Hypertension Essentia

Hypertension
Essentials
Norman M. Kaplan, MD
Division of Hypertension, University of Texas
Southwestern Medical Center
Dallas, Texas
Michael A. Weber, MD
Professor of Medicine, State University of New York
Downstate College of Medicine
Editor-in-Chief, Journal of Clinical Hypertension
Brooklyn, New York
2010
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ABOUT THE AUTHORS
Norman Kaplan, MD, is clinical professor of internal medicine

at the University of Texas Southwestern Medical Center at Dallas
where he has been on the faculty for more than 40 years. For the
last 20 years, his teaching, writing, and research have focused
primarily on clinical aspects of hypertension. He has lectured exten-
sively and contributed over 500 papers to medical literature. The
ninth edition of his textbook, Kaplans Clinical Hypertension, was
published in 2006. He was a member of the third, fourth, fth,
and sixth Joint National Committees on Detection, Evaluation, and
Treatment of High Blood Pressure. He has been made a Master of
the American College of Physicians, and he received the Lifetime
Achievement Award by the American Heart Associations Council
for High Blood Pressure Research, and the Stevo Julius Award for
Leadership in Medical Communication presented by the International Society of Hypertension.
He served on the Executive Committees of the American Society of Hypertension and the AHA
Council for High Blood Pressure Research. He is involved as either editor or reviewer with most
of the journals that publish papers about hypertension.
Michael A. Weber, MD, is professor of medicine at the SUNY

Downstate College of Medicine in Brooklyn, NY. He received his
medical degree from Sydney University in Australia.
His career has focused primarily on hypertension and preven-
tive cardiology. He has published numerous research articles in
medical literature and has authored or edited 16 books. Together
with Dr. Suzanne Oparil, he is responsible for the widely used ref-
erence volume, Hypertension. He is also the editor-in-chief of the
Journal of Clinical Hypertension.
Dr. Weber is one of the founders of The American Society of
Hypertension and has served as its president. He has also worked
as Chair of the ASH Hypertension Specialists Program. He is a Fel-
low of The American College of Physicians, The American College
of Cardiology, and The American Heart Association. He has served on the Cardiovascular and
Renal Drugs Advisory Board of the Food and Drug Administration and is now a consultant to
that agency. He worked for ten years as Chairman of the Formulary Committee of a major
pharmacy benets provider serving many of the leading health plans in the United States.
His main current research interests are in clinical trials of patients at high risk of cardio-
vascular events or strokes and he also participates actively in trials on patients with metabolic
disorders such as diabetes and kidney disease. Dr. Weber currently serves on the steering
committees of several national and international clinical outcomes trials.
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TABLE OF CONTENTS
SECTION 1. DIAGNOSIS, EVALUATION, AND Mechanism of Action ............................. 36

TREATMENT OF HYPERTENSION ................. 1 Major Uses ............................................. 37
Administration and Monitoring .............. 37
1. OVERVIEW OF HYPERTENSION................ 2 Frequent or Severe Adverse Effects ........ 37
Denition ................................................. 2 Angiotensin II Receptor Blockers................ 38
Incidence.................................................. 2 Mechanism of Action ............................. 38
Natural History ......................................... 2 Clinical Effects ........................................ 38
Etiology .................................................... 2 Administration and Side Effects .............. 40
Pathophysiology ....................................... 2 Direct Renin Inhibitors (DRI)....................... 41
Approach to Diagnosis and Treatment ..... 2 -Blockers .................................................. 42
Effect of Treatment .................................. 3 Mechanism of Action ............................. 42
Awareness, Treatment, and Control ......... 3 Properties ............................................... 42
Prevention ................................................ 3 Major Uses ............................................. 42
2. EVALUATION OF HYPERTENSION ........... 5 Frequency of Serious Side Effects ........... 43
Step 1. Conrm and Stage Hypertension ..... 5 Vasodilating -Blockers .............................. 44
Proper Blood Pressure Measurement Calcium Channel Blockers .......................... 44
Technique............................................. 5 Mechanism of Action ............................. 44
Exclude White-Coat Hypertension and Major Uses ............................................. 44
Pseudohypertension ............................. 8 Frequency of Serious Adverse Effects ..... 45
Staging Blood Pressure ............................. 8 -1 Adrenergic Blockers............................. 45
Ambulatory Blood Pressure Monitoring .... 8 Central -Adrenergic Agents ..................... 46
Step 2. Evaluate the Patient Clinically .......... 9 Direct Vasodilators .................................... 47
Overview .................................................. 9 Choices of Therapy .................................... 47
Assessment of Target Organ Damage .... 11
Detection of Secondary Hypertension..... 11 SECTION 2. OTHER TOPICS IN
Step 3. Risk Stratication ........................... 12 HYPERTENSION.................................................51
Overview ................................................ 12
5. HYPERTENSIVE CRISIS ............................ 52
Low-Risk (Group A) ................................ 13
Intermediate-Risk (Group B) ................... 13 6. RESISTANT HYPERTENSION ................... 57
High-Risk (Group C) ................................ 14
Step 4. Initiate Treatment and Optimize 7. IDENTIFIABLE (SECONDARY)
Compliance ............................................ 14 HYPERTENSION ....................................... 60
Blood Pressure Goals .............................. 14 APPENDIX. Clinical Trials ............................ 71
Approach to Treatment .......................... 15 ACCOMPLISH ......................................... 71
Therapeutic Lifestyle Changes ................ 15 ALLHAT .................................................. 73
Drug Therapy ......................................... 17 ANBP2 ................................................... 75
Optimizing Patient Compliance .............. 18 ASCOT ................................................... 77
3. TREATMENT OF ESSENTIAL CONVINCE ............................................. 79
HYPERTENSION ....................................... 20 DORADO DAR 311 .............................. 81
EXFORGE-HCT ........................................ 83
4. ANTIHYPERTENSIVE DRUG HYVET.................................................... 85
CLASSES: MECHANISM OF ACTION AND INVEST ................................................... 87
SELECTED FEATURES .............................. 34 LIFE ........................................................ 89
Diuretics and Potassium Sparers ................ 34 ONTARGET............................................. 90
Mechanism of Action ............................. 34 TEKTURNA HCT ...................................... 92
Major Uses ............................................. 34 VALUE.................................................... 94
Dosage and Administration .................... 34
Frequent or Serious Adverse Effects ....... 36 REFERENCES ................................................ 96
Aldosterone Blockers ................................. 36
INDEX ......................................................... 100
ACE Inhibitors............................................ 36
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ABBREVIATIONS
ACC American College of EPA eicosapentaenoic acid

Cardiology ESRD end-stage renal disease
ACE angiotensin converting enzyme g gram
ACLS advanced cardiovascular life GFR glomerular filtration rate
support
GI gastrointestinal
ADP adenosine diphosphate
HCTZ hydrochlorothiazide
AHA American Heart Association
HDL high-density lipoprotein
ARB angiotensin II receptor blocker
hx history
ATP III Adult Treatment Panel III
ISA intrinsic sympathomimetic
(National Cholesterol
activity
Education Program)
IV intravenous
AV atrioventricular
JNC-VI The Sixth Report of the Joint
BID twice daily
National Committee on
BMI body mass index Detection, Evaluation, and
BP blood pressure Treatment of High Blood
BUN blood urea nitrogen Pressure
CABG coronary artery bypass grafting kg kilogram
CHD coronary heart disease L liter
CHF congestive heart failure LDL low-density lipoprotein
CI contraindication Lp(a) lipoprotein(a)
CNS central nervous system LV left ventricular; left ventricle
CO cardiac output LVEF left ventricular ejection fraction
COPD chronic obstructive pulmonary LVH left ventricular hypertrophy
disease MAO monoamine oxidase
CrCI creatinine clearance max maximum
CRP C-reactive protein mcg microgram (g)
CT computerized tomography mcL microliter (L)
DHA docosahexaenoic acid mg milligram
EBCT electron beam computerized Ml myocardial infarction
tomography min minute
ECG electrocardiogram mL milliliter
Echo echocardiogram; MRI magnetic resonance imaging
echocardiography
NCEP National Cholesterol Education
EF ejection fraction Program (Adult Treatment
e.g. for example Panel III)
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vi Abbreviations
NHLBI National Heart, Lung, and qh every hours

Blood Institute qmonth once a month
NIDDM non-insulin-dependent diabetes qweek once a week
NPO nothing by mouth RVR renal vein renin
NYHA New York Heart Association sl sublingual
O2 oxygen TG triglycerides
PCI percutaneous coronary TIA transient ischemic attack
intervention TID three times daily
PE pulmonary embolism TLC therapeutic lifestyle changes
PO per os by mouth; oral TOD/CCD Target organ damage/clinical
PRA plasma renin activity cardiovascular disease
prn take as needed V/Q ventilation/perfusion
qd every days VLDL very-low-density lipoprotein
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Section 1. Diagnosis, Evaluation, and Treatment of Hypertension 1
Section 1
DIAGNOSIS, EVALUATION, AND TREATMENT
OF HYPERTENSION
Chapter 1. Overview of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Chapter 2. Evaluation of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Chapter 3. Treatment of Essential Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Chapter 4. Antihypertensive Drug Classes: Mechanism of Action
and Selected Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Section 1
Diagnosis, Evaluation, and Treatment of Hypertension
Hypertension affects over 70 million Americans, including 60% of those over the age of
60. Proper treatment reduces by 30% the incidence and fatality from coronary heart dis-
ease, heart failure, stroke, and kidney disease. Despite these benecial effects, hypertension
is underdiagnosed and undertreated: as of 2004, only 72% of adults with hypertension were
aware of their condition, only 61% were receiving medications, and only 35% had blood pres-
sures less than 140/90 mmHg.
Hypertension Essentials is an authoritative, concise, and practical step-by-step guide to the
detection, evaluation, and treatment of hypertension. Primary and secondary risk reduction
measures are also emphasized, forming the basis for a management strategy aimed at halt-
ing the progression of atherosclerosis, stabilizing rupture-prone plaques, preventing arterial
thrombosis, and improving cardiovascular and cerebrovascular prognosis.
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2 Hypertension Essentials
Chapter 1
Overview of Hypertension
A. Denition. Hypertension is dened by a systolic blood pressure 140 mmHg or a diastolic
blood pressure 90 mmHg, based on the average of two or more readings taken at each
of two or more visits after the initial screen. A single recording may be sufcient if systolic
or diastolic blood pressures are markedly elevated, especially if symptoms are present, but
even very high elevations in blood pressure may occur transiently during extreme stress
or acute illness. Blood pressure 135/85 mmHg outside the doctors ofce also could
be considered elevated. In fact, the term prehypertension has been coined to describe
patients with blood pressures in the range 120139 mmHg systolic or 8089 diastolic.
Such patients are obvious targets for lifestyle interventions that could prevent or delay the
onset of hypertension.
B. Incidence. About one third of the adult U.S. populationincluding 60% of persons over
age 60have hypertension. Each year, almost two million new cases of hypertension
occur, 75% of which are Stage 1 disease (140159/9099 mmHg). Among individuals
aged 5565 years without hypertension, the residual lifetime risk for developing Stage 1
or Stage 2 hypertension ( 160/100 mmHg) is 90% and 35%60%, respectively (Vasan
et al, 2002).
C. Natural History. Untreated hypertension increases the risk of nonfatal and fatal coronary
artery disease, stroke, congestive heart failure, renal disease, and all-cause mortality
(Figure 1.1). Depending on the level of hypertension, gender, age, other risk factors for
atherosclerosis, target organ damage, and clinical cardiovascular disease, the 10-year risk
of a cardiovascular event varies from less than 10% to more than 40%.
D. Etiology. More than 90% of hypertension is idiopathic (essential), while 5%10% can be
ascribed to identiable causes (secondary hypertension; Chapter 7).
E. Pathophysiology. Essential hypertension is caused by increased vascular reactivity, the

inappropriate retention of salt and water, or both. Over years, this leads to accelerated
atherosclerosis in large vessels, obliterative changes or thinning and rupture of small
vessels, and increased workload and hypertrophy of the heart.
F. Approach to Diagnosis and Treatment. As shown in Figure 1.2, management of

the patient with elevated blood pressure centers on: (1) conrming the diagnosis of
hypertension; (2) evaluating the patient clinically for other cardiovascular risk factors (found
in a majority of people with hypertension), target organ damage, clinical cardiovascular
disease, and secondary hypertension; (3) initiating therapy based on assessing the severity
of the hypertension and concomitant risks; and (4) optimizing treatment compliance and
controlling other cardiovascular risk factors.
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Chapter 1. Overview of Hypertension 3
HEREDITY-ENVIRONMENT
Age
PRE-HYPERTENSION 0 30
Normotension EARLY HYPERTENSION 20 40
ESTABLISHED HYPERTENSION 30 50
UNCOMPLICATED COMPLICATED
Accelerated- CARDIAC LARGE CEREBRAL RENAL

malignant Hypertrophy VESSEL Ischemia Nephro-
course Failure Aneurysm Thrombosis sclerosis
Infarction Dissection Hemorrhage Failure
Figure 1.1. Natural History of Hypertension

