniques with other lifestyle changes, like
diet and exercise. Be aware that herbal therapies may conflict with other drugs you take. Some
herbs actually raise blood pressure. Tell your doctor if you take herbal or other dietary
supplements.
6 / 27

Living With High Blood Pressure

Hypertension is often a lifelong condition. It's important to take your medications and continue
to monitor your blood pressure. If you keep it under control, you can lower your odds of stroke,
heart disease, and kidney failure.

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Next Slideshow Title

Uses
This product is used to treat high blood pressure (hypertension). Lowering high blood pressure
helps prevent strokes, heart attacks, and kidney problems.

This product contains 3 medications: olmesartan, amlodipine, and hydrochlorothiazide.

Olmesartan is an angiotensin receptor blocker (ARB) and amlodipine is a calcium channel
blocker. They both work by relaxing blood vessels so blood can flow more easily.
Hydrochlorothiazide is called a "water pill" (diuretic) and causes your body to get rid of extra
salt and water by making more urine.

How to use Tribenzor

Read the Patient Information Leaflet if available from your pharmacist before you start taking
this medication and each time you get a refill. If you have any questions, ask your doctor or
pharmacist.

Take this medication by mouth with or without food as directed by your doctor, usually once
daily. If you take this drug too close to bedtime, you may need to wake up to urinate. Therefore,
it is best to take this medication at least 4 hours before your bedtime.

The dosage is based on your medical condition and response to treatment.

Take this medication regularly to get the most benefit from it. To help you remember, take it at
the same time each day. It is important to continue taking this medication even if you feel well.
Most people with high blood pressure do not feel sick. It may take up to 2 weeks before you get
the full benefit of this drug.

If you also take certain drugs to lower your cholesterol (bile acid-binding resins such as
cholestyramine, colestipol), take olmesartan/amlodipine/hydrochlorothiazide at least 4 hours
before or at least 4 to 6 hours after these medications.
Tell your doctor if your condition does not improve or if it worsens (your blood pressure
readings remain high or increase).

https://www.webmd.com/drugs/2/drug-154439/tribenzor-oral/details

TRIBENZOR works 3 different ways to help lower blood pressure

The reason why TRIBENZOR can help lower your high blood pressure is the way that it works.
TRIBENZOR combines 3 medicines. Each works to
lower blood pressure in a different way. TRIBENZOR has a specific medical agent designed to
block angiotensin II, a natural chemical in your body
that can raise blood pressure by causing blood vessels to tighten and narrow. By blocking this
chemical, TRIBENZOR widens and relaxes blood
vessels to help lower blood pressure.

Second, TRIBENZOR has a medicine that works directly on the specific muscles that tighten
and narrow blood vessels to relax and widen
vessels even more.

Finally, TRIBENZOR also has a medicine that helps reduce water content, since retaining too
much water can raise blood pressure.

Tribenzor

Generic Name: amlodipine, hydrochlorothiazide, and olmesartan (am LOE di peen, HYE droe
KLOR oh THYE a zide, and OL me SAR tan)
Brand Names: Tribenzor

Medically reviewed on March 7, 2018.

 Overview
 Side Effects
 Dosage
 Professional
 Interactions

More







What is Tribenzor?
Tribenzor contains a combination of amlodipine, hydrochlorothiazide, and olmesartan.
Amlodipine is a calcium channel blocker that relaxes (widens) blood vessels and improves blood
flow.

Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from
absorbing too much salt, which can cause fluid retention.

Olmesartan is an angiotensin II receptor antagonist that keeps blood vessels from narrowing,
which lowers blood pressure and improves blood flow.

Tribenzor is used to treat high blood pressure (hypertension).

Tribenzor is usually given after other blood pressure medicines have been tried without
successful treatment.

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14 Essential Health Screenings That All Men Should Consider

Important information
You should not take Tribenzor if you are allergic to sulfa drugs, or if you are unable to urinate.

Do not use Tribenzor if you are pregnant. If you become pregnant, stop taking this
medicine and tell your doctor right away.

If you have diabetes, do not use Tribenzor together with any medication that contains aliskiren
(Amturnide, Tekturna, Tekamlo).

Before taking this medicine

You should not use Tribenzor if you are allergic to amlodipine, hydrochlorothiazide, or
olmesartan, or:
  if you are allergic to any sulfa drug; or
 if you are unable to urinate.

If you have diabetes, do not use Tribenzor together with any medication that contains aliskiren
(Amturnide, Tekturna, Tekamlo).

You may also need to avoid taking this medicine with aliskiren if you have kidney disease.

To make sure Tribenzor is safe for you, tell your doctor if you have:

 kidney disease;
 liver disease;
 heart disease;
 an electrolyte imbalance (such as high levels of calcium, or low levels of potassium or
magnesium in your blood);
 low blood pressure;
 glaucoma;
 lupus;
 gout;
 diabetes; or
 a penicillin allergy.

Do not use if you are pregnant. If you become pregnant, stop taking Tribenzor and tell
your doctor right away. Olmesartan can cause injury or death to the unborn baby if you take the
medicine during your second or third trimester.

It is not known whether amlodipine, hydrochlorothiazide, and olmesartan passes into breast milk
or if it could harm a nursing baby. You should not breast-feed while using Tribenzor.

How should I take Tribenzor?

Tribenzor is usually taken once per day. Follow all directions on your prescription label. Your
doctor may occasionally change your dose to make sure you get the best results. Do not take this
medicine in larger or smaller amounts or for longer than recommended.

You may take Tribenzor with or without food.

Your chest pain may become worse when you first start taking this medicine or when your dose
is increased. Call your doctor if your chest pain is severe or ongoing.

Your blood pressure will need to be checked often.

Vomiting, diarrhea, or heavy sweating can cause you to become dehydrated. This can lead to
very low blood pressure, electrolyte disorders, or kidney failure while you are taking Tribenzor.
Drink plenty of water each day while you are taking this medication.
Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than
usual.

If you need surgery or medical tests, tell the surgeon ahead of time that you are using Tribenzor.

It may take up to 2 weeks before your blood pressure improves. Keep using Tribenzor as
directed, even if you feel well. High blood pressure often has no symptoms. You may need to use
blood pressure medication for the rest of your life.

Store at room temperature away from moisture and heat.

Tribenzor dosing information

Usual Adult Dose for Hypertension:

Amlodipine/hydrochlorothiazide/olmesartan is not indicated as initial treatment of hypertension.

It is indicated as replacement (substituted for its individually titrated components) or add-
on/switch therapy (to provide additional blood pressure lowering for patients not adequately
controlled on maximally tolerated, labeled, or usual doses of any two of the following
antihypertensive classes: angiotensin receptor blockers {ARBs}, calcium channel blockers
{CCBs}, and diuretics).

Initial dose: Dose orally once daily with or without food

Dosage may be increased after 2 weeks. The full blood pressure lowering effects are attained
within 2 weeks after a change in dose.

Maximum dose: amlodipine/hydrochlorothiazide/olmesartan 10/25/40 mg orally once daily

Usual Geriatric Dose for Hypertension:

Patients greater than or equal to 75 years: Initial dosage of the amlodipine component should be
2.5 mg, which is not available with the amlodipine/hydrochlorothiazide/olmesartan combination
product.

See also: Dosage Information (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your
next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
What should I avoid while taking Tribenzor?
Do not use potassium supplements or salt substitutes while you are taking this medicine, unless
your doctor has told you to.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of
this medicine.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly
and steady yourself to prevent a fall.

Tribenzor side effects

Get emergency medical help if you have signs of an allergic reaction to Tribenzor: hives;
difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

 worsening chest pain;

 a light-headed feeling, like you might pass out;
 an unusual skin rash;
 pain or burning when you urinate;
 severe or ongoing diarrhea with weight loss;
 blurred vision, tunnel vision, eye pain, or seeing halos around lights;
 signs of an electrolyte imbalance - dry mouth, increased thirst, lack of energy, confusion,
vomiting, muscle pain or weakness, fast heartbeats, feeling restless, little or no urine, or a
seizure (convulsions); or
 kidney problems - little or no urination, painful or difficult urination, swelling in your
feet or ankles, feeling tired or short of breath.

Common Tribenzor side effects may include:

 dizziness;
 headache, tired feeling;
 nausea, diarrhea;
 runny or stuffy nose, sore throat;
 swollen joints; or
 painful urination.

This is not a complete list of side effects and others may occur. Call your doctor for medical
advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

See also: Side effects (in more detail)

What other drugs will affect Tribenzor?

Many drugs can interact with Tribenzor. Not all possible interactions are listed here. Tell your
doctor about all your current medicines and any you start or stop using, especially:

 any other blood pressure medicines;

 lithium;
 a diuretic or "water pill";
 insulin or oral diabetes medicine;
 steroid medicine;
 vitamin or mineral supplements that contain potassium;
 a barbiturate - butabarbital, phenobarbital, secobarbital;
 cholesterol-lowering medicines - simvastatin, Zocor, and others;
 narcotic pain medicine - OxyContin, Vicodin, and others; or
 NSAIDs (nonsteroidal anti-inflammatory drugs) - aspirin, ibuprofen (Advil, Motrin),
naproxen (Aleve), and others.

This list is not complete and many other drugs can interact with Tribenzor. This includes
prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all
your medicines to any healthcare provider who treats you.

https://www.drugs.com/tribenzor.html

DESCRIPTION

Tribenzor provided as a tablet for oral administration, is a fixed combination of olmesartan

medoxomil (ARB), amlodipine (CCB), and hydrochlorothiazide (thiazide diuretic).

