Professional Documents
Culture Documents
Guia Ash PDF
Guia Ash PDF
State University of New York, Downstate College of Medicine, Brooklyn, NY;1 Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital,
McGill University, Montreal, Canada;2 Calhoun Cardiology Center, University of Connecticut, Farmington, CT;3 Department of Medicine, Weil Cornell
College of Medicine, New York, NY;4 Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden;5 Cardiovascular
Associates, Virginia Beach, VA;6 Department of Medicine, Wayne State University, Detroit, MI;7 Department of Pharmacy Practice and Science,
University of Iowa, Iowa City, IA;8 Department of Medicine, University of Miami Miller School of Medicine, Miami, FL;9 MediCiti Institutions,
Hyderabad, India;10 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA;11 State University School of Medicine,
Port Au Prince, Haiti;12 Hypertension Center of Haiti, Port Au Prince, Haiti;13 Department of Medicine, Mayo Clinic, Rochester, MN;14 Jersey Shore
University Medical Center, Neptune, NJ;15 Hypertension Center, University of Pennsylvania, Philadelphia, PA;16 George Institute for Global Health,
University of Sydney, Sydney, NSW, Australia;17 Arterial Hypertension and Metabolic Unit, University Hospital, Favaloro Foundation, Buenos Aires,
Argentina;18 ASH Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, IL;19 The Shanghai Institute of Hypertension,
Shanghai Jiaotong University School of Medicine, Shanghai, China;20 Hypertension in Africa Research Team, North West University, Potchefstroom,
South Africa;21 Department of Medicine, University of Rochester Medical Center, Rochester, NY;22 Institute of Cardiovascular and Medical Sciences,
University of Glasgow, Glasgow, UK;23 Virginia Commonwealth University, Richmond, VA;24 and Department of Physiology, University of Melbourne,
Melbourne, Vic, Australia25
INTRODUCTION
Address for correspondence: Michael A. Weber, MD, Division of
Cardiovascular Medicine, State University of New York, Downstate College
About one third of adults in most communities in the
of Medicine, 450 Clarkson Avenue, Box 97, Brooklyn, NY 11203 developed and developing world have hypertension.
E-mail: michaelwebermd@cs.com Hypertension is the most common chronic condition
dealt with by primary care physicians and other
DOI: 10.1111/jch.12237 health practitioners.
Most patients with hypertension have other risk well to treatment with calcium channel blockers and
factors as well, including lipid abnormalities, glucose diuretics but have smaller blood pressure reductions
intolerance, or diabetes; a family history of early car- with angiotensin-converting enzyme inhibitors,
diovascular events; obesity; and cigarette smoking. angiotensin receptor blockers, and b-blockers. How-
The success of treating hypertension has been lim- ever, appropriate combination therapies provide
ited, and despite well-established approaches to powerful antihypertensive responses that are similar
diagnosis and treatment, in many communities fewer in black and white patients. Most patients will
than half of all hypertensive patients have adequately require more than one antihypertensive drug to
controlled blood pressure. maintain blood pressure control.
Stage 2 hypertension: systolic blood pressure the arm with the higher reading should be used for
≥160 mm Hg or diastolic blood pressure ≥100 mm measurements thereafter.
Hg. The blood pressure should be taken after patients
have emptied their bladders. Patients should be
CAUSES OF HYPERTENSION seated with their backs supported and with their
legs resting on the ground and in the uncrossed
Primary Hypertension position for 5 minutes.
About 95% of adults with high blood pressure have The patient’s arm being used for the measurement
primary hypertension (sometimes called essential should be at the same level as the heart, with the arm
hypertension). resting comfortably on a table.
The cause of primary hypertension is not known, It is preferable to take 2 readings, 1 to 2 minutes
although genetic and environmental factors that affect apart, and use the average of these measurements.
blood pressure regulation are now being studied. It is useful to also obtain standing blood pressures
Environmental factors include excess intake of salt, (usually after 1 minute and again after 3 minutes) to
obesity, and perhaps sedentary lifestyle. check for postural effects, particularly in older
Some genetically related factors could include inap- people.
propriately high activity of the renin-angiotensin- In general, the diagnosis of hypertension should be
aldosterone system and the sympathetic nervous confirmed at an additional patient visit, usually 1 to
system and susceptibility to the effects of dietary salt 4 weeks after the first measurement. On both occa-
on blood pressure. sions, the systolic blood pressure should be ≥140 mm
Another common cause of hypertension is stiffening Hg or the diastolic pressure ≥90 mmHg, or both, in
of the aorta with increasing age. This causes hyper- order to make a diagnosis of hypertension.
tension referred to as isolated or predominant If the blood pressure is very high (for instance, a
systolic hypertension characterized by high systolic systolic blood pressure ≥180 mm Hg), or if available
pressures (often with normal diastolic pressures), resources are not adequate to permit a convenient
which are found primarily in elderly people. second visit, the diagnosis and, if appropriate,
treatment can be started after the first set of readings
Secondary Hypertension that demonstrate hypertension.
This pertains to the relatively small number of cases, For practitioners and their staff not experienced in
about 5% of all hypertension, where the cause of the measuring blood pressures, it is necessary to receive
high blood pressure can be identified and sometimes appropriate training in performing this important
treated. technique.