Source: Kaplan's Clinical Hypertension, 8th edition (Kaplan NM, ed.)
G. Effect of Treatment. Effective control of hypertension reduces the risk of fatal and non-
fatal stroke, coronary heart disease (CHD), and heart failure by 15%50% and limits the
progression to more severe hypertension. Early diagnosis and treatment may also prevent
the onset and worsening of renal insufciency.
H. Awareness, Treatment, and Control. Hypertension is grossly underdiagnosed and

undertreated: Only 72% of adults with hypertension are aware of their diagnosis; only
61% are receiving medications, half of whom discontinue therapy on their own; and only
35% of hypertensive patients have blood pressures < 140/90 mmHg (NHANES 1999
2004). In a report of 800 hypertensive men, 40% had blood pressures 160/90 mmHg
despite six or more hypertension-related visits per year; increases in therapy occurred
in only 6.7% of ofce visits (Berlowitz et al, 1998). It is now known that systolic blood
pressure, not diastolic blood pressure, is the major risk and primary goal of therapy.
I. Prevention. The need to prevent hypertension is reected in the following facts: (1) a
signicant proportion of cardiovascular disease occurs in persons with blood pressure
higher than 120/80 mmHg but less than 140/90 mmHg, the level recommended for
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therapy; (2) treatment, though generally effective, still results in signicant nancial costs
and side effects; (3) noncompliance remains an important obstacle to blood pressure
control; and (4) in adequately treated hypertensive patients the risk of CHD remains higher
than of persons with normal blood pressure. Lifestyle modications can prevent or delay
the onset of hypertension and should be recommended to all people at risk, particularly
those with prehypertension (blood pressures between 120/90 and 139/89 mmHg) (The
Seventh Report of the Joint National Committee). Therapeutic lifestyle changes include
weight control, regular physical activity, restriction of sodium intake (< 2.4 gm/d sodium
or 46 gm/d sodium chloride), maintenance of dietary potassium intake (> 90 mmol/d),
and consumption of a diet high in fruits, vegetables, and low-fat dairy products and low
in saturated and total fats.
Confirm Diagnosis
Employ proper technique (pp. 58)
Exclude white-coat and pseudohypertension (p. 8)
Stage hypertension (p. 9)
Evaluate the Patient Clinically

History, physical examination, laboratory (p. 10)
Evaluate for target organ damage (p. 11)
Evaluate for secondary causes (p. 11, Chapter 7)
Risk stratify the patient (pp. 1214)
Initiate Therapy
Lifestyle modification (pp. 1517)
Drug therapy (pp. 1733)
Control other cardiovascular risk factors (p. 13)
Ensure patient compliance and follow-up (pp. 1819)
Figure 1.2. Approach to Diagnosis and Treatment of Hypertension
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Chapter 2. Evaluation of Hypertension 5
Chapter 2
Evaluation of Hypertension
STEP 1. CONFIRM AND STAGE HYPERTENSION
A. Proper Blood Pressure Measurement Technique. Improper technique can result in the
overdiagnosis or underdiagnosis of hypertension (Table 2.1). In addition, some patients
found to have an elevated blood pressure on initial exam will not have persistently
elevated blood pressures on repeat measurements. White-coat hypertension and
pseudohypertension can also lead to overdiagnosis and potentially inappropriate use
of antihypertensive therapy. To avoid overtreatment, unless the blood pressure is very
clearly elevated or there are signs of hypertensive target organ disease, it is important to
repeat blood pressure measurements over weeks to ensure that hypertension is present
and persistent. The use of home blood pressure measurements using reliable automated
devices also can be most valuable in establishing the diagnosis. The scheduling of follow-
up ofce measurements based on initial screening blood pressure is shown in Table 2.2.
To employ proper technique, the following steps are recommended:
1. Have the patient sit quietly for at least 5 minutes in a chair with back supported
and arm supported at heart level, either passively or by a table. (Standing, sitting
unsupported, or actively holding the arm at heart level can raise blood pressure by
510 mmHg.)
2. Ensure no caffeine or smoking within the last 3060 minutes and no recent use of
exogenous adrenergic stimulants (e.g., phenylephrine in nasal decongestants), which
can cause transient elevations in blood pressure.
3. Use an appropriate size cuff. The bladder should encircle about 80% of the arm
circumference. If arm circumference is > 33 cm, a large cuff must be used to avoid
articially high readings.
4. Apply the cuff so that the lower margin is 23 cm above the antecubital space.
Ensure the middle of the bladder overlies the brachial artery pulse.
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Table 2.1. Factors Affecting the Accuracy of Sphygmomanometer Blood Pressure
Recordings
Increases Recorded BP Decreases BP No Effect on BP
Examinee Examinee Examinee

Soft Korotkoff sounds Soft Korotkoff sounds Menstrual phase
(diastolic BP effect) (systolic BP effect) Chronic caffeine use
Pseudohypertension Recent meal Phenylephrine nasal spray
(white-coat reaction) Missed auscultatory gap Cuff self-ination
To physician High stroke volume
To nonphysician Examination
Paretic arm (stroke) Setting, equipment Thin shirtsleeve under cuff
Pain, anxiety Noisy environment Bell vs. diaphragm
Acute smoking Faulty aneroid device Cuff ination per se
Acute caffeine Low mercury level Hour of day (during work
Acute ethanol Leaky bulb hours)
Distended bladder Room temperature
Examiner
Talking, signing Reading to next lowest
5 or 10 mmHg
Setting, equipment Expectation bias
Environment noise Impaired hearing
Leaky bulb valve
Blocked manometer Examination
Cold hands or Left vs. right arm
stethoscope Resting too long (25 min)
Elbow too high
Examiner Too rapid deation
Expectation bias Excess bell pressure
Impaired hearing
Examination
Cuff too narrow
Cuff not centered
Cuff over clothing
Elbow too low
Cuff too low
Short rest period
Back unsupported
Arm unsupported
Too slow/fast deation
Adapted from: JAMA 1995;273:12111218.
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Table 2.2. Follow-Up Schedule of Blood Pressure Measurements
Initial Screening BP (mmHg)*
Systolic Diastolic Follow-Up Schedule
< 120 < 80 Recheck in 2 years

120129 8085 Recheck in 1 year
130139 8689 Conrm within 6 months
140159 9099 Re-evaluate or refer to source of care within
160+ 100+ 1 month
Consider immediate care
* If systolic and diastolic pressures fall into different categories, follow recommendation for the shorter
follow-up.
The scheduling of follow-up should be modied by reliable information about past blood pressure mea-
surements, other cardiovascular risk factors, and target-organ disease.
Provide advice about therapeutic lifestyle changes.
Adapted from: JNC-VI (Arch Intern Med 1997;24:1346).
5. Inate the bladder quickly ~ 20 mmHg above systolic pressure (i.e., disappearance
of radial pulse). Ensure the arm cuff is at the level of the heart.
6. Deate the bladder at 23 mmHg per second, recording pressures at both the
beginning and disappearance of the Korotkoff sounds. More rapid deation can
underestimate systolic pressure and overestimate diastolic pressure.
7. Wait 12 minutes and repeat the measurement. A third reading should be

obtained if the variance exceeds 5 mmHg.
8. Other tips: If blood pressures differ between arms, the higher recording should
be used. If arm blood pressure is elevated, a leg pressure should be measured,
especially in young patients, to detect coarctation of the aorta. Many experts now
recommend measuring the ankle blood pressure so as to provide an ankle/brachial
blood pressure index: a value below 0.9 is suggestive of peripheral artery disease.
For patients with atrial brillation or sinus rhythm with frequent extrasystoles, record
the average of several blood pressure measurements. It is also important to check
for orthostatic changes before initiating drug therapy, especially in diabetics and the
elderly; after starting, changing or increasing antihypertensives; and in patients with
lightheadedness or dizziness.
9. Blood pressure devices: It is now becoming more common for health professionals
as well as patients to rely on automated oscillometric electronic devices for blood
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pressure measurements. These instruments provide more consistent readings

than sphygmomanometers; there is less inter-observer variability and less bias in
determining the blood pressure values. It is important, however, to regularly conrm
the accuracy of these devices.
B. Exclude White-Coat Hypertension and Pseudohypertension. It is important to

exclude conditions that can lead to the faulty diagnosis and possible overtreatment of
hypertension.
1. White-Coat Hypertension. White-coat hypertension is dened as hypertension
that occurs only during doctors ofce visits and may be responsible for over 20%
of apparent hypertension (JAMA 1988;259:225228). The diagnosis should be
suspected in patients with persistent elevations in blood pressure but without
evidence of target organ damage and is conrmed by ambulatory or home
monitoring demonstrating blood pressure measurements consistently at normal
levels. White-coat hypertension is more common among women and is mainly
associated with going into the physicians ofce. Over 10-year follow-up, patients
with white-coat hypertension are at little if any increased risk for end-organ damage
compared to those with normal blood pressure and are at lower risk than those
with sustained hypertension (Khattar RS et al, 1998). Nevertheless, people with
white coat hypertension typically show evidence of early target organ changes and
should be regarded as being at a somewhat increased cardiovascular risk. Treatment
consists of lifestyle modications and close follow-up. Drug therapy is reserved for
persistent elevations in blood pressure.
2. Pseudohypertension. Pseudohypertension occurs when the blood pressure cuff

pressure needed to completely compress an extremely calcied and rigid brachial
artery greatly exceeds intra-arterial pressure; this results in articial elevations in blood
pressure measurements. Pseudohypertension should be suspected in elderly patients
with evidence of generalized atherosclerosis; patients whose radial artery can still be
palpated when cuff pressure exceeds auscultatory systolic blood pressure (Oslers
sign); and patients with persistently elevated blood pressure measurements who
develop hypotensive symptoms on drug therapy. For a true blood pressure reading,
intra-arterial recording should be considered.
C. Staging Blood Pressure. All patients with hypertension should have their blood pressure
staged to help guide initial treatment (Table 2.3 and Step 3 [p. 12]).
D. Ambulatory Blood Pressure Monitoring. Home readings should be considered in

the routine evaluation of hypertension to help exclude white-coat hypertension and
facilitate long-term management. Ambulatory monitoring also can be used for the
evaluation of drug resistance, episodic hypertension, hypotensive symptoms associated
with antihypertensive medications or autonomic dysfunction, carotid sinus syncope, and
pacemaker syndromes (along with ambulatory ECG monitoring). Home and ambulatory
recordings correlate more closely with target organ damage than do clinic measurements.
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Table 2.3. Blood Pressure Stages

Stage* Systolic BP (mmHg) Diastolic BP (mmHg)
Normal < 120 and < 80

Prehypertension 120139 or 8089
Hypertension
Stage 1 140159 or 9099
Stage 2 160 or 100
* Classication for patients not taking antihypertensive drugs and not acutely ill. When systolic and dia-
stolic pressures fall into different categories, the higher category should be used to classify blood pres-
sure status (e.g., 160/92 mmHg should be classied as stage 2 hypertension). Isolated systolic hyper-
tension is dened by a systolic BP 140 mmHg with a diastolic BP < 90 mmHg and should be staged
appropriately (e.g., 170/85 mmHg is dened as stage 2 isolated systolic hypertension). In addition to
blood pressure stage, the presence or absence of target organ disease and concomitant cardiovascular
risk factors is important for risk stratication and initial treatment (Table 2.6, p. 14).
Optimal blood pressure for cardiovascular risk
Based on the average of two or more readings taken at each of two or more visits after an initial
screening
Adapted From: JNC-VI (Arch Intern Med 1997;157:24132446).
Compared to treatment based on conventional monitoring, antihypertensive treatment

based upon ambulatory monitoring is associated with less intensive drug treatment,
fewer symptoms, reduced left ventricular mass, and more sustained blood pressure
control (Staessen JA, 1997). Ambulatory monitoring also can be used to detect so-called
masked hypertension, in which ofce measurements are lower than home measurements.
In a study of 713 older (age 6583 years) hypertensives undergoing ambulatory blood
pressure monitoring in the Second Australian National Blood Pressure Study (Mancia,
2002), more than 25% had higher daytime ambulatory recordings than clinic recordings.
This phenomenon, which can lead to undertreatment of hypertension, was especially
common in smokers and previously treated hypertensives.
STEP 2. EVALUATE THE PATIENT CLINICALLY
A. Overview. Once the diagnosis of hypertension has been conrmed, the next step is to
evaluate the patient by history, physical examination, and laboratory testing (Table 2.4). This
information is used to identify cardiovascular risk factors, target organ damage, and clinical
cardiovascular disease, which in turn is used to risk stratify the patient and determine the
best initial therapy (Step 3). If secondary hypertension is suggested, screening evaluation
should be considered (Chapter 7).
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10 H y p e r t e n s i o n Essentials
Table 2.4. Clinical Evaluation of the Hypertensive Patient
History
Known duration and levels of elevated blood pressure
History or symptoms of coronary heart disease, heart failure, cerebrovascular disease,
peripheral vascular disease, renal disease, diabetes mellitus, dyslipidemia, other comorbid
conditions, gout, sexual dysfunction
Family history of hypertension, premature coronary disease, stroke, diabetes, dyslipidemia,
renal disease
History of recent changes in weight, physical activity, smoking or other tobacco use
Dietary assessment including intake of sodium, alcohol, saturated fat, caffeine
All prescribed and over-the-counter medications, herbal remedies, illicit drugs
Results and adverse effects of previous antihypertensive therapy
Psychosocial and environmental factorsfamily situation, employment status and working
conditions, educational levelthat may inuence hypertension control
Symptoms suggesting a secondary cause of hypertension (Table 2.5)
Physical Examination
Two or more BP measurements separated by 12 minutes using an appropriate
technique (p. 7)
Contralateral arm BP
Measurement of height, weight, and waist circumference
Vital signs, including postural BP, arm and leg BP
Funduscopic exam for hypertensive/arteriosclerotic retinopathy (arteriolar narrowing, AV
nicking, exudates, ame-shaped hemorrhages, papilledema)
Cardiac exam for heart size, clicks, murmurs, gallops
Lung exam for rales, bronchospasm
Abdominal exam for masses, bruits, enlarged kidneys, abnormal aortic pulsation
Neck exam for distended veins, enlarged thyroid, carotid bruits
Peripheral vascular exam for decreased pulses, trophic skin changes, bruits, edema
Neurologic exam for evidence of stroke
Skin for striae (Cushings Syndrome), xanthomas (hyperlipidemia), needle marks (drug abuse)
Nose exam for perforated septum (cocaine abuse), neurobromas
Laboratory Testing
Hematocrit
Serum potassium (baseline prior to diuretic therapy and to screen for primary and secondary
hyperaldosterone states)
Serum creatinine (assessment of target organ damage and renal etiology of
hypertension)
Fasting blood sugar and lipid prole (risk factors for atherosclerosis)
Urinalysis (assessment of target organ damage and renal etiology of hypertension)
Electrocardiogram (assessment of target organ damage)
Optional tests include serum uric acid (baseline prior to diuretic therapy); serum calcium
(baseline prior to diuretic therapy and as a screen for hyperparathyroidism); creatinine
clearance; urine for microalbuminuria, best as albumin/creatinine ratio on early morning
void specimen; 24-hour urine protein, better as albumin/creatinine ratio on morning void
specimen; glycosylated hemoglobin; thyroid stimulating hormone; echocardiogram (for
LVH); ankle/arm index; plasma renin or renin/aldosterone ratio. Other tests when secondary
hypertension is suspected (Chapter 7)
77883_CH02_print.indd 10 9/29/09 10:51:17 AM