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the

gastrointestinal tract.

The olmesartan medoxomil component of Tribenzor is chemically described as 2,3-dihydroxy-2-

butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5ylphenyl)benzyl]imidazole-
5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C29H30N6O6.

The amlodipine besylate component of Tribenzor is chemically described as 3-ethyl-5methyl

(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-
3,5pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is
C20H25CIN2O5•C6H6O3S.

The hydrochlorothiazide component of Tribenzor is chemically described as 6-chloro-3,4-

dihydro-2H-1,2,4-benzo-thiazidiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is
C7H8CIN3O4S2.

The structural formula for olmesartan medoxomil is:

The structural formula for amlodipine besylate is:

The structural formula for hydrochlorothiazide is:

Tribenzor contains olmesartan medoxomil, a white to light yellowish-white powder or crystalline

powder, amlodipine besylate, a white to off-white crystalline powder, and hydrochlorothiazide, a
white or practically white, crystalline powder. The molecular weights of olmesartan medoxomil,
amlodipine besylate, and hydrochlorothiazide are 558.6, 567.1, and 297.7, respectively.
Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol.
Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol.
Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Each tablet of Tribenzor also contains the following inactive ingredients: silicified
microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium
stearate. The color coating contains polyvinyl alcohol, macrogol/polyethylene glycol 3350,
titanium dioxide, talc, iron oxide yellow (20 /5 /12.5 mg, 40 /5 /12.5 mg, 40 /5 /25 mg, 40 /10
/12.5 mg, and 40 /10 /25 mg tablets), iron oxide red (20 /5 /12.5 mg, 40 /10 /12.5 mg, and 40 /10
/25 mg tablets), and iron oxide black (20 /5 /12.5 mg tablets).

https://www.rxlist.com/tribenzor-drug.htm

Medication name
Generic name: Olmesartan/amlodipine/hydrochlorothiazide - Oral

Pronunciation: (OL-me-SAR-tan/am-LOE-di-peen/HYE-droe-KLOR-oh-THYE-a-zide)

Brand name(s): Tribenzor

Warning
This drug can cause serious (possibly fatal) harm to an unborn baby if used during pregnancy. Therefore,
it is important to prevent pregnancy while taking this medication. Consult your doctor for more details
and to discuss the use of reliable forms of birth control while taking this medication. If you are planning
pregnancy, become pregnant, or think you may be pregnant, tell your doctor right away.

Uses
This product is used to treat high blood pressure (hypertension). Lowering high blood pressure helps
prevent strokes, heart attacks, and kidney problems.This product contains 3 medications: olmesartan,
amlodipine, and hydrochlorothiazide. Olmesartan is an angiotensin receptor blocker (ARB) and
amlodipine is a calcium channel blocker. They both work by relaxing blood vessels so blood can flow
more easily. Hydrochlorothiazide is called a "water pill" (diuretic) and causes your body to get rid of
extra salt and water by making more urine.

How to use
Read the Patient Information Leaflet if available from your pharmacist before you start taking this
medication and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take
this medication by mouth with or without food as directed by your doctor, usually once daily. If you take
this drug too close to bedtime, you may need to wake up to urinate. Therefore, it is best to take this
medication at least 4 hours before your bedtime.The dosage is based on your medical condition and
response to treatment.Take this medication regularly to get the most benefit from it. To help you
remember, take it at the same time each day. It is important to continue taking this medication even if
you feel well. Most people with high blood pressure do not feel sick. It may take up to 2 weeks before
you get the full benefit of this drug.If you also take certain drugs to lower your cholesterol (bile acid-
binding resins such as cholestyramine, colestipol), take olmesartan/amlodipine/hydrochlorothiazide at
least 4 hours before or at least 4 to 6 hours after these medications.Tell your doctor if your condition
does not improve or if it worsens (your blood pressure readings remain high or increase).

Precautions
Before taking this product, tell your doctor or pharmacist if you are allergic to olmesartan, amlodipine,
or hydrochlorothiazide; or if you have any other allergies. This product may contain inactive ingredients,
which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before
using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease,
liver disease, severe loss of body water and minerals (dehydration), untreated mineral imbalance (such
as high/low potassium, low magnesium, high calcium), gout, lupus, a certain heart valve condition
(aortic stenosis).This drug may make you dizzy. Alcohol or marijuana can make you more dizzy. Do not
drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic
beverages. Talk to your doctor if you are using marijuana.Severe sweating, diarrhea, or vomiting can
increase the risk for lightheadedness or a serious loss of body water (dehydration). Report prolonged
diarrhea or vomiting to your doctor. To prevent dehydration, drink plenty of fluids unless your doctor
directs you otherwise.If you have diabetes, this product may affect your blood sugar. Check your blood
sugar regularly as directed and share the results with your doctor. Your doctor may need to adjust your
diabetes medication, exercise program, or diet.This product may affect your potassium levels. Before
using potassium supplements or salt substitutes that contain potassium, consult your doctor or
pharmacist.This medication may make you more sensitive to the sun. Limit your time in the sun. Avoid
tanning booths and sunlamps. Use sunscreen and wear protective clothing when outdoors. Tell your
doctor right away if you get sunburned or have skin blisters/redness.Before having surgery, tell your
doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs,
and herbal products).Older adults may be more sensitive to the side effects of this drug, especially
dizziness and change in the amount of urine (kidney problems).This medication is not recommended for
use during pregnancy. It may harm an unborn baby. Consult your doctor for more details. (See also
Warning section.)It is unknown if olmesartan passes into breast milk. Hydrochlorothiazide and
amlodipine pass into breast milk. Consult your doctor before breast-feeding.

Drug interactions
See also How to Use and Precautions sections.Drug interactions may change how your medications work
or increase your risk for serious side effects. This document does not contain all possible drug
interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and
herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage
of any medicines without your doctor's approval.Some products that may interact with this drug
include: aliskiren, cisapride, dofetilide, lithium, drugs that may increase the level of potassium in the
blood (such as ACE inhibitors including benazepril/lisinopril, birth control pills containing
drospirenone).Some products have ingredients that could raise your blood pressure. Tell your
pharmacist what products you are using, and ask how to use them safely (especially cough-and-cold
products, diet aids, or NSAIDs such as ibuprofen/naproxen).This product may interfere with certain
laboratory tests, possibly causing false test results. Make sure laboratory personnel and all your doctors
know you use this drug.
Side effects
Dizziness, lightheadedness, tiredness, or headache may occur as your body adjusts to the medication. If
any of these effects persist or worsen, tell your doctor or pharmacist promptly.To reduce the risk of
dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.Remember that
your doctor has prescribed this medication because he or she has judged that the benefit to you is
greater than the risk of side effects. Many people using this medication do not have serious side
effects.This product may cause a loss of too much body water (dehydration) and salt/minerals. Tell your
doctor right away if you have any symptoms of dehydration or mineral loss, including: extreme thirst,
very dry mouth, muscle cramps/weakness, fast/slow/irregular heartbeat, confusion.Tell your doctor
right away if you have any serious side effects, including: fainting, severe tiredness, big toe/joint pain,
swelling hands/ankles/feet, symptoms of a high potassium blood level (such as muscle weakness,
slow/irregular heartbeat), signs of kidney problems (such as change in the amount of urine),
severe/persistent diarrhea.Get medical help right away if you have any very serious side effects,
including: decrease in vision, eye pain.Some people who already have severe heart disease may rarely
develop worsening chest pain or a heart attack after starting this medication or increasing the dose. Get
medical help right away if you experience: worsening chest pain, symptoms of a heart attack (such as
chest/jaw/left arm pain, shortness of breath, unusual sweating).A very serious allergic reaction to this
drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic
reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness,
trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed
above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada -
Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-
866-234-2345.

Missed dose
If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the
missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

Overdose
If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911.
Otherwise, call a poison control center right away. US residents can call their local poison control center
at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose
may include: severe dizziness, fainting.