The main types of secondary hypertension are Some patients may have blood pressures that are high
chronic kidney disease, renal artery stenosis, exces- in the clinic or office but are normal elsewhere. This is
sive aldosterone secretion, pheochromocytoma, and often called white-coat hypertension. If it is suspected,
sleep apnea. consider getting home blood pressure readings (see
A simple screening approach for identifying second- below) to check this possibility. Another approach is
ary hypertension is given later. to use ambulatory blood pressure monitoring, if it is
available. In this procedure, the patient wears an arm
MAKING THE DIAGNOSIS OF HYPERTENSION cuff connected to a device that automatically mea-
Blood pressure can be measured by either a conven- sures and records blood pressures at regular intervals
tional sphygmomanometer using a stethoscope or by usually over a 24-hour period.
an automated electronic device. The electronic It can be helpful to measure blood pressures at home.
device, if available, is preferred because it provides If available, the electronic device is simpler to use
more reproducible results than the older method and and is probably more reliable than the sphygmoma-
is not influenced by variations in technique or by the nometer. The average of blood pressures measured
bias of the observers. If the auscultatory method is over 5 to 7 days, if possible in duplicate at each
used, the first and fifth Korotkoff sounds (the measurement, can be a useful guide for diagnostic
appearance and disappearance of sounds) will cor- and treatment decisions.
respond to the systolic and diastolic blood pressures.
Arm cuffs are preferred. Cuffs that fit on the finger or
wrist are often inaccurate and should, in general, not EVALUATING THE PATIENT
be used. Often, high blood pressure is only one of several
It is important to ensure that the correct size of the cardiovascular risk factors that require attention.
arm cuff is used (in particular, a wider cuff in Before starting treatment for hypertension, it is
patients with large arms [>32 cm circumference]). useful to evaluate the patient more thoroughly. The
At the initial evaluation, blood pressure should be three methods are personal history, physical exam-
measured in both arms; if the readings are different, ination. and selective testing.
be indicated by distended jugular veins, rales on also associated with an increased risk of cardio-
chest examination, an enlarged liver, and peripheral vascular events. Ideally, an albumin/creatinine
edema. ratio should be obtained, but even dipstick
Neurologic examination. Why is this important? evidence of albuminuria (+1 or greater) is
This may reveal signs of previous stroke and affect helpful.
treatment selection. o Red and white cells. Why are these important?
Eyes: If possible, the optic fundi should be checked Positive findings can be indicative of urinary tract
for hypertensive or diabetic changes and the areas infections, kidney stones, or other potentially
around the eyes for findings such as xanthomas. serious urinary tract conditions, including bladder
Pulse: It is important to check peripheral pulse rates; tumors.
if they are diminished or absent, this can indicate • Electrocardiography. Why is this important? Elec-
peripheral artery disease. trocardiography (ECG) can help identify previous
myocardial infarctions or left atrial and ventricular
hypertrophy (which is evidence of target organ
TESTS damage and indicative of the need for good control
Blood sample
of blood pressure). ECG might also identify cardiac
Note: This preferably should be a fasting sample so
arrhythmias such as atrial fibrillation (which would
that a fasting blood glucose level and more accurate
dictate the use of certain drugs) or conditions such as
lipid profiles can be obtained.
heart block (which would contraindicate certain
I. Electrolytes. Why is this important? There is a
drugs, eg, b-blockers, rate-slowing calcium channel
special emphasis on potassium: high levels can
blockers). Echocardiography, if available, can also
suggest renal disease, particularly if creatinine is
be helpful in diagnosing left ventricular hypertrophy
elevated. Low values can suggest aldosterone
and quantifying the ejection fraction in patients with
excess. In addition, illnesses associated with severe
suspected heart failure, although this test is not
diarrhea are common in some communities and
routine in hypertensive patients.
can cause hypokalemia and other electrolyte
changes.
OVERALL GOALS OF TREATMENT
II. Fasting glucose concentration. Why is this impor-
I. The goal of treatment is to manage hypertension and
tant? If elevated, this could be indicative of
to deal with all the other identified risk factors for
impaired glucose tolerance, or, if sufficiently high,
cardiovascular disease, including lipid disorders, glu-
of diabetes. If available, glycated hemoglobin
cose intolerance or diabetes, obesity, and smoking.
should be measured to further assess an elevated
II. For hypertension, the treatment goal for systolic
glucose level and help in making a diagnosis.
blood pressure is usually <140 mm Hg and for
III. Serum creatinine and blood urea nitrogen. Why
diastolic blood pressure <90 mm Hg. In the past,
are these important? Increased creatinine levels
guidelines have recommended treatment values of
are usually indicative of kidney disease; creatinine
<130/80 mm Hg for patients with diabetes, chronic
is also used in formulae for eGFR. When appro-
kidney disease, and coronary artery disease. How-
priate, use formulae designed for eGFR calcula-
ever, evidence to support this lower target in patients
tions in patients of African ancestry.
with these conditions is lacking, so the goal of <140/
IV. Lipids. Why are these important? Elevated LDL
90 mm Hg should generally be used, although some
cholesterol or low values of high-density lipoprotein
experts still recommend <130/80 mm Hg if albu-
cholesterol are associated with increased cardiovas-
minuria is present in patients with chronic kidney
cular risk. High LDL cholesterol can typically be
disease.
treated with available drugs, usually statins.