B. Assessment of Target Organ Damage. Risk stratication plays an important role in

determining initial therapy (pp. 1214). All hypertensive patients should be evaluated for
target organ damage and clinical cardiovascular disease, including:
Cerebrovascular disease: transient ischemic attack, stroke
Cardiovascular disease: angina, prior myocardial infarction or coronary revascularization,
heart failure, left ventricular hypertrophy
Retinopathy: hemorrhages, exudates, papilledema
Nephropathy: increased serum creatinine, albuminuria, microalbuminuria
Peripheral artery disease: claudication, reduced ankle/brachial index, absence of
peripheral pulses
C. Detection of Secondary Hypertension. Hypertension that can be ascribed to an

identiable cause (secondary hypertension) represents ~ 5% of the total hypertensive
population. Indications for work-up include: (1) history, physical examination, and
laboratory results suggesting a secondary cause (Table 2.5); (2) resistance to drug
therapy; (3) blood pressure worsening after a period of good control; (4) accelerated or
malignant hypertension. Screening evaluation for secondary hypertension is described
in Chapter 7.
Table 2.5. Causes of Secondary Hypertension (Chapter 7)
Cause Features
Renovascular hypertension Age < 30 years or > 60 years, diastolic pressure 120
mmHg, recent onset or exacerbation of hypertension
(< 2 years), malignant hypertension, systolic-diastolic
bruit in epigastrium or upper quadrants of abdomen,
refractory hypertension, acquired resistance to
antihypertensive therapy especially in elderly patients,
deterioration in renal function after ACE inhibitors or
angiotensin II receptor blockers
Pheochromocytoma Spells of headache, palpitations, tachycardia,
inappropriate perspiration, tremor, pallor; unusually
labile blood pressure; recent weight loss; recent onset
or discovery of diabetes; malignant hypertension;
pressor response to antihypertensive drugs or during
induction of anesthesia; refractory hypertension.
(Symptoms are usually but not necessarily
paroxysmal.)
Hyperthyroidism Palpitations, tremor, weight loss, sweating, increased
appetite
77883_CH02_print.indd 11 9/29/09 10:51:17 AM

Table 2.5. Causes of Secondary Hypertension (Chapter 7) (cont'd)
Cause Features
Primary aldosteronism Unprovoked hypokalemia with inappropriate kaliuresis
(24-hour urinary potassium 40 mEq and serum
potassium 3.5 mEq/L), refractory hypertension
Cushings syndrome Truncal obesity, moon facies, ecchymosis, striae, acne,
hirsutism, muscle weakness, osteoporosis, glucose
intolerance, hypokalemia
Coarctation of the aorta Absent, delayed, or diminished arterial pulsations in
lower extremities, especially in patients < 30 years of
age
Medications Birth control pills, amphetamines (diet pills, cold
capsules, nasal spray). MAO inhibitors (e.g., phenelzine,
tranylcypromine, isocarboxazid), tricyclic antidepressants
(e.g., amitriptyline, desipramine, nortriptyline,
imipramine, doxepin), SSRIs, cocaine abuse, adrenal
steroids, exogenous thyroid hormone, cyclosporine.
erythropoietin
Others Renal parenchymal disease, alcohol > 2 oz. per
day, acromegaly, hypothyroidism, hypercalcemia
(hyperparathyroidism), congenital adrenal hyperplasia,
pregnancy-induced, neurological disorders (increased
intracranial pressure, sleep apnea, quadriplegia, acute
porphyria, familial dysautonomia, lead poisoning,
Guillain-Barre syndrome), acute stress (surgery,
psychogenic hyperventilation, hypoglycemia, burns,
alcohol withdrawal, sickle cell crisis, after resuscitation,
perioperative), systolic hypertension (aortic valvular
insufciency, arteriovenous stula, patent ductus
arteriosus, thyrotoxicosis, Pagets disease of bone,
beriberi, rigidity of aorta)
STEP 3. RISK STRATIFICATION
A. Overview. There are two separate approaches to decision making. Some experts (as
in JNC 7) make treatment decisions based primarily on blood pressure levels. Others,
however, believe that concomitant risk factors such as dyslipidemias, abnormal glucose
levels, smoking, target organ damage, or prior events should intensify and accelerate
77883_CH02_print.indd 12 9/29/09 10:51:17 AM

treatment of hypertension. The following is such an approach: Hypertensive patients can

be stratied into one of three risk groups based on the presence of major risk factors,
target organ damage, and clinical cardiovascular disease. The level of blood pressure and
risk group are then used to determine initial therapy (Table 2.6). Major risk factors include
smoking, dyslipidemia, diabetes, age > 60 years, and family history of cardiovascular
disease. Target organ damage/clinical cardiovascular disease (TOD/CCD) includes left
ventricular hypertrophy, angina, prior myocardial infarction or coronary revascularization,
heart failure, stroke or transient ischemic attack, hypertensive nephropathy or retinopathy,
and peripheral arterial disease. For any level of hypertension, the risk of coronary heart
disease increases with the number of cardiovascular risk factors present (Figure 2.1).
B. Low-Risk (Group A). These individuals lack risk factors or TOD/CCD. Stage 1
hypertension should be treated with lifestyle modication for up to 1 year before initiating
drug therapy. Stage 2 and 3 hypertension require initial therapy with lifestyle modication
and antihypertensive drugs.
C. Intermediate-Risk (Group B). These individuals have at least 1 risk factor, not including
diabetes, and no TOD/CCD. The majority of hypertensive patients fall into this category.
For Stage 1 hypertension, a 6-month trial of lifestyle modication is indicated before
initiating drug therapy, although initial therapy with antihypertensive drugs should be
considered if multiple risk factors are present. Stages 2 and 3 hypertension require initial
therapy with lifestyle modication and antihypertensive drugs.
400
180 Systolic BP
342
8-year rate per 1,000
300
150 Systolic BP
253 253
200
183 181 105 Systolic BP
154 152
100 128
90 106 104
61 72
55
33
0
Cholesterol (mg/dL) 185 260 260 260 260
Glucose intolerance + + +
Cigarettes + +
ECG-LVH +
Figure 2.1. Cardiovascular Risk Factors and Rate of Coronary Heart Disease
For a given level of hypertension, the risk of coronary heart disesae increases according to the number of
cardiovascular risk factors present. From: JAMA 1996;275:1571.
77883_CH02_print.indd 13 9/29/09 10:51:17 AM

Table 2.6. Risk Stratication and Initial Treatment of Hypertension
Blood Pressure Risk Group A (no Risk Group B ( 1 Risk Group C (TOD/
Stage (mmHg)* RF or TOD/CCD) RF; no diabetes or CCD or diabetes)
TOD/CCD)
High-normal (130 Lifestyle modication Lifestyle modication Drug therapy

139/8589)
Stage 1 (140 Lifestyle mod. Lifestyle mod. Drug therapy
159/9099) (12 mos) (6 mos)
Stage 2 (160 Drug therapy Drug therapy Drug therapy
179/100109)
Stage 3 ( 180/ 110) Drug therapy Drug therapy Drug therapy
RF = cardiovascular risk factor; TOD/CCD = target organ disease/clinical cardiovascular disease
(left ventricular hypertrophy, angina, prior myocardial infarction or coronary revascularization, heart
failure, stroke or transient ischemic attack, hypertensive nephropathy or retinopathy, peripheral arterial
disease)
* When systolic and diastolic pressures fall into different categories, the higher category should be used
to classify blood pressure status (e.g., 160/92 mmHg should be classied as stage 2 hypertension).
Isolated systolic hypertension is dened by a systolic BP of 140 mmHg with a diastolic BP < 90
mmHg and should be staged appropriately (e.g., 170/85 mmHg is dened as stage 2 isolated systolic
hypertension).
For individuals with multiple risk factors, consider early initiation of drug therapy
For individuals with high-normal BP and either heart failure, renal insufciency, or diabetes, early drug
therapy is recommended
Adapted From: JNC-VI (Arch Intern Med 1997;157:24132446)
D. High-Risk (Group C). These individuals have TOD/CCD or diabetes and require the most
aggressive therapy. Persons in this group with blood pressures 140/90 mmHg require
prompt pharmacologic therapy. JNC-VI also recommends initial drug therapy for persons
with high-normal blood pressure (130130/8589 mmHg) and either heart failure, renal
insufciency, or diabetes.
STEP 4. INITIATE TREATMENT AND OPTIMIZE COMPLIANCE
A. Blood Pressure Goals. The goal of blood pressure control is to reduce disability and death
associated with hypertension using the least intrusive means. As shown in Figure 2.2, blood
pressure should be reduced to < 140/90 mmHg for the general population. Lower targets
have been established for patients with chronic kidney disease, diabetes, heart failure, or
prior MI or stroke ( 130/80) mmHg). It is important to appreciate that while diastolic
blood pressure was considered to be the major risk and goal of therapy in the past, it is
77883_CH02_print.indd 14 9/29/09 10:51:17 AM

now known that systolic blood pressure is the major risk and goal of therapy. To achieve
maximum cardiovascular and renovascular protection, systolic and diastolic blood pressure
should be reduced to established targets. Initial therapy is based on blood pressure stage
and risk group category (Table 2.6, p. 14).
B. Approach to Treatment. The choice of initial drug therapy is based on patient

characteristics (e.g., elderly, African-American) and associated medical conditions (e.g.,
diabetes mellitus, heart failure, dyslipidemia), as described in Chapter 3. All patients
should be given instructions on therapeutic lifestyle changes, and aggressive control of
cardiovascular risk factors, particularly smoking, is mandatory.
C. Therapeutic Lifestyle Changes. Lifestyle modications should be initiated either

prior to or simultaneous with drug therapy (Table 2.6). In general, if blood pressure
is 140159/9099 mmHg and there is no evidence of target organ damage or other
cardiovascular risk factors, some clinicians might elect to institute lifestyle changes rst
and readdress the need for drug therapy after monitoring blood pressure over 26
months. Therapeutic lifestyle changes lower blood pressure, improve lipid prole and
insulin resistance, and reduce overall cardiovascular risk. The following instructions should
be given to all patients:
Lose weight if overweight. Weight reduction (~ 10 lb.) reduces blood pressure in

overweight hypertensives and enhances the effect of antihypertensive drugs. Weight
reduction also can improve overall cardiovascular health by improving diabetes and
lipid prole.
Limit alcohol intake to no more than 1 oz (30 mL) of ethanol (24 oz [720 mL] of
beer, 10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day or 0.5 oz
(15 mL) of ethanol per day for women and lighter-weight people. Small amounts of
alcohol do not raise blood pressure and have been associated with a lower risk for
coronary heart disease.
Increase aerobic physical activity to 3045 minutes most days of the week.
Regular aerobic activity can reduce weight, improve diabetes, raise HDL cholesterol
and lower lipoprotein(a), reducing the risk of cardiovascular disease and stroke.
Normotensive individuals who are sedentary are 20%50% more likely to develop
hypertension than their aerobically-t counterparts.
Reduce sodium intake to no more than 100 mmol/d (2.4 gm/d sodium or 6 gm/d
sodium chloride). A diet with moderate sodium restriction can lower blood pressure,
reduce the need for antihypertensive drugs, limit diuretic-induced potassium loss,
and possibly induce regression of LVH. Patients should be instructed to minimize
processed food consumption and use of the salt shaker.
Maintain adequate intake of dietary potassium (~ 90 mmol/d).
Maintain adequate intake of dietary calcium and magnesium for general health.
Eat a diet high in fruits, vegetables, and low-fat dairy foods and low in
saturated and total fat. The Dietary Approaches to Stop Hypertension (DASH)
diet has been shown to signicantly lower blood pressure in hypertensive patients
77883_CH02_print.indd 15 9/29/09 10:51:18 AM