Notes
Do not share this medication with others.Lifestyle changes that may help this medication work better
include exercising, stopping smoking, and eating a low-cholesterol/low-fat diet. Consult your doctor for
more details.Laboratory and/or medical tests (including kidney function, blood mineral levels such as
potassium) should be performed periodically to monitor your progress or check for side effects.Have
your blood pressure checked regularly while taking this medication. Learn how to monitor your own
blood pressure at home, and share the results with your doctor.
Storage
Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all
medications away from children and pets.Do not flush medications down the toilet or pour them into a
drain unless instructed to do so. Properly discard this product when it is expired or no longer needed.
Consult your pharmacist or local waste disposal company.

https://healthy.kaiserpermanente.org/health/care/consumer/health-wellness/drugs-and-natural-
medicines/drug-encyclopedia/medicine-information/!ut/p/a1/hdBNb4IwGMDxz-
LBo_bBKpTdEDNWGOgyMlkvC2JXSWpLStX47QfOHczeemvz6z9PixgqEFPlsRalrbUqZb9n7lsOdDmfOwGAQ
2dAVzHJFoRMIMRojWLEhNSbC37dWdvcDWEIlVaWK2u42nLDzRAQk7oqJUcFV6NDe4O35iC4qs6jRhsrue1
1f0YXqJi5juc7__Jv8UBtMBGIGf7eDzA-
mG7APtFeGqfTaSy0FpKPK73vCj9c2enWouJWdg9mf_8JXMF9_PwJllOfAE3Dh5BmCUDkXcEqAEpSmDkQY
Beom-PESzMHoukVAKZPl0K0cqGzSZ68-
AkGmHyBX1YAqNmTM5bHR74m1qc1FcFg8AFaq7RR/dl5/d5/L2dBISEvZ0FBIS9nQSEh/

For Immediate Release

2010.07.27

Company name: DAIICHI SANKYO COMPANY, LIMITED

Representative: Joji Nakayama, President and CEO
(Code no.: 4568, First Section of Tokyo, Osaka and Nagoya Stock Exchanges)
Please address inquiries to Toshiaki Sai, Corporate Officer,
Vice President, Corporate Communications Department
Telephone: +81-3-6225-1126 (Public Relations)
+81-3-6225-1125 (Investor Relations)
http://www.daiichisankyo.com/

FDA APPROVES TRIBENZOR™, A NEW THREE-IN-ONE COMBINATION PRODUCT

FOR THE TREATMENT OF HIGH BLOOD PRESSURE

One in Three US Adults Have Hypertension and Many Are Uncontrolled on Two or
More Antihypertensive Medications

Parsippany, NJ – July 26, 2010 – Daiichi Sankyo, Inc. announced today that the U.S. Food and
Drug Administration (FDA) approved TRIBENZOR™ (olmesartan medoxomil, amlodipine,
hydrochlorothiazide), a new three-in-one combination product taken once-daily for the treatment
of hypertension in patients who are not adequately controlled on any two of the following
antihypertensive drug classes: angiotensin receptor blockers, calcium channel blockers and
diuretics. TRIBENZOR is not indicated for initial therapy.
Approximately 56 percent of patients taking current blood pressure-lowering therapies do not
reach current recommended blood pressure goal of <140/90 mm Hg or <130/80 mm Hg for
patients with diabetes, chronic renal disease, or chronic cardiovascular disease. More than two-
thirds of patients with high blood pressure will require two or more antihypertensive medications
in order to achieve goal blood pressure control.

A fixed-dose combination treatment, TRIBENZOR, simplifies dosing regimens, reduces pill

burden and has the potential to lower co-pays for patients that require three medications to keep
blood pressure within recommended levels. Research also shows that the use of fixed-dose
antihypertensive combination treatments may improve patient compliance as compared to taking
each medication separately.

“Generally speaking, it can be a struggle for some patients who need to take multi-pill regimens
to take their medications as prescribed,” said Joseph L. Izzo, MD, Chief of Medicine, Erie
County Medical Center, Buffalo, NY. “TRIBENZOR is a three-in-one pill that offers a simple,
convenient and consistently effective therapy for patients, and may be just what some patients
need to help bring their blood pressure to goal.”

TRIBENZOR combines three widely prescribed antihypertensive medications, each working in a

different way, to lower blood pressure. It combines the complementary actions of olmesartan
medoxomil (which blocks angiotensin II receptors), amlodipine (which inhibits the entrance of
calcium into the blood vessel walls), and hydrochlorothiazide (a diuretic which reduces water
volume in the blood). Together these three medications allow blood vessels to relax so that blood
can flow more easily.

After eight weeks of treatment, TRIBENZOR produced highly statistically significantly greater
reductions in both systolic and diastolic blood pressures compared to each of the three dual
combination therapies. According to the TRIBENZOR pivotal registration trial that included a
total of 2,492 patients with hypertension (mean baseline blood pressure 168.5/100.9 mm Hg), the
switch to TRIBENZOR 40/10/25 mg from each of the following three dual combination
therapies: (i) amlodipine/ hydrochlorothiazide 10/25 mg, (ii) olmesartan/hydrochlorothiazide
40/25 mg, and (iii) olmesartan/ amlodipine 40/10 mg, yielded a further mean reduction after
eight weeks of treatment in systolic blood pressure/diastolic blood pressure of 8.1/5.4 mm Hg,
7.6/5.4 mm Hg, and 8.4/4.5 mm Hg, respectively (P<0.0001 vs. each dual combination therapy).

“Our comprehensive cardiovascular product portfolio provides a variety of treatment options to

patients in a number of disease categories including hypertension, heart disease, diabetes and
cholesterol,” said Joseph P. Pieroni, President and CEO of Daiichi Sankyo, Inc. “Although
hypertension is a mature category, the differences among patients will continue to support the
need for differentiated products to achieve optimal results. The approval of TRIBENZOR shows
Daiichi Sankyo is committed to optimizing individual patient care.”

The most common adverse reactions (incidence ³2 percent) seen in clinical trials for
TRIBENZOR were dizziness, peripheral edema, headache, fatigue, nasopharyngitis, muscle
spasms, nausea, upper respiratory tract infection, diarrhea, urinary tract infection, and joint
swelling.
For more information about TRIBENZOR, including full prescribing information, please visit
www.tribenzor.com.

https://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/005716.html

Abstract
Obtaining the target blood pressure level by monotherapy can be challenging currently,
especially for the patients who are suffering from other diseases meanwhile. It is demonstrated
that a majority of hypertensive patients need two or more antihypertensive drugs to lower their
blood pressure effectively. Consequently, fixed-dose which can be defined as that several active
agents were combined in single pharmaceutical formulations appears to be a novel and
underlying power in overcoming the cardiovascular disease. Based on the analysis of some
literature and relative data from FDA, the advantages of fixed-dose combination are elucidated
and formulations of common dual, triple-combinations were summarized. Clinical practices
proved that fixed-dose combinations had many benefits comparing with single drug and separate
agents in terms of effects, convenience, compliance, and costs to a certain extent. From the
patients' perspective, the fixed-dose combination therapy will be increasingly utilized in blood
pressure control in the future.

 Next article in issue

Keywords
Hypertension therapy
Fixed-dose combination
Monotherapy

1. Introduction
Hypertension, a common cardiovascular disease, should take the most responsibility for the
morbidity and mortality caused by disease in the world every year. Hypertension is the primary
cause of cardiovascular disease (CVD) and deaths globally [1]. Report from the American Heart
Association showed that based on 2007–2010 data, 33.0% of US adults ≥20 years of age were in
hypertension [2]. According to an incomplete statistics in the year of 2001, the mortality induced
by hypertension takes the proportions of 12.5%–14.2% in the total fatalities in the world [3].
Although people have made substantial efforts in blood pressure control and got great
achievement accordingly, we also have a long way on the path to optimized blood pressure
control in the view of clinical practice. As early as 1999, WHO/ISH guidelines [4] have
recommended the monotherapy from six classes and fixed-dose with the definition of combining
two or more active agents in a single pharmaceutical formulation for the initial treatment of
hypertension. Statistics shows that only a minority of hypertension patients can obtain rational
blood pressure by monotherapy, that is to say, most patients need combination therapy to control
their disease. A survey on the trends in the use of antihypertensive agents in France from 2002 to
2012 supported the view mentioned above with the result that the prescriptions of fixed-dose
combinations increased from 19% to 30% [5]. Combination therapy can be two or more agents
administered separately or in a fixed-dose combination dosing, and the latter seems to be more
popular in clinical practice based on its advantages in terms of convenience, cost, compliance,
efficacy and aggressive effects.

2. Advantages of fixed-dose combinations

2.1. Monotherapy versus combination therapy

A number of clinical trials show that most hypertensive patients were unlikely to achieve a
normal blood pressure by taking single drug for a quite long term. Hence, doctors tend to give a
higher dose at the first time, however, high dose therapy usually only bring a modest
antihypertensive effect stepped with some severe side effects [6], supporting the perspective that
patients may not obtain more at a higher dose when a drug can't meet their needs at a
recommended dose [7].

2.2. Combination therapy with separate agents versus fixed-dose combinations

Combination therapy rises as an alternative for the patients who fail to lower their blood pressure
by monotherapy or who are in co-morbidities conditions. Combination therapy was classified
into two kinds: one is various drugs were prescribed separately; the other is drugs in fixed-dose
combinations. Undoubtedly, the former brought much trouble for the patients especially the
elders who were tired of taking a series of pills every day. But the fixed-dose combination can
solve this problem well by offering a relative simple regimen with fewer pills or once-daily
dosing. Anyway, patients suffering a chronic disease like hypertension prefer simple prescribing
program. Although fixed-dose formulations are still in suspicious by physicians in some areas, it
should be acknowledged that fixed-dose in combination is a natural trend in the history of
improving the blood pressure control. Some rational fixed-dose formulations have been widely
practiced in treating other disease such as type 2 diabetes mellitus (sitagliptin and metformin) [8]
and so on.