III. Are there other exceptions to <140/90 mm Hg?
V. Hemoglobin/hematocrit. Why are these impor-
Most evidence linking the effects on cardiovascular
tant? These measurements can identify issues
or renal outcomes to treated blood pressures have
beyond hypertension and cardiovascular disease,
been based on clinical trials in middle-aged to elderly
including sickle cell anemia in vulnerable popu-
patients (typically between 55 and 80 years). Some
lations and anemia associated with chronic kid-
recent trials suggest that in people 80 or older,
ney disease.
achieving a systolic blood pressure of <150 mm Hg
VI. Liver function tests. Why are these important?
is associated with strong cardiovascular and stroke
Certain blood pressure drugs can affect liver
protection and so a target of <150/90 mm Hg is now
function, so it is useful to have baseline values.
recommended for patients in this age group. We
Also, obese people can have fatty liver disorders
have almost no clinical trial evidence regarding
that should be identified and considered in overall
blood pressure targets in patients younger than 50
management.
years. Diastolic blood pressure may be important in
Urine sample this age group, so achieving a value <90 mm Hg
o Albuminuria. Why is this important? If present, should be a priority. In addition, it is also a
this can be indicative of kidney disease and is reasonable expectation that targets <140/90 mm
Hg (eg, < 130/80 mm Hg) could be appropriate in but greater amounts of alcohol can raise blood
young adults and can be considered. pressure and should therefore be discouraged. In
IV.It is important to inform patients that the treatment women, alcohol should be limited to 1 drink a day.
of hypertension is usually expected to be a life-long V. Cigarette smoking: Stopping smoking will not reduce
commitment and that it can be dangerous for them blood pressure, but since smoking by itself is such a
to terminate their treatment with drugs or lifestyle major cardiovascular risk factor, patients must be
changes without first consulting their practitioner. strongly urged to discontinue this habit. Patients
should be warned that stopping smoking may be
NONPHARMACOLOGIC TREATMENT associated with a modest increase in body weight.
Several lifestyle interventions have been shown to
reduce blood pressure. Apart from contributing to the DRUG TREATMENT OF HYPERTENSION
treatment of hypertension, these strategies are beneficial I. Starting treatment: (see the algorithm in the
in managing most of the other cardiovascular risk Figure). Treatment with drugs should be started
factors. In patients with hypertension that is no more in patients with blood pressures >140/90 mm Hg in
severe than stage 1 and is not associated with evidence whom lifestyle treatments have not been effective.
of abnormal cardiovascular findings or other cardiovas- (Note: As discussed earlier in Section 12 on
cular risks, 6 to 12 months of lifestyle changes can be Nonpharmacologic Treatment, drug treatment
attempted in the hope that they may be sufficiently can be delayed for some months in patients with
effective to make it unnecessary to use medicines. stage 1 hypertension who do not have evidence of
However, it may be prudent to start treatment with abnormal cardiovascular findings or other risk
drugs sooner if it is clear that the blood pressure is not factors. In settings where healthcare resources are
responding to the lifestyle methods or if other risk highly limited, clinicians can consider extending the
factors appear. Also, in practice settings where patients nondrug observation period in uncomplicated stage
have logistical difficulties in making regular clinic visits, 1 hypertensive patients provided there is no evi-
it might be most practical to start drug therapy early. In dence for an increase in blood pressure or the
general, lifestyle changes should be regarded as a appearance of cardiovascular or renal findings).
complement to drug therapy rather than an alternative. In patients with stage 2 hypertension (blood
pressure ≥160/100 mm Hg), drug treatment should
I. Weight loss: In patients who are overweight or be started immediately after diagnosis, usually with
obese, weight loss is helpful in treating hypertension, a 2-drug combination, without waiting to see the
diabetes, and lipid disorders. Substituting fresh fruits effects of lifestyle changes. Drug treatment can also
and vegetables for more traditional diets may have be started immediately in all hypertensive patients
benefits beyond weight loss. Unfortunately, these in whom, for logistical or other practical reasons,
diets can be relatively expensive and inconvenient for the practitioner believes it is necessary to achieve
patients, and can work only if patients are provided more rapid control of blood pressure. The presence
with a strong support system. Even modest weight of other cardiovascular risk factors should also
loss can be helpful. accelerate the start of hypertension treatment.
II. Salt reduction: High-salt diets are common in many II. For patients older than 80 years, the suggested
communities. Reduction of salt intake is recom- threshold for starting treatment is at levels ≥150/
mended because it can reduce blood pressure and 90 mm Hg. Thus, the target of treatment should be
decrease the need for medications in patients who <140/90 mm Hg for most patients but <150/
are “salt sensitive,” which may be a fairly common 90 mm Hg for older patients (unless these patients
finding in black communities. Often, patients are have chronic kidney disease or diabetes, when
unaware that there is a large amount of salt in foods <140/90 mm Hg can be considered).
such as bread, canned goods, fast foods, pickles, III. The treatment regimen:
soups, and processed meats. This intake can be Most patients will require more than one drug to
difficult to change because salty foods are often part achieve control of their blood pressure.
of the traditional diets found in many cultures. A In general, increase the dose of drugs or add new
related problem is that many people eat diets that are drugs at approximately 2- to 3-week intervals.
low in potassium, and they should be taught about This frequency can be faster or slower depend-
available sources of dietary potassium. ing on the judgment of the practitioner. In
III. Exercise: Regular aerobic exercise can help reduce general, the initial doses of drugs chosen should
blood pressure, but opportunities to follow a struc- be at least half of the maximum dose so that
tured exercise regimen are often limited. Still, only one dose adjustment is required thereafter.
patients should be encouraged to walk, use bicycles, It is generally anticipated that most patients
climb stairs, and pursue means of integrating phys- should reach an effective treatment regimen,
ical activity into their daily routines. whether 1, 2, or 3 drugs, within 6 to 8 weeks.