Begin or Continue Lifestyle Modifications

Lose weight if overweight
Limit alcohol to no more than 1 oz (30 mL) of ethanol per day (24 oz [720 mL] of beer, 10 oz
[300 mL] of wine, or 2 oz [60 mL] of 100-proof whiskey). Limit alcohol to 0.5 oz (15 mL) per
day for women and lighter-weight people
Increase aerobic physical activity to 3045 minutes most days of the week
Reduce sodium intake to 100 mmol/d (2.4 gm/d sodium or 6 gm/d sodium chloride)
Maintain adequate intake of dietary potassium (~ 90 mmol/d), calcium, and magnesium
Stop smoking for overall cardiovascular health
Increase dietary intake of fruits, vegetables, and grains; reduce intake of dietary saturated fat,
trans fats, and cholesterol
Not at Blood Pressure Goal

General population: < 140/90 mmHg
Post-MI, heart failure, or renal insufficiency: 130/85 mmHg
Diabetes mellitus: 130/80 mmHg
Renal insufficiency with proteinuria 1 gm/d: 125/75 mmHg
Initiate Drug Therapy

Initiate drug therapy based on patient characteristics and coexistent conditions (pp. 2133)
No response or troublesome Inadequate response but

side effects well-tolerated
Substitute another drug from Add second agent from different class
different class (diuretic if not already used);
consider low-dose combination therapy
Not at blood
pressure goal
Continue adding agents from other classes (diuretic if not already used)
Identify cause of inadequate response (pp. 5758)
Consider referral to a hypertension specialist
Figure 2.2. Treatment of Hypertension

* Drug therapy should be initiated concurrently with lifestyle modication in most patients (Table 2.6, p. 14)
77883_CH02_print.indd 16 9/29/09 10:51:18 AM

(Appel et al, 1997). Alternative therapeutic diets include the Therapeutic Lifestyle
Changes (TLC) diet, as recommended by the National Cholesterol Education Program
Adult Treatment Panel III, or a Mediterranean-style diet, which has been shown to
reduce sudden death and total mortality in patients with prior myocardial infarction.
Stop smoking for overall cardiovascular health (p. 13).
D. Drug Therapy
1. Initial Therapy. The choice of initial drug therapy should be individualized, based on
patient characteristics and associated medical conditions (Chapter 3). In general, most
patients should be started on a long-acting once-daily drug that can be titrated based
on the patients age and response (e.g, every 24 weeks for stage 1 hypertension).
About 40%50% of patients can be controlled with monotherapy. In patients with
stage 2 hypertension, or who are at least 20/10 mmHg above their treatment target,
starting with a two-drug combination should be considered. Moreover, in high-risk
patients (BP 180/110 mmHg, clinical cardiovascular disease, target organ damage),
intervals between visits to intensify treatment should be reduced. Hospitalization
or emergency room referral should be considered for persons with blood pressures
200/120 mmHg and symptomatic target organ ndings.
2. Intensication of Therapy. The sequence for intensication of drug therapy depends

on the response to and tolerance of initial therapy. If the initial drug has no effect
on blood pressure or causes bothersome side effects, another drug from a different
drug class should be substituted. If a partial response is obtained and the drug is
well tolerated, a higher dose can be given or a second agent from a different drug
class can be added. (If a diuretic or a calcium channel blocker is not chosen as initial
therapy, one of these should probably be added next, as this strategy will enhance
the effect of most other types of antihypertensive drugs.) If target blood pressure is
still not attained, continue adding drugs from other classes. Before proceeding to
each successive treatment step, examine potential reasons for lack of responsiveness,
including pseudohypertension (p. 8), nonadherence to therapy, volume overload,
drug-related causes (pp. 5758), and secondary causes of hypertension (Chapter 7).
Elevated blood pressure alone in asymptomatic patients without new or worsening
target organ damage rarely requires emergency control.
3. Combination Drug Therapy. Once-daily, xed-dose combination therapy is

becoming a common approach for initial treatment of hypertension. The different
mechanisms of action of the two drugs may result in fewer side effects and better
blood pressure control in many hypertensive patients. Additionally, for the 60% of
patients (and 75% of diabetics) who require more than one antihypertensive drug,
once-daily, xed-dose combination therapy may improve compliance. Contemporary
combinations for initial therapy most typically include an ACE inhibitor or angiotensin
II receptor blocker with either a low dose thiazide or, perhaps preferably, a calcium
channel blocker (amlodipine being the best studied of these). For subsequent therapy,
the most obvious third drug would be either a calcium channel blocker or a thiazide,
depending on which was already included in the regimen. If needed, addition of
77883_CH02_print.indd 17 9/29/09 10:51:18 AM

blockers, alpha blockers, or centrally acting agents could then be considered.

Aldosterone antagonists in low doses can be helpful adjuncts also. It should again be
noted that the selection of certain drug types might be mandated by the presence of
concomitant diseases.
4. Stepdown Therapy. Monotherapy ultimately provides adequate blood pressure

control for up to 50% of patients. Therefore, if blood pressure has been well-
controlled on two drugs for 6 months, gradual withdrawal of the rst drug may
be attempted. Close monitoring is advised because hypertension may return after a
delay of months. Attempts to completely discontinue antihypertensive therapy are
generally not recommended without sustained and substantial improvements in
lifestyle.
E. Optimizing Patient Compliance (Table 2.7). Because 50% or more of hypertensive

patients adjust or discontinue antihypertensive therapy without the knowledge of their
physicians, education about dietary, lifestyle, and pharmacologic measures is essential.
Drugs should be chosen that are affordable, treat coexistent disease when present,
and have convenient dosing and favorable side-effect proles. Patients also should be
educated about the silent nature of the disease and its risks if left untreated. Adherence
to antihypertensive therapy can be improved by challenging patients to play an active role
in their disease: recording blood pressure at home, reporting side effects, involving their
families, challenging them to reach and maintain the therapeutic goal. Patients should
be encouraged to record and report their blood pressure prior to their morning drug
dose (to ensure protection against the surge in blood pressure upon awakening) and in
the early evening (to ensure coverage throughout the day). Compliance measures should
be reinforced at every visit. A reasonable treatment goal for out-of-ofce blood pressure
measurements should be lower than the 140/90 mmHg criterion used in the ofce.
Table 2.7. Guidelines to Improve Patient Adherence to Antihypertensive Therapy

Be aware of the problem and be alert to signs of patient nonadherence.
Establish the goal of therapy: to reduce blood pressure to near normotensive levels with
minimal or no side effects.
Educate the patient about the disease and its treatment.
Discuss the silent nature of the disease; discuss the need for lifelong treatment: discuss
common rationalizations given to justify discontinuing medications on own; encourage visits
and calls to allied health personnel; allow the pharmacist to monitor therapy; give feedback to
the patient via home blood pressure readings; make contact with patients who do not return.
Keep care inexpensive and simple.
Do the least workup needed to rule out secondary causes; obtain follow-up laboratory data
only yearly unless indicated more often; use home blood pressure readings; use nondrug, low-
cost therapies; be cost conscious when selecting therapies; use once-daily doses of long-acting
drugs; if appropriate, use combination tablets; tailor medication to daily routines.
77883_CH02_print.indd 18 9/29/09 10:51:18 AM

Table 2.7. Guidelines to Improve Patient Adherence to Antihypertensive
Therapy (cont'd)
Prescribe according to pharmacologic principles.
Be willing to stop unsuccessful therapy and try a different approach, but explain this to the
patient right at the start of therapy.
Anticipate side effects.
Adjust therapy to reduce side effects that do not spontaneously disappear.
Continue to add effective and tolerated drugs, stepwise, to achieve the goal of therapy
Adapted from: JNC-VI (Arch Intern Med 1997;157:24132446)
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Chapter 3
Treatment of Essential Hypertension
The goal of antihypertensive drug therapy is to reduce the risk of death, myocardial infarc-
tion, heart failure, stroke, and onset or progression of renal insufciency. Blood pressure
should be reduced to < 140/90 mmHg for the general population. Lower targets have been
established for higher-risk patients. A target of < 130/80 mmHg is recommended for those
with chronic kidney disease (eGFR < 60) or diabetes. Likewise, some authorities have recom-
mended targets of < 130/90 mmHg for patients with coronary disease or with a history of
stroke. To achieve maximum cardiovascular and renovascular protection, both systolic and
diastolic blood pressure should be reduced to established targets. The choice of antihyperten-
sive drug therapy requires consideration of individual patient characteristics and associated
medical conditions (pp. 2123). Certain antihypertensive medications treat coexistent disease,
thereby simplifying the patients drug regimen, improving compliance, and reducing cost
(e.g., ACE inhibitors in hypertensives with heart failure, blockers in those with angina pec-
toris). Moreover, randomized trials have demonstrated the superiority of one antihypertensive
agent over another in special populations despite similar degrees of blood pressure lowering
(losartan vs. atenolol in hypertensives with LVH in the LIFE trial, p. 89). This chapter is organized
by patient characteristics and associated medical conditions. Therapeutic recommendations
are based on antihypertensive drug effectiveness, the ability to treat coexistent conditions,
and side effect prole. Not all recommendations are supported by randomized clinical trials,
and renement of these recommendations awaits the results of ongoing investigation. Dosing
guidelines for commonly prescribed antihypertensive medications, selected drug interactions
with antihypertensive therapy, and xed-dose antihypertensive drug combinations are listed
in Chapter 4. Patients receiving drug therapy should be given individualized instructions on
therapeutic lifestyle changes, and aggressive control of concomitant cardiovascular risk fac-
tors is mandatory. Recommendations on how to achieve these goals and to provide optimal
care for hypertension patients are listed in Table 3.1.
77883_CH03_print.indd 20 9/29/09 10:52:37 AM

Table 3.1. Treatment of Essential Hypertension
Subset Drug Therapy Comments
Angina b-blocker, 2nd generation calcium Reduce BP gradually to prevent hypotensive episodes
antagonist (amlodipine, felodipine), or and myocardial ischemia. Avoid agents that increase
nitrates heart rate and myocardial oxygen consumption (e.g.,
77883_CH03_print.indd 21
ACE inhibitor for secondary prevention in hydralazine, liquid nifedipine) unless combined with
patients with prior MIa
a b-blocker. Thiazide diuretics should be used in low
doses due to unfavorable effects of high doses on
insulin resistance, lipids (increased cholesterol and
triglycerides), and electrolytes (decreased K+, Mg++,
Ca++).
Arrhythmia Diuretic, ACE inhibitor, ARB, or a-blocker Avoid antihypertensives that depress sinus node
Sinus bradycardia or sick sinus function, such as b-blockers, clonidine, aldomet,
syndrome diltiazem, verapamil.
Atrial/brillation/utter or SVT b-blocker, diltiazem, verapamil, or clonidine Avoid monotherapy with direct vasodilators (e.g.,
(no WPW syndrome) hydralazine, nifedipine); these agents can activate
the sympathetic nervous system and accelerate AV
conduction.
AV block ACE inhibitor, ARB, diuretic, or a-blocker Avoid agents that depress AV conduction, such as
b-blockers, verapamil, and diltiazem.
Benign prostatic hypertrophy a-blocker Provides relief of obstructive symptoms. Doxazosin
was less effective than chlorthalidone at preventing
Chapter 3. Treatment of Essential Hypertension
heart failure in ALLHAT (pp. 7576), although there

was no difference in overall mortality despite study
design restrictions that prevented optimal BP control in
patients randomized to doxazosin.
21
9/29/09 10:52:37 AM
Table 3.1. Treatment of Essential Hypertension (Cont'd)
Black Diuretic, calcium antagonist, or a-b Blacks have earlier onset and increased
blocker prevalence, severity, morbidity, and mortality from
b-blockers and ACE inhibitors are less hypertension compared to whites. This includes a
effective as monotherapy (though 1.3-fold increase in non-fatal stroke, a 1.8-fold increase
higher doses may rectify this) but may
in fatal stroke, a 1.5-fold increase in cardiac deaths
be indicated for comorbid conditions
22 H y p e r t e n s i o n
(non-diabetic or diabetic nephropathy. LV and a 3-fold increase in hypertension-related end-

dysfunction, post-MI). Their effectiveness stage renal disease.b Lifestyle modication is extremely
is enhanced by increased doses and important due to the high prevalence of cigarette
especially by the addition of a diuretic smoking, obesity, and Type 2 diabetes. Blacks are also
or a calcium channel blocker. The very responsive to reductions in salt intake. In AASK,
aldosterone antagonist, eplerenone (or ramipril resulted in a slower rate of progression to renal
very low doses of spironolactone), dysfunction compared to amlodipine in patients with
also should be considered
hypertensive nephrosclerosis and overt proteinuria. In
> 1 drug is often required: anticipate
combination therapy ALLHAT, blacks were more responsive to and fared
better with chlorthalidone than lisinopril.c
COPD with bronchospasm or Calcium antagonist, ACE inhibitor, or ARB Drugs used to treat COPD can increase blood pressure,
asthma including methylanthenes, steroids, and over-the-counter
drugs with ephedrine or pseudoephedrine. b-blockers
Essentials
and a-b-blockers increase airway resistance and should