2.3. Fixed-dose combinations

When monotherapy was replaced by fixed-dose combination pills, one may ask whether fixed-
dose formulations can offer enough advantages to defeat traditional monotherapy. Fixed-dose
combination pill as a promising choice to hypertensive patients may have some potential
superiorities as follows:

Firstly, fixed-dose formulations usually can give patients some surprising effects comparing with
only taking anyone ingredient of the combinations. Fixed-dose combinations sometimes may
provide a synergistic effect in a perfect combination except the usual addictive effect. Since
drugs in formulations from different classes exert their effects based on individual mechanism
with different action sites and action time, fixed-dose combinations in hypertension have a
potential for a modest and long term action. Clinical trials demonstrated that angiotensin II
receptor blockers (ARB) such as valsartan can minimize the peripheral edema caused by a
calcium channel blocker such as amlodipine [9], which is in concert with the notion that
combining two antihypertensive agents from different classes in a formulation in many cases
may partly offset the adverse effects from each other. Besides, all the side effects from drugs in
combination can also be decreased because of the low dose. In summary, for rational fixed-dose
combinations, they may control hypertension well without additional side effects. Matthew R.
Weir et al. [10] conducted a titrate-to-goal study by switching patients who can't obtain target
blood pressure level on monotherapy to fixed-dose combinations of amlodipine and olmesartan
medoxomil ± hydrochlorothiazide with a satisfying result that the majority of subjects achieved
blood pressure goals without suffering severe adverse effects.

Next, there is a psychological problem must be taken into consideration in treating the chronic
disease. Since most hypertension patients are elders who have poor memory and can't act easily,
the convenience and compliance brought by therapy are especially important. A mete-analysis
based on a certain number of database demonstrated that fixed-dose combinations brought a
tremendous improvement in compliance and persistence for the treatment of hypertension [11].
Combination therapy with fixed-dose usually can exhibit its effects with fewer pills or once-daily
dosing formulation, then improve patients compliance and psychological state largely.

At last, cost may also be an obstacle in blood pressure control for part patients. Combination
therapy with fixed-dose may be less costly than the drugs administered separately, what's more,
combination therapy may reduce the prescribing cost with fewer medications and offer the poor
patients a lower overall health care costs. Statistical analysis shows that the cost of angiotensin-
converting enzyme inhibitors (ACEI)/ARB and thiazide diuretics administered in single
combination products can bring a cost-saving about $27–45 million per year for the Canadian
health care system than drugs administered separately [12]. Fig. 1 showed advantages of fixed-
dose combinations versus monotherapy and separate agents.

3.6. Triple fixed-dose combinations

When patients can't obtain target blood pressure with two drugs in combination, there are triple
fixed-dose combinations to choose. Three-in-one fixed-dose combination of reserpine, apresoline
and hydrochlorothiazide was the first triple fixed-dose formulation to be marketed in US, which
exhibit obvious advantages over placebo in trial. Tribenzor®, a triple fixed-dose combination
consisting of amlodipine, olmesartan medoxomil and hydrochlorothiazide, was approved by
FDA in July 2010, and trial certificated that the formulation can provide an effective and safe
hypertension control in obese patients [23] except the normal hypertensive patients. Researches
on the triple therapy exhibit that this prescription with less pills may improve adherence and
clinical outcomes without increasing cost [24]. There are also other triple fixed-dose
combinations arising such as Exforge HCT® (amlodipine + valsartan + hydrochlorothiazide;
Novartis Pharmaceuticals, East Hanover, NJ), and Amturnide®
(amlodipine + aliskiren + hydrochlorothiazide; Novartis), thus three-in-one combinations with
fixed-dose seem to have a huge market prospect in the near future.
4. Dosage form of fixed dose combination
There are many types of fixed dose combinations comprising oral, inhalation and parental on
market in many medical field [25]. Among the common types, oral dosage forms of tablet and
capsule provide simplified treatment regimens, greater patient convenience and compliance.
Formulation technologies such as multi-layer tablets, multiparticulate systems, active film
coating, and hot-melt granulation are developed in the design of formulation. Reviews of the
Physicians' Desk Reference (PDR) show that infections, cardiovascular, hormone, allergies and
pain are the top five medical areas for fixed dose combinations of oral dosage forms,
nevertheless hypertension treatment takes 80% in cardiovascular [26].

5. Precautions of the applications of fixed-dose combinations

In spite of proven benefits of fixed-dose combinations in treating hypertension, there are some
problems should be considered in applying them. Practically, some products of fixed-dose
combinations are widely used in the area of hypertension, however some others are unnecessary
and even brought negative effects in some cases [27]. Firstly, rational combinations of different
agents should be chose based on the complementary pharmaceutical mechanisms or the effective
prohibition of the counter-regulatory response [28]. Next, safety can be a key point to consider
during the application of fixed-dose combinations. The prescription of combination products
consisting of aliskiren (ALI) ACEI and ARB was warned of possible drawbacks by the FDA
when using then in patients with complications of diabetes or renal impairment [29].

6. Conclusion
When monotherapy encountered bottlenecks in treating hypertension, fixed-dose combinations
were recommended as an effective and safe regimen for initiating therapy especially for the
patients with complications. Each drug in perfect combination will exert its best effectiveness
with fewer side effects. Additionally, fixed-dose combinations also brought economical benefits
for patients with fewer medications compared with several drugs administered separately. Based
on the clinical practice and market research, fixed-dose formulations are becoming a promising
choice for hypertensive patients gradually.

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K. Clara, K. Koon, S. RangarajanPrevalence, awareness, treatment, and control of
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countries
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Alan S. Go, Dariush Mozaffarian, Véronique L. RogerHeart disease and stroke
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P.M. Kearney, M. Whelton, K. Reynolds, et al.Global burden of hypertension:
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from 2002 to 2012: FLAHS surveys
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T.C. FaganRemembering the lessons of basic pharmacology
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T. Stanton, J.L. ReidFixed dose combination therapy in the treatment of
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C. Reasner, L. Olansky, T.L. Seck, et al.The effect of initial therapy with the fixed-
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monotherapy in patients with type 2 diabetes mellitus
Diabetes Obes Metab, 13 (7) (2011), pp. 644-652
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B. Waeber, L.M. RuilopeAmlodipine and valsartan as components of a rational and
effective fixed-dose combination
Vasc Health Risk Manag, 5 (2009), pp. 165-174
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M.R. Weir, W.A. Hsueh, S.D. Nesbitt, et al.A titrate-to-goal study of switching
patients uncontrolled on antihypertensive monotherapy to fixed-dose combinations
of amlodipine and olmesartan medoxomil ± hydrochlorothiazide
J Clin Hypertens (Greenwich), 13 (2011), pp. 404-412
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A.K. Gupta, S. Arshad, N.R. PoulterCompliance, safety, and effectiveness of fixed-
dose combinations of antihypertensive agents: a meta-analysis
Hypertension, 55 (2010), pp. 399-407
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[12]
V. Stankus, B. Hemmelgarn, N. Campbell, et al.Reducing costs and improving
hypertension management
Can J Clin Pharmacol, 16 (1) (2009), pp. 151-155
[13]
I.G. Okpechi, H.S. Schoeman, B. Longo-Mbenza, et al.Achieving blood pressure goals
study in uncontrolled hypertensive patients treated with a fixed-dose combination of
ramipril/hydrochlorothiazide: the astral study
Cardiovasc J Afr, 22 (2) (2011), pp. 79-84
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K. Maeda, M. Adachi, A. KinoshitaEfficacy and safety of the losartan-
hydrochlorothiazide combination tablet in patients with hypertension uncontrolled
by angiotensin II receptor antagonist therapy: the Aichi Research on Combination
therapy for Hypertension (ARCH) study
Intern Med, 51 (2012), pp. 1167-1175
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A. Mugellini, V. NieswandtCandesartan plus hydrochlorothiazide: an overview of its
use and efficacy
Expert Opin Pharmacother, 13 (2012), pp. 2699-2709
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G. Marazzi, M. Volterrani, G. Caminiti, et al.Effectiveness of nebivolol and
hydrochlorothiazide association on blood pressure, glucose, and lipid metabolism in
hypertensive patients
Adv Ther, 27 (2010), pp. 655-664
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[17]
G.A. Macgregor, N.D. Markandu, R.A. BanksCaptopril in essential hypertension;
contrasting effects of adding hydrochlorothiazide or propranolol
Br Med J, 284 (1982), pp. 693-696
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Peter S. Sever, Franz H. MesserliHypertension management 2011: optimal
combination therapy
Eur Heart J, 32 (2011), pp. 2499-2506
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[19]
C.G. Egan, R. PontremoliRole of the fixed-dose combination lercanidipine–enalapril
in renal protection
J Nephrol, 24 (2011), pp. 428-437
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[20]
 S.K. Sharma, P. Ruggenenti, G. RemuzziManaging hypertension in diabetic patients –
focus on trandolapril/verapamil combination
Vasc Health Risk Manag, 3 (2007), pp. 453-465
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[21]
P. Bramlage, W.P. Wolf, T. Stuhr, et al.Effectiveness and tolerability of a fixed-dose
combination of olmesartan and amlodipine in clinical practice
Vasc Health Risk Manag, 6 (2010), pp. 803-811
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[22]
J.M. Flack, D.A. Calhoun, L. Satlin, et al.Efficacy and safety of initial combination
therapy with amlodipine/valsartan compared with amlodipine monotherapy in
black patients with stage 2 hypertension: the EX-STAND study
J Hum Hypertens, 23 (2009), pp. 479-489
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[23]
W.A. Hsueh, A. Shojaee, J.F. Maa, et al.Efficacy of amlodipine/olmesartan
medoxomil ± HCTZ in obese patients uncontrolled on antihypertensive
monotherapy
Curr Med Res Opin, 28 (2012), pp. 1809-1818
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[24]
S. Panjabi, M. Lacey, T. BancroftTreatment adherence, clinical outcomes, and
economics of triple-drug therapy in hypertensive patients
J Am Soc Hypertens, 7 (1) (2013), pp. 46-60
ArticleDownload PDFView Record in Scopus
[25]
Y. Luo, Y. Zu, S. AhmadChallenges of fixed dose combination product development
Am Pharm Rev, 10 (2007), pp. 120-126
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[26]
M. PudipeddiBiopharmaceutical challenges in development of fixed-dose
combination
Eastern Pharmaceutical Technology Meeting. Somerset, New Jersey, USA (2010)
[27]
S. TaddeiFixed-dose combination therapy in hypertension
High Blood Press Cardiovasc Prev, 19 (2) (2012), pp. 55-57
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[28]
M. Gorostidi, A. SierraCombination therapy in hypertension
Adv Ther, 30 (2013), pp. 320-336
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[29]
Benjamin J. Epstein, Niren K. Shah, Nancy L. Borja-HartManagement of hypertension
with fixed-dose triple-combination treatments
Ther Adv Cardiovasc Dis, 7 (2013), pp. 246-259
 CrossRefView Record in Scopus