IV.Alcohol consumption: Up to 2 drinks a day can be If the untreated blood pressure is at least 20/
helpful in protecting against cardiovascular events, 10 mm Hg above the target blood pressure,
FIGURE. This algorithm summarizes the main recommendations of these guidelines. At any stage it is entirely appropriate to seek help from a
hypertension expert if treatment is proving difficult. In patients with stage 1 hypertension in whom there is no history of cardiovascular, stroke,
or renal events or evidence of abnormal findings and who do not have diabetes or other major risk factors, drug therapy can be delayed for
some months. In all other patients (including those with stage 2 hypertension), it is recommended that drug therapy be started when the
diagnosis of hypertension is made. CCB indicates calcium channel blocker; ACE-i, angiotensin-converting enzyme inhibitors; ARB, angiotensin
receptor blocker; thiazide, thiazide or thiazide-like diuretics. Blood pressure values are in mm Hg.
consider starting treatment immediately with 2 expensive than individual drugs. Once-daily
drugs. drugs can be taken at any time during the day,
IV. Choice of drugs: most usually either in the morning or in the
This should be influenced by the age, ethnicity/ evening before sleep. If multiple drugs are
race, and other clinical characteristics of the needed, it is possible to divide them between
patient (Table I). the morning and the evening.
The choice of drugs will also be influenced by The choice of drugs will further be influenced by
other conditions (eg, diabetes and coronary their availability and affordability. In many
disease) associated with the hypertension cases, it is necessary to use whichever drugs
(Table II). Pregnancy also influences drug choice. have been provided by government or other
Long-acting drugs that need to be taken only agencies. For this reason, we will only make
once daily are preferred to shorter-acting drugs recommendations for drug classes, not individ-
that require multiple doses because patients are ual agents, recognizing that there may be a
more likely to follow a simple treatment regi- limited selection of drugs that can be prescribed
men. For the same reason, when more than one by a practitioner. Even among generic drugs
drug is prescribed, the use of a combination there can be a wide variation in cost.
product with two appropriate medications in a Recommendations for drug selection are shown
single tablet can simplify treatment for patients, in Table I (Part 1) for patients whose primary
although these products can sometimes be more problem is hypertension, and in Table I (Part 2)
TABLE I. Drug Selection in Hypertensive Patients With or Without Other Major Conditions
Add Second Drug If
Needed to Achieve a If Third Drug is Needed to Achieve
Patient Type First Drug BP <140/90 mm Hg a BP of <140/90 mm Hg
White and other non-black CCBa or thiazide diuretic (Although ACE ARBb or ACE inhibitor (or Combination of CCB + ACE inhibitor
patients: 60 y and older inhibitors or ARBs are also usually effective) CCB or thiazide if ACE or ARB + thiazide diuretic
inhibitor or ARB used first)
Hypertension and chronic ARB or ACE inhibitor Note: in black patients, CCB or thiazide diureticc The alternative second drug
kidney disease good evidence for renal protective effects of (thiazide or CCB)
ACE inhibitors
Hypertension and clinical b-Blocker plus ARB or ACE inhibitor CCB or thiazide diuretic The alternative second step drug
coronary artery diseased (thiazide or CCB)
Hypertension and stroke ACE inhibitor or ARB Thiazide diuretic or CCB The alternative second drug (CCB
historye or thiazide)
Hypertension and heart Patients with symptomatic heart failure should usually receive an ARB or ACE inhibitor + b-blocker + diuretic +
failure spironolactone regardless of blood pressure. A dihydropyridine CCB can be added if needed for BP control.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; eGFR,
estimated glomerular filtration rate.
a
CCBs are generally preferred, but thiazides may cost less.
b
ARBs can be considered because ACE inhibitors can cause cough and angioedema, although ACE inhibitors may cost less.
If eGFR <40 mL/min, a loop diuretic (eg, furosemide or torsemide) may be needed.
c
d
Note: If history of myocardial infarction, a b-blocker and ARB/or ACE inhibitor are indicated regardless of blood pressure.
e
Note: If using a diuretic, there is good evidence for indapamide (if available).
for patients who have a major comorbidity important property that is not shared by the others in
associated with their hypertension. The Figure 1 its class. Table II provides a list of commonly used
displays an algorithm that summarizes the use of antihypertensive drugs and their doses.
therapy for most patients with hypertension.
The recommendations for particular drug classes Angiotensin-converting enzyme Inhibitors
are made with the recognition that sometimes These agents reduce blood pressure by blocking the
only alternative drug classes will be available. renin-angiotensin system. They do this by preventing
However, most of the time, the use of any drugs conversion of angiotensin I to the blood pressure-
that reduce blood pressure is more likely to help raising hormone angiotensin II. They also increase
protect patients from strokes and other serious availability of the vasodilator bradykinin by block-
events than giving patients no drug at all. ing its breakdown.