be avoided. Even b-1-blockers may lose cardioselectivity
at higher doses and provoke bronchospasm. ACE
inhibitor-induced cough is no more common in COPD
patients than in the general population (5%15%) but
may complicate bronchospastic disease. ARBs can be
used if a cough develops. In patients with severe COPD,
Calcium antagonists may antagonize hypoxic pulmonary
vasoconstriction and worsen gas exchange.
9/29/09 10:52:37 AM
Diabetes ACE inhibitor or ARB + CCB or thiazide BP goal: 130/80 mmHg ( 125/75 mmHg for
diuretic. If BP remains elevated, follow renal insufciency with proteinuria > 1 gm/d).
with either a calcium antagonist or Aggressive control of BP is indicated for diabetic
thiazide and then a low-dose b-blocker. hypertensives, as the risk of cardiovascular mortality
Diabetic nephropathy: Type 1: ACE compared to nondiabetic hypertensives is increased
inhibitor; Type 2: ARB. These agents 3-fold.
reduce the progression of nephropathy. The Hypertension Optimum Treatment (HOT) study
Vast majority of diabetics require 2 conrmed the benet of aggressive BP lowering by
antihypertensive drugs; many require 3 demonstrating a 5%10% reduction in cardiovascular
drugs. Consider xed-dose combination events for diabetics with a diastolic BP target of
therapy to control BP, reduce side 80 mmHg vs. 90 mmHg.d The benet of treating
effects, and improve compliance. to a lower BP target was conrmed in the United
Check for orthostatic BP changes in all Kingdom Diabetes Prevention Study.e
hypertensive diabetics. If present, use ACE inhibitors are the drug class of choice for
standing BP to guide therapy. Type 1 diabetics due to their proven ability to reduce
Aggressive control of BP and lipids is cardiovascular events and slow the progression of
the most important factor for improving diabetic nephropathy; they are also well-tolerated
cardiovascular prognosis in Type 2 and metabolically neutral.
diabetes. For individuals > 55 years with hypertension
or another cardiovascular risk factor (coronary
disease, dyslipidemia, microalbuminuria, smoking),
an ACE inhibitor should be considered to reduce
cardiovascular events, based on results of the HOPE
trial.f
For patients with prior MI, addition of a b-blocker

should be considered to reduce mortality.
23
9/29/09 10:52:37 AM
Diabetes ARBs were renoprotective in 2 trials of Type 2

diabetic nephropathy, independent of their effect
on blood pressure. In these trials, ARBs reduced the
combined endpoint of doubling of baseline creatinine,
development of end-stage renal disease, or death by
16%20%. They also slowed the progression of renal
disease by 20%25% and reduced rst hospitalization

for heart failure by 23%32%,g according to the IDNT
and RENAAL trials. It was estimated that ARBs delayed
the time to dialysis or renal transplantation by 2 years.
In trials of hypertensive and nonhypertensive Type 2
diabetics with microalbuminuria and normal GFR,
ARBs slowed the progression to diabetic nephropathy
and increased the likelihood of restoration to
normalbuminuria,h according to the IRMA 2 and
MARVAL trials.
Among 3577 diabetics in HOPE, ramipril reduced
the primary outcome of MI, stroke, or cardiovascular
death by 25% after adjusting for changes in BP,i
suggesting cardioprotective effects beyond BP
lowering. Ramipril also reduced the risk of overt
nephropathy by 24%, though data on preventing
Essentials
end-stage renal disease are not conclusive.

For diabetics without heavy proteinuria, diuretics,
calcium antagonists, and b-blockers have also been
shown to reduce morbidity and mortality.j The
combination of ACE inhibitors and calcium antagonists
appears to have additive antiproteinuric effects.
9/29/09 10:52:37 AM
ACE inhibitors, ARBs, and a-blockers improve insulin
sensitivity, but ACE inhibitors and ARBs can induce
hyperkalemia and a-blockers can aggravate postural
hypotension. Calcium antagonists do not effect
insulin resistance. Diuretics and non-vasodilatory
b-blockers may increase insulin resistance and the risk
of developing diabetes. b-blockers may also prolong
insulin-induced hypoglycemia and mask hypoglycemic
symptoms such as tachycardia.
A recent technical review of management of
hypertension in diabetics from the American Diabetes
Association.k
Elderly (age > 65) Diuretic, calcium antagonist, ACE More than 60% of the elderly have BP > 140/90
inhibitor, ARB, a-blockers in men with mmHg. Systolic BP and pulse pressure are better
benign prostatic hypertrophy. predictors of cardiovascular outcome than
Traditional b-blockers are effective diastolic BP.
but have not been shown to be Rule-out pseudohypertension and white-coat
cardioprotective and are more likely to hypertension (p. 8) prior to initiating therapy;
cause side effects. these conditions lead to the overdiagnosis and
Isolated systolic hypertension: see p. 32 overtreatment of hypertension and are more
Be sure to measure BP in seated and common in the elderly.
standing positions, to detect orthostatic Avoid drugs associated with postural hypotension
hypotension. If present, use standing BP to (e.g., labetalol, guanethidine, high-dose diuretics),
since the elderly often have impaired baroreceptor
guide therapy. Also check for orthostatic
sensitivity and cerebral autoregulation. If a systolic
changes after starting, changing, or drop in BP > 20 mmHg or a diastolic drop > 10
increasing antihypertensive therapy.
mmHg occurs upon standing, attempt to overcome

the problem: sleep with head of bed elevated, arising
slowly, isometric exercise before standing.
25
9/29/09 10:52:37 AM
Elderly (age > 65) The incidence of dementia was reduced by 50%
among elderly patients with systolic hypertension
treated with a dihydropyridine calcium antagonist in
the SYST-EUR trial.l
The HYVET trial demonstrated that combination
treatment based on a non-thiazide diuretic and an
ACE inhibitor in hypertensive patients aged > 80 yrs

produced a signicant 21% mortality reduction.
Sudden onset of hypertension in elderly patients
suggests the presence of atherosclerotic
renovascular disease.
Gout All drug classes except diuretics. Consider Diuretics may be used in patients with asymptomatic
the ARB, losartan, which increases urinary hyperuricemia but should be avoided in poorly-
uric acid loss. controlled gout.
Heart failure, systolic ACE inhibitor, ARB*, diuretic, a-b-blocker Hypertensive patients often manifest a decrease in
dysfunction (carvedilol), cardioselective b-blocker systolic BP when heart failure develops. However,
(bisoprolol, metoprolol), vasodilatory mean BP is usually unchanged or increased due to
b-blocker (nebivolol) a rise in diastolic BP, reecting elevated systemic
If needed for angina or resistant vascular resistance.
hypertension, a second-generation ACE inhibitors, cardioselective b-blockers, amlodipine,
Essentials
calcium antagonist (amlodipine, carvedilol, and combination therapy with hydralazine

felodipine) can be added. and isosorbide have been shown to decrease
cardiovascular morbidity and mortality. ARBs were
equally efcacious and better tolerated than ACE
inhibitors in the ELITE II trial.m In Val-HeFT, valsartan
reduced morbidity and mortality in heart failure but
may have had a detrimental effect when combined
with ACE inhibitors and b-blockers.n
9/29/09 10:52:37 AM
First-generation calcium antagonists should be
used cautiously in patients with cardiomyopathy
due to their negative inotropic properties. Use of
second-generation agents (amlodipine, felodipine)
appears safe.o
Heart failure, diastolic See LVH (p. 28), but in view of common Treated the same as for LVH (p. 28).
pulmonary congestion, diuretic therapy
usually required.
Hypertrophic obstructive b-blocker or verapamil Calcium antagonists and b-blockers improve LV
cardiomyopathy (high ejection relaxation and symptomatic status in most patients.
fraction) Agents that decrease preload (diuretics, nitrates) or
afterload (ACE inhibitors, ARBs, b-blockers, direct
vasodilators) may worsen LV outow tract obstruction
and cause profound hypotension.
High cholesterol Lifestyle modications may lower Typical effects of drugs on lipid prole:
BP, improve lipid prole, and reduce a-blockers decrease total cholesterol (5%10%) and
cardiovascular risk increase HDL (5%10%).
ACE inhibitor, ARB, calcium antagonist, Calcium antagonists, ACE inhibitors, ARBs have no
or low-dose diuretic; possibly a-blocker effect on lipid parameters.
b-blockers have no effect on total cholesterol but
increase triglycerides (10%15%) and decrease HDL
(10%). b-blockers with ISA may increase HDL. Newer
type b-blockers (carvedilol, nebivolol) have less or
absent adverse effects on lipid measurements.
Thiazide diuretics (high doses) increase total cholesterol

(5%) and triglycerides (20%25%) but have no effect on
HDL. Low-dose diuretics have few if any effects on lipids.
Guanabenz decreases total cholesterol (10%15%).
27
9/29/09 10:52:37 AM
Liver disease All agents except methyldopa and labetalol Methyldopa and labetalol can be associated with
serious liver dysfunction, including hepatitis and
fulminant hepatic necrosis. Many antihypertensives are
hepatically-metabolized and require dosage adjustment.
Left ventricular hypertrophy ACE inhibitor, ARB, calcium antagonist; LVH is a major risk factor for stroke, MI, and cardiac
(LVH) b-blockers have lesser effects. Sodium death. Weight loss, low sodium diet, and all drugs
restriction may also reduce LVH except direct vasodilators decrease LV wall thickness.
LVH with severe diastolic dysfunction: In LIFE, losartan decreased the primary endpoint of
calcium antagonist or b-blocker. Avoid cardiovascular death, MI, or stroke by 15% (11% vs.
preload reducing agents (nitrates 13%. P = 0.021) at 4 years compared to atenolol in
diuretics), which may cause hypotension 9193 hypertensive patients with LVH by ECG, due
primarily to a reduction in stroke (5% vs. 7%).p In
1195 diabetics in LIFE, losartan reduced the primary
endpoint by 24% (18% vs. 23%, P = 0.031), including
death by 39% (6% vs. 10%) and admission for heart
failure by 40% (p. 89).
Myocardial infarction b-blocker (without ISA) and ACE inhibitor, b-blockers prevent recurrent MI and reduce long-term
ARB mortality,q adding to the benets of ACE inhibitors.r
Ramipril is approved for high-risk patients 55 years
Essentials
to reduce the risk of MI, stroke, and death from

cardiovascular causes, according to the HOPE trial.
Diltiazem or verapamil can be used if b-blockers prove
ineffective following non-Q-wave MI or Q-wave MI
with preserved LV function (may improve event-free
survival).
9/29/09 10:52:37 AM
Osteoporosis Thiazide diuretic Hypertension is associated with increased bone-mineral
loss in elderly females, which may contribute to the risk
of hip fractures.s
Thiazide diuretics decrease the rate of bone-mineral
losst and may prevent hip fracture in osteopenic post-
menopausal females.u
Peripheral vascular disease Vasodilator, ACE inhibitor, ARB*, or Claudication may worsen as BP is lowered. Ramipril is
calcium antagonist approved for patients 55 years to reduce the risk of MI,
Avoid non-selective b-blockers, which stroke, and death from cardiovascular causes, according
may induce peripheral vasoconstriction to the HOPE trial. It is unknown whether antihypertensive
and increase symptoms
therapy halts the progression of carotid/peripheral
atherosclerosis and aneurysms. Consider addition of an
antiatherosclerotic statin to lower lipids and reduce the
risk of future cardiovascular events. Antiplatelet drugs
(aspirin or clopidogrel) are also recommended.
Prior stroke or TIA ACE inhibitor with or without diuretic; ARB. Thiazide diuretics have been shown to reduce the
recurrence of stroke by 20%30%.v In the PROGRESS
trial of 6105 patients with prior stroke or TIA with or
without hypertension, the combination of perindopril
(ACE inhibitor; 4 mg/d) plus indapamide (indoline
diuretic) reduced the risk of recurrent stroke by 43%
compared to placebo;w perindopril alone had no effect
on recurrent stroke. However, in HOPE, ramipril reduced
the risk of MI, stroke, or death by 35% at 5 years in

patients with known cerebrovascular disease.x
29
9/29/09 10:52:38 AM

Pregnancy Methyldopa or hydralazine If patient enters pregnancy on diuretic, therapy
should be continued. Methyldopa and hydralazine
are the only drugs approved in the U.S., but calcium
antagonists and labetalol are widely used outside the
U.S. ACE inhibitors, ARBs, and direct renin inhibitors are
contraindicated (fetal toxicity).

Preoperative If oral intake must be interrupted, parental Patients with preoperative hypertension, even if
or transdermal medications may be used. controlled, may have labile BP during anesthesia/surgery.
Proceed with surgery unless the diastolic BP exceeds
110 mmHg. Patients on chronic diuretics may need uids
to restore intravascular volume and prevent intraoperative
hypotension. Agents that increase shear force (e.g.,
hydralazine) increase the risk of post-op bleeding from
vascular suture lines and should be avoided.
Pulmonary hypertension Endothelial antagonists e.g., bosentan Instruct patients to avoid isometric activity, administer
Primary (Note: side effect issues, including annual inuenza and pneumonia vaccines, and treat
teratogenicity, limit use in systemic pulmonary infections aggressively. An endothelial-1
hypertension) antagonist (bosentan) was shown to be of benety and
Essentials
has been approved for this indication.