Teva Announces Approval of Generic Tribenzor® in the United States

November 07, 2016 09:00 AM Eastern Standard Time

JERUSALEM--(BUSINESS WIRE)--Teva Pharmaceutical Industries Ltd., (NYSE and

TASE:TEVA) today announced approval of generic Tribenzor®1(olmesartan medoxomil,
amlodipine and hydrochlorothiazide) tablets in the U.S. and is in the final stages of launch
preparation. Teva also recently received approval and launched generic Azor®2 (amlodipine and
olmesartan medoxomil) tablets in the U.S. These products enhance Teva’s antihypertensive
portfolio.

Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets are a combination of an

angiotensin II

receptor blocker, a dihydropyridine calcium channel blocker and a thiazide diuretic indicated for
the treatment of hypertension, to lower blood pressure.

Amlodipine and olmesartan medoxomil tablets are a dihydropyridine calcium channel blocker
and angiotensin II receptor blocker combination product indicated for the treatment of
hypertension, alone or with other antihypertensive agents, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily
strokes and myocardial infarctions. Many patients will require more than one drug to achieve
their blood pressure goals.

Teva is committed to strengthening its generics business through continued investment in

complex, high-quality products. With nearly 600 generic medicines available, Teva has the
largest portfolio of FDA-approved generic products on the market. These products enhance
Teva’s already comprehensive product portfolio.

Teva has over 300 product registrations pending FDA approval and holds the leading position in
first-to-file opportunities, with over 100 pending first-to-files in the U.S. Currently, one in six
generic prescriptions dispensed in the U.S. is filled with a Teva generic product.

Tribenzor® had annual sales of approximately $240 million in the U.S. and Azor® had annual
sales of approximately $354.1 million in the U.S., according to IMS data as of August 2016.

About Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide Tablets

Olmesartan medoxomil, amlodipine, hydrochlorothiazide tablets are indicated for the treatment
of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and
nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have
been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic
classes including the class to which this drug principally belongs. There are no controlled trials
demonstrating risk reduction with olmesartan medoxomil, amlodipine, hydrochlorothiazide
tablets.

Control of high blood pressure should be part of comprehensive cardiovascular risk

management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake.

Olmesartan medoxomil, amlodipine, hydrochlorothiazide tablets are not indicated for the initial
therapy of hypertension.

Important Safety Information

WARNING: Fetal Toxicity. When pregnancy is detected, discontinue olmesartan medoxomil,

amlodipine, and hydrochlorothiazide tablets as soon as possible. Drugs that act directly on the
renin-angiotensin system can cause injury and death to the developing fetus.

Because of the hydrochlorothiazide component, olmesartan medoxomil, amlodipine, and

hydrochlorothiazide tablets are contraindicated in patients with anuria or hypersensitivity to
other sulfonamide-derived drugs. Do not coadminister aliskiren with olmesartan medoxomil,
amlodipine, and hydrochlorothiazide tablets in patients with diabetes.

Other serious adverse reactions that may occur include: hypotension, particularly in volume- or
salt-depleted patients; increased angina and/or myocardial infarction; impaired renal function;
electrolyte and metabolic imbalances; hypersensitivity reactions; exacerbation or activation of
systemic lupus erythematosus; acute transient myopia and acute angle-closure glaucoma; sprue-
like enteropathy; and vasodilation. Increased drug exposure may occur in patients with hepatic
impairment. Avoid use in patients with severely impaired renal or hepatic function.

Most common adverse reactions (incidence ≥ 2%) in a controlled clinical trial: dizziness,
peripheral edema, headache, fatigue, nasopharyngitis, muscle spasms, nausea, upper respiratory
tract infection, diarrhea, urinary tract infection, and joint swelling.

For more information, please see accompanying full Prescribing Information, including Boxed
Warning.

About Amlodipine and Olmesartan Medoxomil Tablets

Amlodipine and olmesartan medoxomil tablets are indicated for the treatment of hypertension,
alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure
reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial
infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a
wide variety of pharmacologic classes including the class to which this drug principally belongs.
There are no controlled trials demonstrating risk reduction with amlodipine and olmesartan
medoxomil tablets.
Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake.

Amlodipine and olmesartan medoxomil tablets may also be used as initial therapy in patients
who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.

Important Safety Information

WARNING: Fetal Toxicity. When pregnancy is detected, discontinue amlodipine and olmesartan
medoxomil tablets as soon as possible. Drugs that act directly on the renin-angiotensin system
can cause injury and death to the developing fetus.

Do not coadminister aliskiren with in patients with diabetes. The 10 mg/20 mg amlodipine and
olmesartan medoxomil tablets contain FD&C Yellow No. 5 (tartrazine) which may cause
allergic-type reactions (including bronchial asthma) in certain susceptible persons and frequently
seen in patients who also have aspirin hypersensitivity.

Other serious adverse reactions that may occur include: hypotension, particularly in volume- or
salt-depleted patients; vasodilation; increased angina and/or myocardial infarction; impaired
renal function; and sprue-like enteropathy. Increased drug exposure may occur in patients with
hepatic impairment Initial therapy with amlodipine and olmesartan medoxomil tablets is not
recommended in hepatically impaired patients or patients ≥ 75 years old.

Most common adverse reaction in a controlled clinical trial (incidence ≥ 3%): edema.

For more information, please see accompanying full Prescribing Information, including Boxed
Warning.

About Teva

Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a leading global
pharmaceutical company that delivers high-quality, patient-centric healthcare solutions used by
millions of patients every day. Headquartered in Israel, Teva is the world’s largest generic
medicines producer, leveraging its portfolio of more than 1,800 molecules to produce a wide
range of generic products in nearly every therapeutic area. In specialty medicines, Teva has a
world-leading position in innovative treatments for disorders of the central nervous system,
including pain, as well as a strong portfolio of respiratory products. Teva integrates its generics
and specialty capabilities in its global research and development division to create new ways of
addressing unmet patient needs by combining drug development capabilities with devices,
services and technologies. Teva's net revenues in 2015 amounted to $19.7 billion. For more
information, visit www.tevapharm.com.

Teva's Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of
1995:
This release contains forward-looking statements, which are based on management’s current
beliefs and expectations and involve a number of known and unknown risks and uncertainties
that could cause our future results, performance or achievements to differ significantly from the
results, performance or achievements expressed or implied by such forward-looking statements.
Important factors that could cause or contribute to such differences include risks relating to: our
ability to develop and commercialize additional pharmaceutical products; competition for our
specialty products, especially Copaxone® (which faces competition from orally-administered
alternatives and a generic version); our ability to integrate Allergan plc’s worldwide generic
pharmaceuticals business (“Actavis Generics”) and to realize the anticipated benefits of the
acquisition (and the timing of realizing such benefits); the fact that following the consummation
of the Actavis Generics acquisition, we are dependent to a much larger extent than previously on
our generic pharmaceutical business; potential restrictions on our ability to engage in additional
transactions or incur additional indebtedness as a result of the substantial amount of debt
incurred to finance the Actavis Generics acquisition; the fact that for a period of time following
the Actavis Generics acquisition, we will have significantly less cash on hand than previously,
which could adversely affect our ability to grow; the possibility of material fines, penalties and
other sanctions and other adverse consequences arising out of our ongoing FCPA investigations
and related matters; our ability to achieve expected results from investments in our pipeline of
specialty and other products; our ability to identify and successfully bid for suitable acquisition
targets or licensing opportunities, or to consummate and integrate acquisitions; the extent to
which any manufacturing or quality control problems damage our reputation for quality
production and require costly remediation; increased government scrutiny in both the U.S. and
Europe of our patent settlement agreements; our exposure to currency fluctuations and
restrictions as well as credit risks; the effectiveness of our patents, confidentiality agreements
and other measures to protect the intellectual property rights of our specialty medicines; the
effects of reforms in healthcare regulation and pharmaceutical pricing, reimbursement and
coverage; competition for our generic products, both from other pharmaceutical companies and
as a result of increased governmental pricing pressures; governmental investigations into sales
and marketing practices, particularly for our specialty pharmaceutical products; adverse effects
of political or economic instability, major hostilities or acts of terrorism on our significant
worldwide operations; interruptions in our supply chain or problems with internal or third-party
information technology systems that adversely affect our complex manufacturing processes;
significant disruptions of our information technology systems or breaches of our data security;
competition for our specialty pharmaceutical businesses from companies with greater resources
and capabilities; the impact of continuing consolidation of our distributors and customers;
decreased opportunities to obtain U.S. market exclusivity for significant new generic products;
potential liability in the U.S., Europe and other markets for sales of generic products prior to a
final resolution of outstanding patent litigation; our potential exposure to product liability claims
that are not covered by insurance; any failure to recruit or retain key personnel, or to attract
additional executive and managerial talent; any failures to comply with complex Medicare and
Medicaid reporting and payment obligations; significant impairment charges relating to
intangible assets, goodwill and property, plant and equipment; the effects of increased leverage
and our resulting reliance on access to the capital markets; potentially significant increases in tax
liabilities; the effect on our overall effective tax rate of the termination or expiration of
governmental programs or tax benefits, or of a change in our business; variations in patent laws
that may adversely affect our ability to manufacture our products in the most efficient manner;
environmental risks; and other factors that are discussed in our Annual Report on Form 20-F for
the year ended December 31, 2015 and in our other filings with the U.S. Securities and Exchange
Commission (the "SEC"). Forward-looking statements speak only as of the date on which they
are made and we assume no obligation to update or revise any forward-looking statements or
other information, whether as a result of new information, future events or otherwise.
1
Tribenzor® is a registered trademark of Daiichi Sankyo Company.
2
Azor® is a registered trademark of Daiichi Sankyo, Inc.