Angiotensin-converting enzyme inhibitors are well
BRIEF COMMENTS ON DRUG CLASSES tolerated. Their main side effect is cough (most
Note: There is an assumption, unless otherwise stated, common in women and in patients of Asian and
that all drugs in a class are similar to each other. We African background). Angioedema is an uncommon
only mention individual agents if they have an but potentially serious complication that can threa-
infarction, left ventricular systolic dysfunction, and Do not combine angiotensin receptor blockers with
diabetic and nondiabetic chronic kidney disease. angiotensin-converting enzyme inhibitors; each of
In general, angiotensin-converting enzyme inhibitors these drug types is beneficial in patients with kidney
are more effective as monotherapy in reducing blood disease, but in combination they may actually have
pressure in white patients than in black patients, adverse effects on renal events.
possibly because the renin-angiotensin system is When starting treatment with an angiotensin recep-
often less active in black patients. However, these tor blocker in patients already taking diuretics, it
drugs are equally effective in reducing blood pressure may be beneficial to skip a dose of the diuretic to
in all ethnic and racial groups when combined with prevent a sudden fall in blood pressure.
either calcium channel blockers or diuretics. Angiotensin receptor blockers must not be used in
Do not combine angiotensin-converting enzyme pregnancy, especially in the second or third trimes-
inhibitors with angiotensin receptor blockers; each ters, since they can compromise the normal devel-
of these drug types is beneficial in patients with opment of the fetus.
kidney disease, but in combination they may actually
have adverse effects on kidney function. Thiazide and Thiazide-like Diuretics
When starting treatment with an angiotensin-con- These agents work by increasing excretion of sodium
verting enzyme inhibitor, there is a risk of hypoten- by the kidneys and additionally may have some
sion in patients who are already taking diuretics or vasodilator effects.
are on very low-salt diets or are dehydrated (eg, Clinical outcome benefits (reduction of strokes and
laborers in hot climates and patients with diarrhea). major cardiovascular events) have been best estab-
For patients taking a diuretic, skipping a dose before lished with chlorthalidone, indapamide, and hydro-
starting the angiotensin-converting enzyme inhibitor chlorothiazide, although evidence for the first two of
helps prevent this sudden effect on blood pressure. these agents has been the strongest.
Angiotensin-converting enzyme inhibitors must not Chlorthalidone has more powerful effects on blood
be used in pregnancy, especially in the second or pressure than hydrochlorothiazide (when the same
third trimesters, since they can compromise the doses are compared) and has a longer duration of
normal development of the fetus. action.
The main side effects of these drugs are metabolic
(hypokalemia, hyperglycemia, and hyperuricemia).
Angiotensin Receptor Blockers The likelihood of these problems can be reduced by
Angiotensin receptor blockers, like angiotensin-con- using low doses (eg, 12.5 mg or 25 mg of hydro-
verting enzyme inhibitors, antagonize the renin- chlorothiazide or chlorthalidone) or by combining
angiotensin system. They reduce blood pressure by these diuretics with angiotensin-converting enzyme
blocking the action of angiotensin II on its AT1 inhibitors or angiotensin receptor blockers, which
receptor and thus prevent the vasoconstrictor effects have been shown to reduce these metabolic changes.
of this receptor. Combining diuretics with potassium-sparing agents
The angiotensin receptor blockers are well toler-
also helps prevent hypokalemia.
ated. Because they do not cause cough and only Diuretics are most effective in reducing blood
rarely cause angioedema, and have effects and pressure when combined with angiotensin-convert-
benefits similar to angiotensin-converting enzyme ing enzyme inhibitors or angiotensin receptor block-
inhibitors, they are generally preferred over angio- ers, although they are also effective when combined
tensin-converting enzyme inhibitors if they are with calcium channel blockers.
available and affordable. Like angiotensin-convert-
ing enzyme inhibitors, angiotensin receptor blockers Note: Thiazides plus b-blockers are also an effective
can increase serum creatinine (see comments about combination for reducing blood pressure, but since both
angiotensin-converting enzyme inhibitors), but usu- classes can increase blood glucose concentrations this
ally this is a functional change that is reversible and combination should be used with caution in patients at
not harmful. risk for developing diabetes.
These drugs do not appear to have dose-dependent side
effects, so it is perfectly reasonable to start treatment Calcium Channel Blockers
with medium or even maximum approved doses. These agents reduce blood pressure by blocking the
These drugs have the same benefits on cardiovascular inward flow of calcium ions through the L channels
and renal outcomes as angiotensin-converting of arterial smooth muscle cells.
enzyme inhibitors. There are two main types of calcium channel
Like angiotensin-converting enzyme inhibitors, they blockers: dihydropyridines, such as amlodipine and
tend to work better in white and Asian patients than nifedipine, which work by dilating arteries; and
in black patients, but, when combined with either nondihydropyridines, such as diltiazem and verapa-
calcium channel blockers or diuretics, they become mil, which dilate arteries somewhat less but also
equally effective in all patient groups. reduce heart rate and contractility.