Pulmonary hypertension Hypoxic lung disease: oxygen (diuretics Calcium antagonists and vasodilators may antagonize
Secondary for right heart failure). hypoxic pulmonary vasoconstriction, exaggerate V/Q
Immunosuppressive therapy for mismatch, and worsen hypoxemia in patients with
collagen vascular disease; valvuloplasty severe hypoxic lung disease.
or valve replacement for mitral
stenosis; repair of congenital shunt;
thromboendarterectomy for proximal
chronic pulmonary embolism.
9/29/09 10:52:38 AM
Chronic kidney disease ACE inhibitor, ARB. Thiazides may not be BP goal: 130/80 mmHg Control of BP slows the
(estimated GFR < 60 ml/min) effective as GFR declines. Loop diuretics progression of renal failure.
require multiple daily (furosemide) or Volume excess contributes signicantly to most cases
once daily (torsemide) doses; metolazone of hypertension. Therefore, diuretics are often used
is effective once daily), calcium alone or in combination with other agents. Thiazides,
antagonist, or labetalol. with the exception of the long-acting and potent
Combination therapy is often required. agent metolazone are ineffective in patients with
May need to add minoxidil for refractory glomerular ltration rates < 30 cc/min. Multiple daily
cases. doses of short-acting loop diuretics (furosemide) or
Proteinuric nephropathy: ACE inhibitor once-daily torsemide may be needed. The addition
or ARB; ACE inhibitor-calcium antagonist of metolazone may improve the efcacy of loop
combination may have additive diuretics. Avoid potassium-sparing diuretics.
antiproteinuric effects. ACE inhibitors have been shown to decrease
Avoid potassium-sparing diuretics and proteinuria and slow functional deterioration in patients
potassium supplements. with diabetic and other proteinuric nephropathies.
End-stage renal disease may require ARBs have benecial renal effects in Type 2 diabetic
dialysis or renal transplantation for BP nephropathy. Hyperkalemia is an important adverse
control. effect, and there is an increased risk of acute renal
failure in patients with bilateral renal artery stenosis or
renal artery stenosis of a solitary kidney.
Chronic kidney disease For diabetic nephropathy, see p. 23. Many If serum creatinine rises 1 mg/dL after starting an ACE
blood pressure medications are excreted by inhibitor or ARB, consider the diagnosis of renal artery
the kidneys and require dose adjustment. stenosis and possibly discontinue these drugs.
Smokers ACE inhibitor, ARB, or calcium antagonist: Hepatically-metabolized b-blockers propranolol, timolol,
possibly a-blocker. metoprolol, labetalol are often less effective in smokers.
31
9/29/09 10:52:38 AM

Systolic hypertension (isolated) Diuretic, ACE inhibitor, ARB or Isolated systolic hypertension occurs in 15% of
in the elderly dihydropyridine calcium antagonist, persons > 60 years of age (and combined systolic/
starting with low doses and adjusting in diastolic hypertension is even more common). The
small increments to lower BP slowly and goal of therapy is to reduce systolic BP to < 140 mmHg
minimize the risk of cerebral ischemia. (though in the HYVET trial there were mortality and
ACE inhibitor or ARB* if heart failure or morbidity benets when systolic BP reduced into 150s).
diabetic nephropathy is present. Low-dose diuretics and long-acting dihydropyridine

Therapeutic lifestyle changes may rarely calcium antagonists have been associated with
be sufcient to control hypertension 25%45% reductions in stroke, MI, and heart failure
(p. 16). over 2 years, according to the SHEP and SYST-EUR
trials. Among diabetic elderly patients in Syst-Eur,
active treatment reduced overall mortality by 55%,
cardiovascular mortality by 76%, strokes by 73%, and
cardiac events by 63%.z
Long-acting calcium antagonists reduced the risk
of dementia by 50% in SYST-EUR (from 7.7 to
3.8 cases/1000 patient years).
b-blockers alone have not been shown to reduce
mortality in the elderly.
Exclude white-coat hypertension and
pseudohypertension (p. 8); consider multiple BP
measurements before starting therapy.
Essentials
Valve disease Valvuloplasty or surgery. Systolic hypertension is unusual. Avoid agents that
Aortic stenosis, severe decrease afterload (nitrates, ACE inhibitors. ARBs,
Mitral stenosis vasodilators, a-blockers) or lower cardiac output
Aortic or mitral regurgitation, (b-blockers, non-dihydropyridine calcium antagonists)
chronic
Mitral valve prolapse
b-blocker or calcium antagonist Agents that slow resting heart rate and blunt exercise-
induced tachycardia improve symptomatic status.
9/29/09 10:52:38 AM
Nifedipine, ACE inhibitor, or ARB; diuretics Afterload reduction improves forward stroke volume
for pulmonary congestion and functional status.
b-blocker b-blockers may be useful for arrhythmias or psychogenic
symptoms.
Women Same as for men No signicant gender differences exist regarding the
management of hypertension or the response to therapy.
Young patient ACE inhibitor, ARB, or calcium antagonist Use agents that do not cause sexual dysfunction or
impair exercise tolerance.
Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; ARB*, angiotensin II receptor blocker for patients who develop
an intolerant cough from ACE inhibitors. See pp. 3941 for drug dosages.
a
N Engl J Med 2000;342:145.
b
JAMA 1997;277:12931298.
c
JAMA 2002;288:29812997.
d
Lancet 1998;351:17551762
e
BMJ 1998;317:703713
f
Lancet 2000;355:253259
g
N Engl J Med 2001;345:851869.
h
Circulation 2002;106:672678; N Engl J Med 2001;345:870878.
i
Lancet 2000;355:253259
j
N Engl J Med 1999;340:677684; BMJ 1998;317:713720)
k
Diabetes Care 2002;25:134147 and 213229.
l
Lancet 1998;352:13471351; Arch Intern Med 2002;162:20462052.
m
Lancet 2000;255:15821587.
n
N Engl J Med 2001;345:16671675.
o
N Engl J Med 1996;335:11071114; Am J Cardiol 1998;82:881887
p
Lancet 2002;359:8951003.
q
JAMA 1988;260:20882093.
r
J Am Coll Cardiol 1997;29:229236
s
Lancet 1999;354:971975.
t
N Engl J Med 1983;309:344.
u
Am J Epidemiol 1994;139:11071115.
v
Stroke 1997;28:25572562.
w
Lancet 2001;358:10331041.
x
N Engl J Med 2000;342:145153.
y
N Engl J Med 2002;346:896903.
33
z
N Engl J Med 1999;340:677684.
9/29/09 10:52:38 AM
Chapter 4
Antihypertensive Drug Classes: Mechanism of Action
and Selected Features
DIURETICS AND POTASSIUM SPARERS (Table 4.1)
A. Mechanism of Action. Thiazide and loop diuretics lower blood pressure by decreasing
intravascular blood volume and peripheral resistance.
B. Major Uses. Diuretics are particularly effective at potentiating the effects of other
antihypertensives; low-dose hydrochlorothiazide (HCT; 12.525 mg) in xed-dose com-
bination with a -blocker, ACE inhibitor, or angiotensin receptor blocker (ARB), is often
used as rst-line therapy. However, such low doses of HCT (when used as a single agent)
have never been shown to reduce cardiovascular events. On the other hand, the longer
acting and more potent chlorthalidone, used in the ALLHAT trial (2002), had the same
effect on the incidence of combined fatal coronary heart disease and nonfatal MI (primary
outcome) as amlodipine or lisinopril. If a diuretic is not chosen initially, it should probably
be added next, as it will enhance the effect of most antihypertensive drugs. Potassium-
sparing diuretics (amiloride, eplerenone, spironolactone, triamterene) are primarily used
with other diuretics to avoid or reverse hypokalemia. Potassium-sparing diuretics should
be avoided in patients with renal insufciency and those taking potassium supplements,
ACE inhibitors, ARBs, or direct renin inhibitors (DRIs).
C. Dosage and Administration. Once-daily dosing is adequate. Recommended starting and

maximal doses for chlorthalidone are 12.5 mg and 25 mg, the equivalent of 25 mg and
50 mg of hydrochlorothiazide. Higher doses increase the risk of electrolyte, carbohydrate,
and lipid disturbances. The major antihypertensive response to diuretics is seen within
12 weeks of starting therapy or adjusting the dose. Patients with moderate renal
insufciency and volume-dependant hypertension who do not respond to thiazides may
require a high-potency diuretic (metolazone or indapamide), a loop diuretic (furosemide,
bumetanide, or the longer-acting agent, torsemide), or a combination of metolazone plus
a loop diuretic.
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Chapter 4. Antihypertensive Drug Classes 35
Table 4.1. Diuretics and Potassium-Sparing Agents
Drug Daily Dosage, mg Duration of Action, hrs
Thiazides
Bendroumethiazide 1.255.0 18
Benzthiazide 50200 1218
Chlorothiazide 2501000 612
Hydrochlorothiazide 12.550 1218
Hydroumethiazide 12.550 1218
Trichlormethiazide 1.04.0 1824
Related sulfonamide compounds
Chlorthalidone 12.550 2472
Indapamide 1.252.5 24
Metolazone
Mykrox 0.51.0 24
Zaroxolyn 2.510 24
Loop Diuretics
Bumetanide 0.55.0 46
Ethacrynic acid* 25100 12
Furosemide 20480 46
Torsemide 540 12
Potassium-sparing agents
Amiloride 510 24
Triamterene 50150 12
Aldosterone blockers
Spironolactone 25100 812
Eplerenone 50100 12
*Not being marketed in the United States.
77883_CH04_print.indd 35 9/29/09 10:51:59 AM

D. Frequent or Serious Adverse Effects

1. Thiazides: More frequenthyperuricemia, hypokalemia, hypomagnesemia, hyper-
glycemia, hyponatremia, hypercalcemia. Less frequentpancreatitis, rashes/other
allergic reactions, sexual dysfunction, photosensitivity reactions, may decrease
excretion of lithium.
2. Loop diuretics: Dehydration, circulatory collapse, hypokalemia, hyponatremia,

hypomagnesemia, hyperglycemia, metabolic alkalosis, hyperuricemia, blood
dyscrasias, rashes.
3. Potassium-sparing diuretics: Amiloride: hyperkalemia, GI disturbances, rash.

Triamterene: hyperkalemia, GI disturbances, nephrolithiasis. Spironolactone and
eplerenone are covered in the next section.
ALDOSTERONE BLOCKERS
Spironolactone and eplerenone bind to the mineralocorticoid receptor and block the bind-
ing of aldosterone, a component of the renin-angiotensin-aldosterone-system. Aldosterone
binds to mineralocorticoid receptors in the kidney, heart, blood vessels, and brain, increasing
blood pressure by direct vasoconstrictor actions as well as by inducing sodium reabsorption
in the kidney. Compared to spironolactone, eplerenone has a greater relative selectivity in
binding to mineralocorticoid receptors rather than to progesterone and androgen receptors,
resulting in a side effect prole that is better tolerated than spironolactone. Blood pressure
lowering is evident within 2 weeks from the start of therapy, with maximal antihypertensive
effects achieved within 4 weeks. Both agents have been shown to lower blood pressure when
given as monotherapy or as part of combination therapy with ACE inhibitors, ARBs, DRIs,
calcium channel blockers, -blockers, or hydrochlorothiazide (Chapman, 2007). Both agents
are generally contraindicated in patients with serum potassium > 5.5 mEq/L, serum creatinine
> 2.0 mg/dL in males or > 1.8 mg/dL in females, or creatinine clearance < 30 mL/min. They also
are contraindicated in patients treated with potassium supplements or potassium-sparing diuret-
ics, e.g., amiloride or triamterene. Because the principal risk of these agents is hyperkalemia,
periodic monitoring of serum potassium is recommended in patients at risk for the develop-
ment of hyperkalemia (e.g., concomitant ACE inhibitors, ARBs or DRIs). Starting doses are
25 mg for spironolactone and 50 mg eplerenone. These agents may provide additional protec-
tion against the pro-brotic effects of aldosterone (Schiffrim, 2006).
ACE INHIBITORS (Table 4.2)
A. Mechanism of Action. An activated renin-angiotensin system plays an important

role in the genesis of hypertension. Angiotensin II causes direct vasoconstriction,
77883_CH04_print.indd 36 9/29/09 10:51:59 AM

salt and water retention, and sympathetic nerve stimulation, all of which increase
blood pressure. ACE inhibitors exert their major antihypertensive effect by blocking the
conversion of angiotensin I to angiotensin II via inhibition of angiotensin converting
enzyme. This results in inhibition of angiotensin Il-mediated vasoconstriction and
aldosterone secretion, thereby lowering blood pressure (Figure 4.1). ACE inhibitors
also inhibit the degradation of bradykinin, which may contribute to their hypo-
tensive effects, but are also likely responsible for the cough seen in about 10% of
patients.
B. Major Uses. ACE inhibitors are powerful antihypertensive agents. In patients with
atherosclerotic vascular disease, systolic heart failure, asymptomatic LV dysfunction,
or prior myocardial infarction, ACE inhibitors improve event-free survival (Matcher
et al, 2008). In patients with Type 1 diabetes or proteinuric nephropathy, they reverse,
or slow, the progression of renal insufciency (Kunz et al, 2008). Possible mechanisms
by which ACE inhibitors improve cardiovascular and renovascular prognosis include
blood pressure lowering, reversal of endothelial dysfunction, reduction in left ventricular
mass and arterial wall stiffness, and lowering of intraglomerular pressure (Lassila
et al, 2004).
C. Administration and Monitoring. Patients recently started on diuretics and those

on severe sodium restriction or dialysis may experience a precipitous drop in blood
pressure early (usually within one hour) after receiving the initial dose of an ACE
inhibitor. This risk can be minimized by withholding diuretics or increasing salt intake
for several days prior to starting a low-dose ACE inhibitor. Alternatively, patients can
be supervised for one hour after the initial dose. (A hypotensive response to ACE
inhibitors does not preclude further therapy once intravascular volume is restored.)
Patients receiving ACE inhibitors should be followed for hyperkalemia, especially those
with signicant renal insufciency, renovascular hypertension, diabetes mellitus, or
hypoaldosteronism. Monitoring for progressive azotemia is warranted in patients with
severe heart failure whose renal function depends on the renin-angiotensin-aldosterone
system. ACE inhibitors should not be used in patients suspected to have bilateral renal
artery stenosis, during pregnancy, or during breastfeeding. ACE inhibitors can be
combined with a diuretic to offset potential potassium retention, or with a calcium
antagonist to provide additional antiproteinuric effects and improve prognosis in the
elderly (Jamerson, 2008).
D. Frequent or Severe Adverse Effects. More frequent: Cough (7%15%); hypotension,

particularly in patients who are volume depleted or receiving diuretics; rash; acute
renal failure in patients with bilateral renal artery stenosis or unilateral renal artery
stenosis of a solitary kidney; angioedema; hyperkalemia, particularly in patients
taking potassium supplements or potassium-sparing diuretics. Less frequent: loss of
taste; blood dyscrasias; increased risk of fetal mortality when administered during
pregnancy.
77883_CH04_print.indd 37 9/29/09 10:51:59 AM