Contacts
IR Contacts:
Kevin C. Mannix, 215-591-8912

Abstract
Hypertensive patients whose blood pressures are more than 20 mmHg above their goal will often
require three or more medications. Careful selection of medications whose actions are
complementary or have an improved adverse effect profile when combined can affect not only
the blood pressure but also patient acceptance, thus improving persistence in taking the
medications as prescribed. This review will highlight the three single-pill three-drug
combinations currently available in the US and will address their efficacy, safety, and
tolerability. All three include the dihydropyridine calcium-channel blocker, amlodipine, and the
thiazide diuretic, hydrochlorothiazide. They each contain a different renin–angiotensin system
blocker. One includes the angiotensin-receptor blocker, olmesartan, while another contains
valsartan. The third combination includes the direct renin inhibitor, aliskiren. All three fixed-
dose combinations (FDC) at maximum doses of each component lowers the blood pressure of
patients with stage II hypertension by 37 to 40 mmHg systolic and 21 to 25 mmHg diastolic,
which is superior to any two of the components that comprise the three-drug FDC. These drugs
are effective in males and females, the elderly, diabetics, minority populations, and patients with
metabolic syndrome. Triple-drug FDCs are well tolerated with a low incidence of adverse
effects, the most common being peripheral edema related to amlodipine. Extrapolation of data
from two-drug FDC suggests that medication compliance (adherence and persistence) should be
better with these FDCs than with the individual components taken as separate medications,
although additional studies are necessary to confirm this.

Keywords: calcium-channel blockers, hypertension, patient tolerability, renin-angiotensin

system antagonists, safety, triple-drug combinations

Introduction
Hypertension is the most prevalent modifiable risk factor for cardiovascular and cerebrovascular
morbidity and mortality. An estimated 30% of the adult population in the United States has
hypertension,1 and a similar prevalence worldwide represents a global health problem.2 The risk
of a cardiovascular or cerebrovascular event is closely linked to the magnitude of blood pressure
(BP) increase3 and is exaggerated at any level of blood pressure in individuals who also have
diabetes mellitus, chronic kidney disease, or coronary artery disease.4–9 A higher BP at the time
of diagnosis indicates that he or she is more likely to require two or more drugs to achieve BP
control. More drugs will likely be required for individuals with coronary artery disease, chronic
kidney disease, or diabetes for whom goals lower than 140/90 mmHg have been
recommended.6,10 Furthermore, there is growing evidence from randomized clinical trials such
as VALUE (Valsartan Antihypertensive Long-Term Use Evaluation),11 Syst-Eur (Systolic
Hypertension in Europe),12 and SHEP (Systolic Hypertension in the Elderly Program)13 to
support the benefit of rapid BP reduction, which can be achieved more effectively by initiating
combination therapy early rather than by sequentially adding medications.

Egan et al recently reported that the number of subjects who met their definition for both treated
but uncontrolled and apparent treatment-resistant hypertension increased during each of three
National Health and Nutrition Examination Survey periods between 1988 and 2008.14 These are
hypertensive subjects that are likely to benefit from at least two and typically three or more
carefully selected antihypertensive drugs with complementary mechanisms of action.15,16

The true incidence of stage 2 hypertension in the US is not well documented because in large
epidemiological surveys, it is often difficult, if not impossible, to obtain BP readings in subjects
who are taking no medications. However, it is generally accepted by hypertension experts that an
individual with a systolic blood pressure (SBP) 20 mmHg above his or her goal will require at
least two drugs to achieve that goal. Anecdotal experience among physicians who treat many
hypertensive patients suggests that a patient is likely to require one antihypertensive drug for
every 10 mmHg above goal BP. Thus, diabetics, whose average systolic pressure is 170 mmHg,
may require as many as four carefully chosen and complementary antihypertensive drugs to
reduce their SBP to 130 mmHg.

Convergence of several concepts in antihypertensive therapy strongly supports the initiation of

drug treatment of hypertension with two drugs with complementary mechanisms of action rather
than starting with a single drug and adding or substituting a second drug at a later time. There are
currently three clinical trials measuring outcomes for which post-hoc analysis of their results
support this approach. Cardiovascular events occurred less frequently among patients whose BP
was lowered to goal within 6 months of initiating therapy compared to those who required a
longer period of time to achieve that goal in the VALUE trial.11,17 Similar observations were
made during post-hoc analysis of event data from Syst-Eur12,18 and SHEP.13,19

Essential hypertension is defined in the Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines10 as a BP reading of
≥140/90 mmHg in nondiabetic patients or ≥130/80 mmHg in those diagnosed with diabetes
mellitus and/or receiving antihypertensive medications, is the most important risk factor in
cardiovascular and cerebrovascular morbidity and mortality worldwide, contributing to
approximately one-half and two-thirds of these diagnoses respectively; an estimated 29% of the
US population carries a diagnosis of hypertension.1 For every increase of 20 mmHg and 10
mmHg in SBP and diastolic BP (DBP) respectively, cardiovascular mortality risk approximately
doubles from an average pressure of 115/75 mmHg.3 Despite the use of multiple drug classes,
success in achieving these absolute goals in the majority has been difficult. Moreover, drug
treatment requirements to achieve goal in the ALLHAT trial20,21 echoed the observation in the
Hypertension Optimal Treatment trial;22 nearly one-half required dual therapy, and
approximately one-fifth required three or more drugs. In 1997, the JNC-VI recommended
combination therapy as a potential choice for treating hypertension refractory to monotherapy.23
Based on these findings, Gradman et al published the American Society of Hypertension position
paper on combination therapy. Given the significant patient population that remains uncontrolled
on dual-drug therapy, three-drug therapy is emerging as a possible alternative.

Historical perspective on single-pill triple-drug combination

therapy
The first triple-drug single-pill combination to be marketed in the US combined reserpine,
apresoline, and hydrochlorothiazide. Marketed in the 1950s under the brand name Ser-Ap-Es®,
elements of this combination were administered to patients in the treatment arm of the first
randomized, placebo-controlled VA Cooperative Trial of patients with severe hypertension.24
Compared to thousands of hypertensive patients enrolled in recent clinical trials of
cardiovascular outcomes in patients receiving two different treatment regimens, a cohort of only
143 subjects, 70 given placebo and 73 given active treatment, with DBPs between 115 and 129
mmHg, showed a significant survival benefit within 18 months in favor of the active treatment
group in this trial.

Despite the publication of compelling rational arguments in favor of combination therapy by

Dollery and others in the 1970s,25 the use of multidrug single-pill combination therapy for
treating most hypertensive patients fell out of favor as the “stepped care” approach to treatment
became the favored paradigm of hypertension experts; this approach was recommended in the
guidelines published in JNC III–IV.26,27 The prevailing philosophy in the 1980s was that this
approach would reduce overtreatment with consequent hypotension and associated comorbidities
and avoid confusion about which of the components in a multidrug combination was linked to a
particular adverse effect. In the academic community, most hypertension experts eschewed
combination therapy, labeling it as “unnecessary polypharmacy.”28

Paradigm shift to combination therapy

The results of clinical trials over the past decade have alerted practicing physicians to the
practical necessity of combination therapy to achieve and maintain goal BPs for most patients
with hypertension, particularly the >95% who have other cardiovascular risk factors.29 For
example, although approximately 75% of older patients with high cardiovascular risk in the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial30 randomized to
one of four monotherapies (chlorthalidone, amlodipine, lisinopril, or doxazosin) showed a blood
pressure < 140/90 mmHg after the first 6 months of treatment, by the end of study follow-up
averaging 4.9 years only 30% remained controlled on a single drug, while 70% required at least
two drugs and approximately 25% were taking 3 or more drugs.20 Similarly, by the time the
Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)
which compared atenolol ± bendroflumethiazide with amlodipine ± perindopril treatment
regimens, was stopped after a median follow-up of 5.5 years, 78% of controlled hypertensive
patients were taking at least two drugs to maintain BP control.31 In a meta-analysis of 354
randomized, placebo-controlled trials by Law et al, low-dose combinations from the five major
classes of antihypertensive drugs (beta-blockers, diuretics, calcium-channel blockers,
angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers) were more
effective in reducing BP and exhibited fewer adverse effects than monotherapy.32 Although
many hypertensive patients can achieve their goal BP with two-drug therapy, there is still a need
for effective and safe three-drug regimens for a significant minority of hypertensive patients
whose BP is not controlled by two drugs alone.