Most experience with these agents has been with the a-Blockers
dihydropyridines, such as amlodipine and nifedipine, a-Blockers reduce blood pressure by blocking arte-
which have been shown to have beneficial effects on rial a-adrenergic receptors and thus preventing the
cardiovascular and stroke outcomes in hypertension vasoconstrictor actions of these receptors.
trials. These drugs are less widely used as first-step agents
The main side effect of calcium channel blockers is than other classes because clinical outcome benefits
peripheral edema, which is most prominent at have not been as well established as with other
high doses; this finding can often be attenuated by agents. However, they can be useful in treating
combining these agents with angiotensin-convert- resistant hypertension when used in combination
ing enzyme inhibitors or angiotensin receptor block- with agents such as diuretics, b-blockers, and angio-
ers. tensin-converting enzyme inhibitors.
Nondihydropyridine calcium channel blockers are To be maximally effective, they should usually be
not recommended in patients with heart failure, but combined with a diuretic. Since a-blockers can have
amlodipine appears to be safe when given to heart somewhat beneficial effects on blood glucose and
failure patients receiving standard therapy (including lipid levels, they can potentially neutralize some of
angiotensin-converting enzyme inhibitors) for this the adverse metabolic effects of diuretics.
condition. The a-blockers are effective in treating benign
Because the nondihydropyridine drugs, verapamil prostatic hypertrophy, and so can be a valuable part
and diltiazem, can slow heart rate, they are some- of hypertension treatment regimens in older men
times preferred in patients with fast heart rates and who have this condition.
even for rate control in patients with atrial fibrilla-
tion who cannot tolerate b-blockers. Nondihydro- Centrally Acting Agents
pyridine drugs can also reduce proteinuria. These drugs, the most well-known of which are
Calcium channel blockers have powerful blood clonidine and a-methyldopa, work primarily by
pressure-reducing effects, particularly when com- reducing sympathetic outflow from the central ner-
bined with angiotensin-converting enzyme inhibitors vous system.
or angiotensin receptor blockers. They are equally They are effective in reducing blood pressure in most
effective in all racial and ethnic groups. patient groups.
The dihydropyridine, but not the nondihydropyri- Bothersome side effects such as drowsiness and dry
dine, agents can be safely combined with mouth have reduced their popularity. Treatment
b-blockers. with a clonidine skin patch causes fewer side effects
than the oral agent, but the patch is not always
b-Blockers available and can be more costly than the tablets.
b-blockers reduce cardiac output and also decrease In certain countries, including the United States,
the release of renin from the kidney. a-methyldopa is widely employed for treating hyper-
They have strong clinical outcome benefits in tension in pregnancy.
patients with histories of myocardial infarction and
heart failure and are effective in the management of Direct Vasodilators
angina pectoris. Because these agents, specifically hydralazine and
They are less effective in reducing blood pressure minoxidil, often cause fluid retention and tachycar-
in black patients than in patients of other ethnic- dia, they are most effective in reducing blood
ities. pressure when combined with diuretics and b-
b-blockers may not be as effective as the other major blockers or sympatholytic agents. For this reason,
drug classes in preventing stroke or cardiovascular they are now usually used only as fourth-line or later
events in hypertensive patients, but they are the additions to treatment regimens.
drugs of choice in patients with histories of myocar- Hydralazine is the more widely used of these agents.
dial infarction or heart failure. The powerful drug minoxidil is sometimes used by
Many of these agents have adverse effects on glucose specialists in patients whose blood pressures are
metabolism and therefore are not recommended in difficult to control. Fluid retention and tachycardia
patients at risk for diabetes, especially in combina- are frequent problems with minoxidil, as well as
tion with diuretics. They may also be associated with unwanted hair growth (particularly in women).
heart block in susceptible patients. Furosemide is often required to cope with the fluid
The main side effects associated with b-blockers are retention.
reduced sexual function, fatigue, and reduced exer-
cise tolerance. Mineralocorticoid Receptor Antagonists
The combined a- and b-blocker, labetalol, is widely The best known of these agents is spironolactone.
used intravenously for hypertensive emergencies, and Although it was originally developed for the treat-
is also used orally for treating hypertension in ment of high aldosterone states, it recently has
pregnant and breastfeeding women. become part of standard treatment for heart failure.
Eplerenone is a newer and better-tolerated agent, Consider secondary causes of hypertension if all
although most experience in difficult-to-control these more simple approaches are unsuccessful.
hypertension has been with spironolactone. o Secondary hypertension can be suggested by the
In addition, these agents can be effective in reducing sudden onset of hypertension, or by the loss of
blood pressure when added to standard 3-drug blood pressure control in patients previously
regimens (angiotensin-converting enzyme inhibitor well managed or by the occurrence of a hyper-
or angiotensin receptor blocker/ calcium channel tension emergency
blocker/diuretic) in treatment-resistant patients. This o Chronic kidney disease: this common secondary
may be because aldosterone excess can contribute to cause of hypertension should normally be
resistant hypertension. revealed by the initial patient evaluation (eg,
Symptomatic side effects of gynecomastia (swelling laboratory tests of creatinine). These patients, if
and tenderness of breasts in both men and women) possible, should be referred to a nephrologist.