2
Renin
1 Inhibition
Adrenergic 3
Blocker Renin
CE
Substrate
Inhibitor
J-G Renin converting 4
Angiotensin I enzyme Angiotensin II Angiotensin
Blocker
aldosterone
synthesis
vasoconstriction
sodium retention
FEEDBACK blood
pressure
Figure 4.1. The renin-angiotensin system and four sites where its activity may
be inhibited. CE, converting enzyme; J-G, juxtaglomerular
ANGIOTENSIN II RECEPTOR BLOCKERS (Table 4.3)
A. Mechanism of Action. Angiotensin II receptor blockers (ARBs) inhibit the nal step of
the renin-angiotensin cascadethe interaction between angiotensin II and the angiotensin II
Type 1 receptor (AT1)which is thought to mediate all pressor effects of this hormone
and some of its effects that promote atherosclerosis. ARBs result in more complete
antagonism of angiotensin II than ACE inhibitors, because angiotensin II can be produced
by non-ACE pathways (Figure 4.2). ARBs do not cause elevations in bradykinin, which
may be responsible for the dry cough seen with ACE inhibitors. Other comparative effects
between ARBs and ACE inhibitors are shown in Table 4.4.
B. Clinical Effects. Studies indicate that: (1) ARBs are as effective at lowering blood
pressure as other antihypertensive agents, and they are especially effective when
used with a diuretic; (2) ARBs are better tolerated than ACE inhibitors and other
antihypertensive agents, with a side effect prole no different than placebo (Mancia
et al, 2003); (3) ARBs reduce proteinuria and slow the deterioration in renal function
in diabetic nephropathy (Brenner et al, 2001); (4) ARBs regress LVH and reduce
77883_CH04_print.indd 38 9/29/09 10:51:59 AM

Table 4.2. Characteristics of Angiotensin-Converting Enzyme Inhibitors
Rate of Duration of Dose
Drug Zinc Ligand Prodrug Elimination Action, h Range, mg
Benazepril Carboxyl Yes Renal 24 540

Captopril Sulfhydryl No Renal 612 25150
Cilazapril Carboxyl Yes Renal 24+ 2.55.0
Enalapril Carboxyl Yes Renal 1824 540
Fosinopril Phosphoryl Yes Renal-hepatic 24 1040
Lisinopril Carboxyl No Renal 24 540
Moexipril Carboxyl Yes Renal 1218 7.530
Perindopril Carboxyl Yes Renal 24 416
Quinapril Carboxyl Yes Renal 24 580
Ramipril Carboxyl Yes Renal 24 1.2520
Spirapril Carboxyl Yes Hepatic 24 12.550
Trandolapril Carboxyl Yes Renal 24+ 18
Table 4.3. Angiotensin II-Receptor Blockers

Active Daily Dosage,
Drug Trade Name Half-Life, h Metabolite mg
Candesartan Atacand 311 Yes 832 in 1 dose
Eprosartan Teveten 57 No 400800 in
12 doses
Irbesartan Avapro 1115 No 150300 in
1 dose
Losartan Cozaar 2 (69) Yes 50100 in
12 doses
Olmesartan Benicar 13 Yes 2040 in 1 dose
Telmisartan Micardis 24 No 4080 in 1 dose
Valsartan Diovan 9 No 80320 in
1 dose
77883_CH04_print.indd 39 9/29/09 10:51:59 AM

Table 4.4. Comparison of ACE Inhibitors and ARBs
ACE Inihibitors ARBs
Plasma renin activity Increased Increased
Levels of angiotensin I Increased Increased
Effects on angiotensin II formed by alternate None Blocked
pathways
Levels of angiotensin II Decreased Increased
Activation of angiotensin II receptor subtypes
AT1 Decreased Decreased
AT2AT4 Decreased Increased
Serum levels of bradykinin Increased No Change
Abbreviations: ACE = angiotensin converting enzyme, ARB = angiotensin II receptor blocker.
the risk of the composite endpoint of death, MI, or stroke to a greater extent than
-blockers in hypertensive patients with LVH (Dahlof et al, 2002); and (5) ARBs are
likely as effective as ACE inhibitors in improving functional status and event-free
survival in heart failure (Lee et al, 2004). Because of their absence of side effects,
ARBs have been used in trials of prehypertension to delay the onset of hypertension
(Julius et al, 2006). In the ONTARGET trial (2008), an ARB, telmisartan, was equally
protective against major cardiovascular events as the ACEI ramipril. However, there
is no reason to substitute telmisartan for ramipril, except in cases of intolerance to
ACE inhibitors, or possibly when telmisartans antihypertensive efcacy might be of
value. For patients without these conditions, ARBs can be considered along with other
available agents as rst-line therapy. Patients who experience side effects from other
classes of drugs often benet from ARBs. Because ARBs have different modes of
action than ACE inhibitors, ARBs may have additive effects with ACE inhibitors on
proteinuria, but the combination induced more side effects than either alone in the
ONTARGET trial and is not recommended for routine use.
C. Administration and Side Effects. Antihypertensive effects usually become apparent

within 12 weeks after initiation of therapy and are augmented by the addition of a
thiazide diuretic. Unlike ACE inhibitors, which can produce a dry, persistent cough in
7%15% of patients, ARBs are rarely associated with this complication. They have
no major effect on routine laboratory parameters. ARBs have been associated with
angioedema less commonly than have ACE inhibitors. Other adverse effects include
hyperkalemia (especially in patients with potassium-sparing diuretics, signicant renal
insufciency, renovascular hypertension, diabetes mellitus, or hypoaldosteronism), and
oliguria/progressive azotemia in patients with severe heart failure whose renal function
77883_CH04_print.indd 40 9/29/09 10:51:59 AM

ANGIOTENSINOGEN other substrates?
non renin renin

RENIN
blockade
ANGIOTENSIN I BK and substrates
non ACE ace ACE

inhibitors
ANGIOTENSIN II
A II RECEPTOR
ANTAGONIST
AT II AT I
? Physiological
Actions Actions
Figure 4.2. ACE inhibitors block the conversion of angiotensin I and angiotensin
II via angiotensin converting enzyme, but do not prevent the formation of
angiotensin II via alternate pathways. Angiotensin II receptor blockers (ARBs)
work at the receptor level to block the binding of angiotensin II to its Type 1
receptor (AT1), which mediates all known pressor effects of angiotensin II.
(BK,bradykinin)
Adapted from: J Human Hypertension. 1995;9:375380
depends on the renin-angiotensin-aldosterone system. Losartan has a uricosuric effect.

ARBs should not be used in patients with bilateral renal artery stenosis, during pregnancy,
or during breast-feeding.
DIRECT RENIN INHIBITORS (DRI)
Only one DRI, aliskerin, is available as of mid 2009. This agent blocks the activity of the enzyme
renin on its protein substrate, angiotensinogen (site 2 in Figure 4.1). Thereby levels of both the
inactive angiotensin I and the active angiotensin II are reduced and the blood pressure falls. The
77883_CH04_print.indd 41 9/29/09 10:51:59 AM

agent lowers blood pressure as well as ACE inhibitors and ARBs and may provide an additive
effect to them. Side effects are similar to the very infrequent side effects seen with ARBs.
In the absence of morbidity and mortality outcome data, DRIs are not recommended in the
place of either an ACE inhibitor or an ARB as rst line therapy, but might be valuable in multi-
drug combinations in treatment-resistant patients. Recently, aliskiren was made available in
a xed-dose combination with the thiazide diuretic, HCT. See the Appendix (p. 92) for more
information.
-BLOCKERS (Table 4.5)
A. Mechanism of Action. -blockers decrease cardiac output by blocking adrenergic

receptors in the heart, resulting in negative chronotropic (heart rate) and inotropic
(contractility) effects. -blockers also decrease renin release from the kidney (site 1 in
Figure 4.1) and are thought to decrease sympathetic outow to the periphery via a
central effect. Overactivity of the sympathetic nervous system increases blood pressure
mainly by increasing cardiac output. The increase in sympathetic nervous system activity
that accompanies the assumption of upright posture after overnight recumbency is likely
responsible for the increase in sudden death, heart attack, and stroke among hypertensive
patients in the early morning hours.
B. Properties. Three principal pharmacologic differences exist between -blockers, resulting

in varying durations of action and side effect proles (Table 4.5):
1. Lipid solubility. Lipid soluble agents more readily penetrate the brain and cause
more CNS side effects than non-lipid soluble agents.
2. -l (cardio) selectivity. Selective and nonselective -blockers lower blood pressure

to similar degrees. However, -1 selective agents may cause fewer side effects in
patients with bronchospasm, peripheral vascular disease, or diabetes, and they also
cause fewer disturbances in lipid metabolism. Nevertheless, patients with coexistent
medical conditions such as migraine, anxiety, and tremor often benet more from a
-2 blockade.
3. Intrinsic sympathomimetic activity (ISA). -blockers with ISA act as partial

agonists when background sympathetic activity is low and are less likely to cause
bradycardia, bronchospasm, claudication, and derangements in lipids than -blockers
without ISA.
C. Major Uses. -blockers are effective antihypertensive agents with proven benets on
survival in post-MI patients and those with systolic heart failure. However, they are less
effective in protecting against stroke as other agents (Lindholm, 2005). Young patients
and nonblacks are more responsive to monotherapy with a -blocker, whereas blacks and
the elderly respond better to diuretics and calcium channel blockers. -blockers should not
be given to patients with marked sinus bradycardia, greater than rst-degree AV block or
77883_CH04_print.indd 42 9/29/09 10:51:59 AM

sick sinus syndrome without a functioning pacemaker, or severe decompensated heart

failure. -blockers should be used with caution in patients with signicant bronchospasm,
peripheral vascular disease, or insulin-requiring diabetes.
D. Frequency of Serious Adverse Effects. More frequent: Fatigue, bradycardia, decreased

exercise tolerance, worsening claudication in patients with peripheral arterial disease,
bronchospasm, masking of symptoms and delayed recovery from hypoglycemia, increase
in serum triglycerides, and lowering of HDL cholesterol. Less common: Insomnia, vivid
dreams or hallucinations, and impotence. Sudden withdrawal can lead to exacerbation of
angina and myocardial infarction. Side effects for -blockers with ISA are similar to other
-blockers, but with less resting bradycardia and lipid changes.
Table 4.5. Pharmacologic Properties of Some -Blockers
Intrinsic Usual Daily

Sympathomimetic Dosage
Drug 1-Selectivity Activity Lipid Solubility (Frequency)
Acebutolol + + + 2001200 mg (1)
Atenolol ++ 25100 mg (2)
Betaxolol ++ 540 mg (1)
Bisoprolol +++ + 2.520 mg (1)
Bucindolol + 50200 mg
Carteolol + 2.510 mg (1)
Carvedilol* +++ 12.550 mg (2)
Celiprolol ++ + 200400 mg (1)
Esmolol ++ 25300 g/kg/min iv
Labetalol* ++ 2001200 mg (2)
Metoprolol ++ ++ 50200 mg (2, 1)
Nadolol 20240 mg (1)
Nebivolol* ++ ++ 510 mg (1)
Penbutolol + +++ 1020 mg (1)
Pindolol +++ ++ 1060 (2)
Propranolol +++ 40240 mg (2, 1)
Timolol ++ 1040 mg (2)
Symbols are: (+, ++, and +++) indicates the magnitude of the effect on various properties; () no effect.
*Vasodilating
77883_CH04_print.indd 43 9/29/09 10:52:00 AM