Triple therapy: rational treatment for hypertension

uncontrolled by two drugs
Three three-drug, single-pill formulations, Tribenzor® (amlodipine + olmesartan +
hydrochlorothiazide; Daiichi Sankyo, Inc., Parsippany, NJ), Exforge HCT® (amlodipine +
valsartan + hydrochlorothiazide; Novartis Pharmaceuticals, East Hanover, NJ), and Amturnide®
(amlodipine + aliskiren + hydrochlorothiazide; Novartis) are currently approved by the US Food
and Drug Administration (FDA) for treating hypertensive patients whose BPs are not controlled
by two drugs in the same class as any of the individual components. The efficacy of each of
these combinations in reducing BP was evaluated in randomized controlled trials against
corresponding combination dual therapy.

The TRINITY (TRIple therapy with olmesartan medoxomil, amlodipine, and

hydrochlorothiazide in hyperteNsIve patienTs StudY) trial33 screened a cohort of 6724
potentially eligible hypertensive patients with seated mean BPs of ≥140/90 on therapy or
≥160/100 on no therapy. Of those screened, 2494 were randomized to one of the following four
treatment regimens: olmesartan (OM) 40 mg + amlodipine (AML) 10 mg, n = 628; OM 40 mg +
hydrochlorothiazide (HCT) 25 mg, n = 637; AML 10 mg + HCT 25 mg, n = 600; OM 40 + AML
10 mg + HCT 25 mg, n = 627. To ameliorate the risk of excessive hypotension, a dual-therapy
titration scheme was employed for the first 4 weeks of the trial. Treatment then continued for the
final 8 weeks on the final combination therapy to which the patient had been assigned. Patients
with either active or recent comorbidities such as cerebrovascular or coronary artery disease,
congestive heart failure New York Heart Association stage III or IV, stage IV chronic kidney
disease, secondary hypertension, chronic atrial fibrillation, heart block worse than 1st degree,
symptomatic resting bradycardia, uncontrolled diabetes mellitus (glycosylated hemoglobin >
9%), or abnormal laboratory values thought to be clinically significant by the investigator, were
excluded.

The baseline demographics of the patients in the four treatment groups were similar. The mean
ages were 54.7 to 55.9 years, 51% to 55.7% were male, 28.8% to 32% were black, 61.7% to
63.5% were obese with a mean body mass index ranging from 33 to 33.2 kg/m2, 15.3% to 15.9%
were diabetic, 20% to 29% had chronic kidney disease (creatinine clearance ≥ 30 but ≤ 60
mL/min), and 55% to 61% had chronic stable cardiovascular disease. Baseline seated SBP
(SeSBP) was 167.9 to 169 mmHg and seated DBP (SeDBP) was 100.7 to 101.3 mmHg. More
than 95% of patients in each group met the JNC 7 criteria10 for stage 2 hypertension (≥160/≥100
mmHg) at baseline. After 12 weeks of therapy, the group receiving triple therapy with OM +
AML + HCT achieved greater least squares mean reductions in both SeSBP (−37.1 mmHg) and
SeDBP (−21.8 mmHg) than in the dual-therapy groups (SeSBP −27.5 to −30.0 mmHg and
SeDBP −15.1 to 18.0 mmHg) (Table 1). The proportion of patients reaching a target BP of
<140/90 was also higher in the triple-therapy group (69.9%) than in the dual-therapy groups
(41.1% to 53.4%). Patient persistence in taking study medication was monitored by pill count at
each visit; with adherence rates ranging from 98% to 98.5% across all treatment groups.

rinity subgroup analyses

Several prespecified subgroup analyses of the Trinity trial data have been conducted and the
results either published or reported in abstract form. As noted previously, approximately 15.5%
(387/2492) of the Trinity Study cohort had diabetes mellitus and the proportion of diabetics
randomized to each of the 4 treatment groups was comparable (91–99 subjects).34 The least
squares mean reduction in SeSBP and SeDBP for patients receiving triple-therapy was similar in
diabetics and non-diabetics (−37.9/−22.0 vs −38.5/−21.5, respectively) and significantly greater
than SeSBP and SeDBP decreases noted in each of the dual-therapy groups. The discrepancy in
SeSBP and SeDBP between diabetics and non-diabetics was greatest (−26.7/−14.7 vs
−31.8/−17.0) in the group randomized to OM 40/HCT 25. A slightly smaller percentage of
diabetic patients (64.2%) in the triple-therapy group achieved a target BP of <140/90 than
nondiabetic patients (70.9%), but the proportion of diabetics and nondiabetics achieving a BP of
<130/80 was identical (41.8%).

Efficacy and safety in each of the four treatment groups was analyzed by age and sex and the
results were reported in abstract form. Approximately 19% of the patients were >65 years old
and there were slightly more men (1318) than women (1174). The same pattern of superior
SeSBP and SeDBP reduction with triple therapy compared to each of the dual therapy arms was
present irrespective of either age or sex.35 As has been demonstrated in numerous previous
studies, the extent of BP reduction obtained with either triple- or dual-therapy in the Trinity trial
was greatest in those who received the most antihypertensive medications, and in those who had
the highest BP values at baseline.36 The least squares mean seated BP responses of black (n =
740, B) and nonblack (n = 1718, NB) patients to either two-drug (OM/ AML, AML/HCT or
OM/HCT) or to three-drug (OM/AML/ HCT) therapy were not significantly different, although
the magnitude of the BP reduction was significantly greater for three-drug therapy (B =
37.1/20.8, NB = 38.9/21.8 mmHg) than for two-drug treatment (B = 28.9 to 30.7/14.5 to 17.0
mmHg, NB = 28.6 to 31.9/14.8 to 18.1 mmHg).37 TEAEs were comparable in black and
nonblack patients across all four treatment groups.

A Trinity trial ambulatory blood pressure substudy evaluated 24-hour ambulatory blood
pressures (ABPM) at baseline and after 12 weeks of therapy in 440 patients from the larger 2492
patient cohort who were randomized to either the triple-therapy combination or one of the three
dual-therapy combination groups.38 Baseline demographic characteristics of the ABPM
substudy cohort had a more varied representation of males, ethnic groups, and diabetics than the
full study cohort but very similar SeSBP and SeDBP across the substudy groups and compared
to the treatment group distribution in the full study cohort. The ABPM results confirmed that
triple-drug combination was more effective in lowering 24-hour mean BP (−30.3/−18.0 mmHg)
than each of the dual-therapy combinations (−18.5 to 23.9 mmHg/−10.7 to −14.5 mmHg). There
was also greater BP reduction during the daytime (8 am to 4 pm) and nighttime (10 pm to 6 am)
with the triple-drug combination. Furthermore, significantly more patients taking the three-drug
combination achieved 24-hour (86.5%), daytime (67.3%), and nighttime (93.3%) ambulatory BP
targets of <130/80 mmHg than those on any of the two-drug component combinations (range
41.9% to 81.1%).

The antihypertensive efficacy and safety of the Exforge- HCT® triple-therapy combination of
valsartan 320 mg (V) + amlodipine 10 mg (AML) + hydrochlorothiazide 25 mg (HCT) was
compared against its dual therapy components at corresponding doses (VAL + AML, AML +
HCT, VAL + HCT) in a randomized, double-blind clinical trial.39 Of the 4285 patients with
moderate to severe hypertension (mean SeSBP/SeDBP ≥ 145/≥ 100 mmHg) who were enrolled
in the trial, 2271 were randomized to one of the four drug treatment groups, and 2060 completed
the 9 weeks of active treatment. To allow patient adaptation to full dose triple-therapy, half the
dose of each drug in either the triple-therapy or dual-therapy component combinations were
administered for the first 2 weeks of active therapy, then full doses were given from weeks 3 to
9. Drug doses for each of the four treatment groups were AML10/HCT 25, VAL320/HCT 25,
AML10/VAL320, and AML10/VAL320/HCT 25. Of the 2271 patients randomized to the
double-blind phase of the trial, 583 were assigned to AML/VAL/HCT, 559 to VAL/HCT, 568 to
AML/VAL, and 561 to AML/HCT. Most demographic characteristics, including sex distribution
(55% men), age (mean = 53 years old), proportion that were ≥ 65 years old (14%), diabetes
(10%), and ethnicity (17% black and 26% Hispanic) were similar across all treatment groups.
Least squares mean SeSBP/SeDBP for the entire cohort was 169.9/106.5 mmHg. The reduction
in SeSBP/SeDBP from baseline to the end of the study in the triple-therapy group was
significantly greater (−39.7/−24.7 mmHg) compared to values in the each of the component
dual-therapy groups (−31.5 to −33.5/−19.5 to 21.5 mmHg) (Table 1). Most of the decline in BP
had occurred by week 5 of active treatment in all groups. The proportion of patients achieving
target BP goals was not reported. A 24-hour ABPM study was conducted in a 283-patient subset
of the larger cohort and the results confirmed the superiority of the triple-drug combination in
reducing BP more than each of the dual-component drug combinations throughout the entire 24-
hour monitoring period.40