and sexual dysfunction are common. These can be o Aldosterone excess: this is suggested by hypo-
minimized by using spironolactone in a low dose (no kalemia during the initial evaluation, although
more than 25 mg daily) or by using the more this condition can occur even when potassium
selective (but more expensive) agent, eplerenone. levels appear normal. About 20% of patients
Hyperkalemia can also become a problem with these whose blood pressures remain high despite
agents, particularly when added to angiotensin- taking 3 drugs have evidence of aldosterone
converting enzyme inhibitors or angiotensin receptor excess. Confirming this diagnosis usually
blockers in patients with reduced renal function. requires assistance from clinical hypertension
These agents should be used with caution when the specialists.
eGFR is <50. In particular, when mineralocorticoid o Sleep apnea: This is common in obese patients.
receptor blockers are combined with angiotensin- Not all patients with sleep apnea have hyperten-
converting enzyme inhibitors or angiotensin receptor sion but there is a clear association. A preliminary
blockers, potassium levels must be monitored within diagnosis can be made by finding a history of
the first month of treatment and then on a regular snoring during sleep and daytime tiredness. A
basis (every 3–6 months). definitive diagnosis usually requires a sleep lab-
oratory study.
TREATMENT RESISTANT HYPERTENSION o Other secondary causes of hypertension such as
Hypertension can be controlled (blood pressure renal artery stenosis or coarctation of the aorta
<140/90 mm Hg in most patients) by using either usually require evaluation by a specialist.
1, 2, or 3 drugs as described earlier (angiotensin-
converting enzyme inhibitor or angiotensin receptor FINAL COMMENT
blocker/ calcium channel blocker/diuretic) in full or The authors of this statement acknowledge that there
maximally tolerated doses. The most widely used are insufficient published data from clinical trials in
two-drug combination, angiotensin-converting hypertension to create recommendations that are com-
enzyme inhibitors plus either calcium channel block- pletely evidence-based, and so inevitably some of our
ers or diuretics, or angiotensin receptor blockers plus recommendations reflect expert opinion and experience.
either calcium channel blockers or diuretics, can We also should point out that because of the major
control blood pressure in about 80% of patients. differences in resources among points of care it is not
Confirm that the blood pressure is truly uncontrolled possible to create a uniform set of guidelines. For this
by checking home pressures, or if available, by using reason we have written a broad statement on the
ambulatory blood pressure monitoring. management of hypertension and have not presumed to
For patients not controlled on 3 drugs, adding a anticipate the conditions or shortfalls that might exist
mineralocorticoid antagonist such as spironolactone, in particular communities. We expect that experts who
a b-blocker, a centrally acting agent, an a-blocker, or are familiar with local circumstances will feel free to
a direct vasodilator will often be helpful. use their own judgment in modifying our recommen-
If blood pressure is still not controlled it is important dations and to create practical instructions to help
to make certain that patients are actually taking their guide front-line practitioners in providing the best care
medicines. Question their families, check their pre- possible.
scriptions, and ask questions about side effects to
help confirm compliance with treatment.
Check whether patients are taking other medicines A NOTE TO COLLEAGUES
that can interfere with their hypertension treatment. The authors of this statement would welcome comments
For example: nonsteroidal anti-inflammatory drugs, and suggestions from colleagues. We recognize that in
cold remedies, and some antidepressants. Also, ask this initial version of the guidelines there will probably
about diet: blood pressures in some patients are be omissions, redundancies, and inaccuracies. Please feel
especially sensitive to factors such as excessive salt free to get in touch with us either by letters to the
intake. Journal or by personal communication.
Acknowledgments: This statement was written under the sponsorship of the ment to Prevent Heart Attack Trial. Major outcomes in high-risk
American Society of Hypertension and the International Society of Hyperten- hypertensive patients randomized to angiotensin-converting enzyme
sion. In addition, the Asia Pacific Society of Hypertension has endorsed these inhibitor or calcium channel blocker vs diuretic: The Antihypertensive
guidelines. The statement was prepared without any external funding. The and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALL-
work and time of the authors was provided by them entirely on a volunteer HAT). JAMA. 2002;288:2981–97.
basis. 10. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and
independent effects of antihypertensive treatment on clinical events in
Disclosures: MAW: Research funding: Medtronics. Consulting: Boehringer- the VALUE Trial. Lancet. 2004;363:2049–51.
Ingelheim, Novartis, Daichi Sankyo, Takeda, Forest. Speaker: Daiichi Sankyo, 11. Redon J, Mancia G, Sleight P, et al. Safety and efficacy of low blood
Takeda, Forest. ELS: Research Funding: Canadian Institutes of Health pressures among patients with diabetes: subgroup analyses from
Research, Canada Research Chairs program of CIHR/Government of Canada, the ONTARGET (ONgoing Telmisartan Alone and in combination
Servier France. Consultant: Servier, Novartis. Speaker: Forest Canada, Pfizer with Ramipril Global Endpoint Trial). J Am Coll Cardiol. 2012;
Japan. WBW: Research Funding: National Institutes of Health. Consulting: 59:74–83.
Safety Committees (DSMB, CEC, Steering Committees); Ardea Biosciences, 12. Weber MA, Bakris GL, Hester A, et al. Systolic blood pressure and
Inc.; AstraZeneca; Dendreon, Forest Research Institute, Inc.; Roche; St. cardiovascular outcomes during treatment of hypertension. Am J
Judes Medical, Takeda Global Research, Teva Neuroscience. SM, LHL, JGK, Med. 2013;126:501–8.
BJM, DLC, JCC, RRJC, ST, AJR, AES, RMT: No conflicts of interest. 13. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure
JMF: Research Funding: Novartis, Medtronic. Consultant: Novartis, Medtron- control and cardiovascular outcomes among hypertensive patients
ic, Back Beat Hypertension. BLC: Research Funding: NIH and VA. VSR: Con- withdiabetes and coronary artery disease. JAMA. 2010;304:61–8.
sultant: Medtronic, Daiichi-Sankyo, Forest. DK: Research Funding: Medtronic. 14. ACCORD Study Group; Cushman WC, Evans GW, Byington RP,
RT: Research Funding: NIH. Consultant: Medtronic, Janssen, Merck, GSK. et al. Effects of intensive blood-pressure control in type 2 diabetes
JC: Research Funding and Speaker: Servier in relation to ADVANCE trial and mellitus. N Engl J Med. 2010;362:1575–85.
Post-trial study. GLB: Research Funding: Takeda. Consultant: Takeda, 15. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine
AbbVie, Daiichi-Sankyo, Novartis, CVRx, Medtronic, Relypsa, Janssen, or hydrochlorothiazide for hypertension in high-risk patients. N Engl
BMS. JW: Consultant and Speaker: Boehringer-Ingelheim, MSD, Novartis, J Med. 2008;359:2417–28.
Omron, Pfizer, Servier, and Takeda. JDB: Research and Consultant: CVRx. 16. The Department of Veterans Affairs Cooperative Study Group on
DS: Research: Medtronic, CVRx. Consultant: Takeda, UCB, Novartis, Med- Antihypertensive Agents; Materson BJ, Reda DJ, Cushman WC, et al;
tronic, CVRx. Speaker: Takeda. SBH: Speaker: Novartis, Servier. Single-drug therapy for hypertension in men. A comparison of six
antihypertensive agents with placebo. N Engl J Med. 1993;328:914–
21.
Suggested Reading 17. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension
1. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of in patients 80 years of age or older. N Engl J Med. 2008;358:1887–
the Joint National Committee on Prevention, Detection, Evaluation, 98.
and Treatment of High Blood Pressure. Hypertension. 2003;42: 18. UK Prospective Diabetes Study Group. Tight blood pressure control
1206–52. and risk of macrovascluar and microvascular complications in type 2
2. Flack JM, Sica DA, Bakris G, et al. Management of high blood diabetes. UKPDS 38. BMJ. 1998;317:703–713.
pressure in Blacks: an update of the International Society on 19. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure
Hypertension in Blacks consensus statement. Hypertension. 2010;56: lowering and antihypertensive drug class on progression of hyperten-
780–800. sive kidney disease: results from the AASK trial. JAMA. 2002;
3. National Institute for Health Care Evidence. CG127. Hypertension: 288:2421–31.
Clinical management of primary hypertension in adults. On-line: 20. Peralta CA, Norris KC, Li S, et al. Blood pressure components and
NICE Clinical Guidelines. February 2011. end stage renal disease in persons with chronic kidney disease. Arch
4. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines Intern Med. 2012;172:41–47.
for the management of arterial hypertension. J Hypertens. 21. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on
2013;31:1281–357. renal and cardiovascular outcomes in patients with type 2 diabetes
5. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of and nephropathy. N Engl J Med. 2001;345:861–9.
usual blood pressure to vascular mortality: a meta-analysis of 22. Weir MR, Bakris GL, Weber MA, et al. Renal outcomes in hyper-
individual data for one million adults in 61 prospective studies. tensive Black patients at high cardiovascular risk. Kidney Int.
Lancet. 2002;360:1903–13. 2012;81:568–76.
6. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure 23. Weber MA, Jamerson K, Bakris GL, et al. Effects of body size and
of reduced dietary sodium and the Dietary Approaches to Stop hypertension treatments on cardiovascular event rates: subanalysis of
Hypertension (DASH) diet. N Engl J Med. 2001;344:3–10. the ACCOMPLISH randomized controlled trial. Lancet.
7. Elmer PJ, Obarzanek E, Vollmer WM, et al. Effects of comprehensive 2013;381:537–545.
lifestyle modification on diet, weight, physical fitness, and blood 24. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension:
pressure control: 18-month results of a randomized trial. Ann Intern diagnosis, evaluation, and treatment. A scientific statement from the
Med. 2006;144:485–95. American Heart Association Professional Education Committee of the
8. SHEP Cooperative Research Group. Prevention of stroke by antihy- Council for High Blood Pressure Research. Hypertension. 2008;51:
pertensive drug treatment in older persons with isolated systolic 1403–19.
hypertension. Final results of the Systolic Hypertension in the Elderly 25. Shivalkar B, Van de Heyning C, Kerremans M, et al. Obstructive sleep
Program (SHEP). JAMA. 1991;265:3255–64. apnea syndrome: more insights on structural and functional cardiac
9. ALLHAT Officers and Coordinators for the ALLHAT Collaborative alterations, and the effects of treatment with continuous positive
Research Group. The Antihypertensive and Lipid-Lowering Treat- airway pressure. J Am Coll Cardiol. 2006;47:1433–9.