The third triple-drug single-pill combination approved in the US for treating patients whose BPs
are not controlled by any two of its components is a combination of the direct renin inhibitor,
aliskiren (ALI), combined with amlodipine and HCT (ALI/AML/HCT), which is marketed in the
US as Amturnide®. Although this three-drug combination was approved by the FDA in
December of 2010, limited information about this combination appears in peer-reviewed
literature. The data reported in this review from the largest trial of this three-drug combination
versus its individual two-drug components (NCT00765674) are derived from the
ClinicalTrials.gov website.41 The efficacy and safety of ALI/ AML/HCT in patients with
moderate to severe hypertension was examined in 1191 subjects randomized to receive ALI/
AML (287 subjects), ALI/HCT (298 subjects), AML/HCT (296 subjects), and ALI/AML/HCT
(310 subjects). The mean age of the participants ranged from 54.4 to 55.4 years across the four
groups; 19% were age 65 or older and 60% were male. Patients in each group were given half
the maximum doses for 4 weeks and then force-titrated to ALI 300 mg/AML 10 mg, ALI 300
mg/HCT 25 mg, ALM 10 mg/HCT 25 mg, and ALI 300 mg/AML 10 mg/HTC 25 mg for the
remaining 4 weeks of the trial. The mean seated office BP was not provided. The reduction in
mean seated office systolic/diastolic BP from baseline to week 8 in group order as listed above
were −31/−18, −28/−14, −31/−17, and −38/−21 mmHg, respectively (Table 1). Using an
arbitrary BP control value of <140/<90 mmHg for all participants, including diabetics, 41%,
33%, 39%, and 62% of patients in each of the four groups were controlled at the end of 8 weeks
of active treatment, respectively. A subset of 576 patients had evaluable 24-hour ABPM data at
both baseline and after 8 weeks of treatment. The average reductions in mean 24-hour SBP/DBP
in the four groups, in the order listed above, were −20/−13, −16/−10, −19/−11, and −25/−16
mmHg. Serious adverse events were reported in three, two, and two patients in the dual-therapy
groups and in six patients in the triple-therapy group, respectively. Events in this last group
included one patient with syncope, one patient with excessive BP elevation, one patient with
psychosomatic disease, one patient with acute coronary syndrome, one patient with
supraventricular arrhythmia, and one patient who developed a thyroid goiter. The most common
adverse event was peripheral edema, occurring in 4%–8% of participants taking combinations
that included amlodipine vs 2% in those receiving ALI/ HCT. The second most common AE was
headache reported in 3%–5% of participants in all treatment groups. Generally, adverse events
were mild-to-moderate in all treatment groups and usually did not result in discontinuation of
study drug.

The Aliskiren/Amlodipine/Hydrochlorothiazide Versus Aliskiren/Amlodipine in US Minority

Patients With Stage II Systolic Hypertension trial randomized 412 self-identified minority
patients with stage II hypertension to either a treatment regimen of ALI 300 mg/AML 10
mg/HCT 25 mg (203 subjects) or ALI 300 mg/AML 10 mg (209 subjects).42 Black patients
comprised 62%, Hispanics/Latinos 27%–29%, and other minorities 9%–10% of those
randomized. The average age was 55 years old, 15%–18% of patients were ≥65 years old, 26%–
31% were diabetic, and body mass index was 32% in each treatment group. Baseline seated
SBP/DBP was 167/95 mmHg in both groups, whereas the baseline 24-hour ABPM SBP/DBP
was 148/87 mmHg in the triple-therapy subgroup of 112 and 149/88 mmHg in the dual-therapy
subgroup of 114. Therapy was initiated with lower doses of each of these drugs during the first 4
weeks of the trial, but was force-titrated to the doses noted above for the last 4 weeks of the trial.
After 8 weeks of treatment, mean seated SBP/DBP had decreased by 36.4/15.2 mmHg with
triple-therapy and 29.5/12.1 with dual-therapy; differences in BP reduction between the two
therapeutic regimens was statistically significant. Subgroup analyses of systolic BP reduction
based on sex, age, mean seated SBP at baseline, presence or absence of diabetes, or metabolic
syndrome mirrored the differences in the three- versus two-drug arms for the entire cohort,
whereas changes in mean seated DBP in some subgroups were not always statistically
significant, even though the pattern of differences was similar. Surprisingly, 24-hour ambulatory
SBP decreased by 23 mmHg with ALI/AML/ HCT and by 21 mmHg with ALI/AML, a
difference that was not statistically or clinically significant. The most common adverse events in
these minority hypertensive patients were similar to those reported in NCT00765674 although
the incidence of peripheral edema was only 2%–3% in these patients, even though all were
taking amlodipine.

A 28–54-week long-term safety study of the triple-drug combination in patients with essential
hypertension (NCT00667719) was completed in October of 2009, but no study findings have
been published or presented on the ClinicalTrials. gov website.43 The ALTITUDE study,44 an
outcomes trial that randomized diabetic patients with chronic kidney disease already taking an
angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker to either aliskiren or
placebo, was discontinued early because of an increase in stroke, hypotension, hyperkalemia, and
worsening renal function in this high-risk patient population. Consequently, Novartis and the
FDA are carefully reviewing the safety data with aliskiren when taken with other
antihypertensive medications; the fate of combination products that contain aliskiren is uncertain.

As noted above, a small proportion of hypertensive patients will not achieve the goal BP with a
three-drug combination. Although an in-depth review is beyond the scope of this publication,
some trials have examined the effects of four-drug therapy on BP and adverse effects. In the
1980s, a limited number of studies compared the control of BP of patients with resistant
hypertension using four drugs that included a diuretic, beta-blocker, hydralazine, and nifedipine
with drugs such as minoxidil and diazoxide.45 While BP could be reduced, the drugs were
poorly tolerated. More recently, a proof-of-concept study demonstrated that a single pill
containing a quarter of the single-pill dose of four antihypertensive medications (atenolol,
bendroflumethiazide, amlodipine, and captopril) was more effective in reducing BP than any of
the single drugs at full dose.46 Additional studies will be required to comprehensively evaluate
the potential advantages of a four-drug combination pill.

Multidrug therapy: advantages of single-pill combinations

Numerous retrospective and few prospective analyses report improved patient compliance with
taking fixed-dose combination (FDC) medications compared to those same medications
prescribed as individual components (IC), irrespective of the therapeutic rationale for prescribing
the medications.47–50 More than a decade ago, Dezii reported that medication persistence after
one year was approximately 20% greater in hypertensive patients prescribed single-pill
combinations of either lisinopril/HCT or enalapril/HCT than when the angiotensin-converting-
enzyme inhibitor and a diuretic were prescribed separately.51 Since then, comparisons of other
antihypertensive FDC vs IC have included an evaluation of two but not all three of the
components of the triple-drug therapies cited in this review. Better medication compliance with
the FDCs of valsartan/amlodipine52 and of valsartan/HCT53 than with their respective ICs has
been reported, whereas compliance has not been formally evaluated with two-drug combinations
versus free components of ALI/AML/HCT or OLM/AML/HCT. However, it remains unclear
whether medication persistence translates into better BP control, reduced adverse effects, and
reduced health care costs.

In a recently published meta-analysis of five studies examining drug compliance in 17,999

hypertensive patients taking FDC or IC, FDCs were associated with 21% better compliance but
with only 4.1/3.1 mmHg lower SBP/DBP and no significant reduction in adverse events.54
Whether increased medication compliance with FDC will ultimately be associated with reduced
cardiovascular events is currently unknown.

Retrospective analyses of large health systems provider databases have reported that not only
does treatment of hypertensive patients with two-drug FDC improve persistence in taking
medications compared to IC, but is also associated with decreases in healthcare utilization
costs.55, 56 In their meta-analysis of 12 retrospective database studies, all-cause and
hypertension-related health care costs were on average $1357 lower for patients prescribed FDC
than those prescribed IC.55 As a confounding factor, racial disparity in both medication
compliance and in health care costs has been reported. Dickson and Plauschinat conducted a
retrospective examination of both medication compliance and healthcare utilization among
African American and Caucasian Medicaid recipients prescribed amlodipine/benazepril FDC
versus a CCB + angiotensin-converting-enzyme inhibitor as an IC.57 Although medication
compliance was higher with FDC than IC in both ethnic groups, compliance rates were 55% in
African American patients and 61% in Caucasian patients. Total healthcare service costs were
much lower for all patients taking FDC ($4605) than IC ($8531), but higher for African
American than for Caucasian patients, while drug costs were higher for Caucasian than African
American patients. It has also been noted that medication persistence and adherence declines as
patient co-payment for FDC and IC drugs increases.58

Summary
Three-drug single-pill fixed-dose combinations expand the options for effectively treating
hypertensive patients with stage II hypertension who have not attained goal BPs with two drugs.
In clinical trials, the reduction in both SBP and DBP is remarkably similar (Table 1). Each of
these fixed dose 3-drug combinations appear to be equally effective in reducing BP toward if not
to recommended goals in both sexes, in African Americans and Hispanic/Latino minorities, in
the elderly, in diabetics, and in obese/overweight patients with metabolic syndrome with minimal
adverse effects. Extrapolation of data from two-drug FDC suggests that medication compliance
(adherence and persistence) is better with these FDCs than with the ICs taken as separate
medications, although this has yet to be rigorously evaluated. An unanswered question is
whether major adverse clinical events will be reduced when FDC rather than IC are prescribed.

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