VASODILATING -BLOCKERS
Modication of the conventional -blocker structure has provided agents with combined
a and -blocking properties, including labetalol, carvedilol, and another that apparently
increases availability of nitric oxide, nebivolol. The antihypertensive effects of these agents
are due mainly to a fall in systemic vascular resistance, with little effect on cardiac output.
Labetalol has been used both orally and intravenously to treat hypertensive emergencies,
including postoperative hypertension and acute aortic dissection. In the COPERNICUS trial,
carvedilol reduced the risk of death or hospitalization in patients with chronic systolic heart
failure by 27%, including patients with Class IV symptoms (Packer et al, 2002). Symptomatic
and metabolic adverse events appear to be less common with the vasodilatory beta blockers
than with the traditional agents.
CALCIUM CHANNEL BLOCKERS (Table 4.6)
A. Mechanism of Action. Calcium channel blockers (CCBs) block or alter cell membrane
calcium ux. Dihydropyridine calcium channel blockers (e.g., amlodipine, felodipine,
nifedipine) lower blood pressure chiey via arteriolar and venous vasodilation; non-
dihydropyridine calcium channel blockers (e.g., verapamil, diltiazem) are less potent
vasodilators and probably lower blood pressure through peripheral vasodilation and a
negative inotropic effect.
B. Major Uses. Controversy about the safety of CCBs arose largely from retrospective case-
controlled studies implicating various short-acting CCBs as a cause of coronary disease,
cancer, and GI bleeding. Although there is a danger from large doses of short-acting
agents, particularly liquid nifedipine, in vulnerable patients with coronary artery disease,
the safety and effectiveness of long-acting calcium channel blockers have now been well-
documented (Eisenberg, 2004). In multiple large trials, long-acting CCBs have reduced
fatal and non-fatal cardiac events, including sudden death, both in older patients with
isolated systolic hypertension (SHEP, 1991) and in high risk hypertensives (Hansson,
2000); benets were especially pronounced in diabetics (Hansson, 1998). A meta-analysis
of CCBs versus conventional therapy, which included 24 trials, demonstrated similar risks
of major cardiovascular events, except for a 9% increase in studies with short-acting
agents (Eisenberg, 2004) (Table 4.7). ALLHAT conrmed the efcacy and safety of CCBs
as antihypertensive agents: There was no difference in the incidence of combined fatal
coronary heart disease and nonfatal MI (primary outcome) or in the risk of cancer or
GI bleeding with amlodipine, chlorthalidone, or lisinopril (ALLHAT, 2002).
Elderly patients and blacks are particularly well-suited for CCBs, and CCBs also have a benecial
role in hypertensive patients with angina, renal insufciency (may have renoprotective effects
and additive antiproteinuric effects when used in conjunction with an ACE inhibitor), or dia-
stolic heart failure. CCBs are also appropriate in combination therapy for difcult-to-control
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Table 4.6. Calcium Channel Blockers Approved for Use in the Treatment of
Hypertension in the United States
Time to Peak Elimination
Drug Form and Dose Effect, hrs Half-Life, hrs
Amlodipine Tablet; 2.510 mg 612 3050
Diltiazem Immediate-release tablet; dose varies 0.51.5 25
Sustained-release tablet; 180480 mg 611 25
Felodipine Sustained-release tablet; 2.510 mg 2.55 1116
Isradipine Tablet; 2.510 mg 1.5 812
Nicardipine Immediate-release tablet; 2040 mg 0.52.0 8
Nifedipine Immediate-release capsule; dose 0.5 2
varies
Nisoldipine Sustained-release tablet; 2040 mg 612 712
Verapamil* Immediate-release tablet; dose varies 0.51.0 4.512
Sustained-release tablet; 120480 mg 46 4.512
*Also available in an intravenous formation, with a time to peak effect ranging from 515 minutes
after administration.
hypertension. CCBs should not be used as initial therapy for hypertensive diabetics, especially
if proteinuria is present (ACE inhibitors or angiotensin II receptor antagonists are preferred), or
for hypertension associated with heart failure (ACE inhibitors with diuretics and cautious use
of -blockers are preferred) or recent MI (ACE inhibitors and -blockers are preferred).
C. Frequency of Serious Adverse Effects. Dihydropyridines: dizziness, headache,

peripheral edema (more than with verapamil and diltiazem; more common in
women), ushing, tachycardia, rash, gingival hyperplasia. Non-dihydropyridines:
dizziness, headache, edema, constipation (especially verapamil), AV block, bradycardia.
-1 ADRENERGIC BLOCKERS
These drugsprazosin, doxazosin, and terazosinlower blood pressure by blocking post-

synaptic a-receptors in arterioles and venules, thus inhibiting sympathetic tone. Postural
hypotension occurs as a transient problem in up to half of the patients taking the short-acting
77883_CH04_print.indd 45 9/29/09 10:52:00 AM

Table 4.7. Major Cardiovascular Events with CCBs versus Other
Antihypertensive Drugs
Major Cardiovascular Events*
N Events/N Patients (%)
Relative Risk
CCB Formulation N Trials CCBs Others (95% CI)
Short-acting 7 1222/9351 (13.1) 1768/11,691 (15.1) 1.09 (1.001.18)
Long-acting 5 2567/31,934 (8.0) 3546/38,278 (9.3) 1.01 (0.961.07)

Non- 4 1359/25,625 (5.3) 1365/25,848 (5.3) 1.00 (0.931.09)
dihydropyridine
Dihydropyridine 8 2430/15,630 (15.5) 3949/24,121 (16.4) 1.05 (0.991.11)
*Major cardiovascular events included myocardial infarction, heart failure, stroke, and cardiovascular
mortality, except in ALLHAT, where composite coronary heart disease included death from coronary
heart disease, nonfatal myocardial infarction, coronary revascularization procedures, and angina requiring
hospitalization, and in INVEST, where the primary outcome was cardiovascular mortality.
Data are from Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med
2004;116:3543.
prazosin. Other adverse side effects include dizziness, vertigo, headache, palpitations,
drowsiness, weakness, anticholinergic effects, and priapism. These drugs have been used
most commonly in hypertensive patients with benign prostatic hypertrophy, due to their
ability to decrease obstructive urinary symptoms. However, their utility as antihypertensive
agents has been called into question in the ALLHAT trial (2000), where doxazosin proved
inferior to chlorthalidone at preventing heart failure, although there was no difference in
overall mortality.
CENTRAL -ADRENERGIC AGENTS
Clonidine, guanabenz, and guanfacine are central adrenergic agonists that stimulate a-2
adrenergic receptors in the brain, thereby inhibiting sympathetic outow to the peripheral
vasculature. Methyldopa lowers blood pressure by forming methylnorepinephrine, which
also is a CNS adrenergic agonist. Rebound hypertension may follow after abruptly discon-
tinuing these agents, particularly oral clonidine. Treatment consists of reinstituting the drug.
Patients known to be erratic in taking medication should not receive these drugs, though
the transdermal form of clonidine works for 7 days and is not associated with rebound prob-
lems. Common adverse effects include sedation, dry mouth, constipation, and orthostatic
symptoms. Methyldopa also can cause mood alteration, impotence, diarrhea, and a positive
direct Coombs test (10%). Methyldopa can cause hepatitis and is contraindicated in active
liver disease.
77883_CH04_print.indd 46 9/29/09 10:52:00 AM

DIRECT VASODILATORS
These drugs enter vascular smooth muscle cells to cause direct vasodilation, in contrast to
antihypertensive agents that vasodilate by inhibiting hormonal vasoconstrictor mechanisms
(e.g., ACE inhibitors), preventing calcium entry into cells that initiate constriction (e.g., cal-
cium channel blockers), or blocking a-receptor-mediated vasoconstriction (e.g., a-l blockers).
Oral direct vasodilators include hydralazine and minoxidil; intravenous agents include hydrala-
zine, nitroprusside, and nitroglycerin. Hydralazine is used infrequently as an antihypertensive
agent, although it may be used in conjunction with isosorbide dinitrate as an alternative to
angiotensin II receptor blockers in systolic heart failure patients intolerant of ACE inhibitors.
It has been used to treat the hypertension of eclampsia also. Adverse effects include tachy-
cardia, angina, headache, dizziness, uid retention, nasal congestion, lupus-like syndrome,
and hepatitis.
Minoxidil has been usually restricted to patients with severe hypertension associated with
renal insufciency. Adverse effects include tachycardia, angina, uid retention, pericardial
effusion, and hirsutism.
To be fully effective, these direct vasodilators should generally be administered in combina-
tion with diuretics and -blockers. Nitroprusside and nitroglycerin are used for hypertensive
crisis (Chapter 5).
CHOICES OF THERAPY
Most recent guidelines from expert committees recommend that therapy may be initiated
with any of the 5 major classes-diuretics, -blockers (now indicated only for those with a
compelling indication as seen in Table 4.8), ACE inhibitors, ARBs or CCBs (Task Force, 2007;
Williams et al, 2004). The 2003 report of the Joint National Committee favored the use of a
thiazide diuretic as the rst choice (Chobanian et al, 2003).
The compelling indications shown in Table 4.8 often include more drugs for some of the
conditions than may be needed for adequate therapy.
Most hypertensives will require 2 or even 3 drugs from different classes to achieve adequate
control, dened as a level below 140/90 mmHg for uncomplicated hypertension, below
130/80 for hypertensives with diabetes, chronic kidney disease or severe coronary disease,
and a systolic below 150 mmHg for those with isolated systolic hypertension. The rst for-
mulation of 3 modern drugs has recently been approved with the diuretic, HCT; the ARB,
valsartan; and the CCB, amlodipine. This single tablet 3-drug combination is called Exforge
HCT. See the Appendix (p. 83) for more information.
A new type of antihypertensive drug, the endothelin antagonist, darusentan, is undergoing
extensive testing and may soon be available, in particular for resistant hypertension.
The general characteristics of the major classes of antihypertensive drugs are shown in
Table 4.9 and the considerations for individualizing therapy are shown in Table 4.10.
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Table 4.8. Clinical Trial and Guideline Basis for Compelling Indications for Individual
Drug Classes
Recommended Drugs
Compelling Indication Diuretic B ACEI ARB CCB Aldo Ant
Heart failure
Post-myocardial infarction
High coronary disease risk
Diabetes
Chronic kidney disease
Recurrent stroke
prevention
Symbol () indicates recommended drug.

Abbreviations: B, -blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin
receptor blocker; CCB, calcium channel blocker; Aldo Ant, aldosterone antagonist.
Modied from Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:
12061252.
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Table 4.9. Characteristics of Major Classes of Antihypertensive Drugs
ACE Inhibitors;
Consideration Diuretics -Blockers -Blockers AII Blockers CCBs
Hemodynamic Initial volume Peripheral vasodilation Initially reduce cardiac Peripheral Peripheral
effect shrinkage; output vasodilation vasodilation
peripheral
vasodilation
Side effects Weakness, palpitations Postural dizziness Bronchospasm; Cough; Flushing; local edema;
Overt fatigue; prolong angioedema constipation
hypoglycemia (verapamil)
Hidden Hypokalemia; Glucose intolerance; Fetal toxicity AV conduction

hypercholesterolemia; hypertriglyceridemia; (verapamil,
glucose intolerance; decrease HDL diltiazem)
hyperuricemia cholesterol
Contraindications Pre-existing volume Orthostatic hypotension Asthma; heartblock Pregnancy Post-MI

contraction (dihydropyridines)
Cautions Diabetes mellitus; gout; Congestive heart Peripheral vascular Renal insufciency; Heart failure
digitalis toxicity failure disease; insulin- renovascular
Chapter 4. Antihypertensive Drug Classes
dependent diabetes; disease

allergy; coronary spasm
Special Effective in blacks and No decrease in Reduce recurrences No CNS side Effective in blacks
advantages elderly; enhance cardiac output; no of coronary disease; effects; treat and elderly;
effectiveness of all alteration in blood reduce manifestations CHF; post-MI, no CNS side
other agents lipids; no sedation; of anxiety; coexisting reduce coronary effects; coronary
relieves symptoms of angina, CHF, disease and CHF; vasodilation
prostatic hypertrophy migraine, tremor renal protection
49
9/29/09 10:52:00 AM
Table 4.10. Considerations for Individualizing Antihypertensive Drug Therapya
May Have Favorable Effects on Comorbid Conditions May Have Unfavorable Effects on Comorbid Conditionsb
Condition Drug Condition Drug
Angina b-blockers, CCB Bronchospastic disease b-blockers
Atrial tachycardia and brillation b-blockers CCB (non-DHP) 2 or 3 heart block b-blockers
Cough from ACE inhibitor ARB Depression CCB (non-DHP)
Cyclosporine-induced CCB Dyslipidemia Central a-agonists
hypertension
Diabetes mellitus, particularly ACEI, ARB, low-dose diuretics, Gout Reserpinec
with proteinuria CCBs, b-blockers
Dyslipidemia a-blockers Heart failure b-blockers (non-ISA)
Essential tremor b-blockers (non-CS) Hyperkalemia Diuretics (high-dose)
Heart failure ACEI, ARB, Carvedilol, b-blockers, Diuretics
diuretics
Hyperthyroidism b-blockers Liver disease CCBb
Migraine b-blockers (non-CS) CCB Peripheral vascular disease ACEI, ARB, DRI, aldo blockers
Osteoporosis Thiazides Pregnancy Labetalol
Preoperative hypertension b-blockers Renal insufciency Methyldopac
Previous MI b-blocker, ACEI, ARB Renovascular disease, b-blockersb
Prostatism a-blockers bilateral ACEIc, ARBc, DRIc
Renal insufciency ACEI, ARB, loop diuretic Type 1 and 2 diabetes Potassium-sparing agents,
Essentials
aldo-blockersb
Systolic hypertension in elderly Diuretics, CCB ACEI, ARB, DRI
b-blockers
High-dose diuretics
ACEI, angiotensin-converting enzyme inhibitor; Aldo, aldosterone; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; DRI, direct renin
inhibitor; DHP, dihydropyridine; non-CS, non-cardioselective; non-ISA, non-intrinsic sympathomimetic activity.
a
Conditions and drugs are listed in alphabetical order.
b
These drugs may be used with special monitoring, unless contraindicated.
c
Contraindicated.
9/29/09 10:52:00 AM
Section 2. Other Topics in Hypertension 51
Section 2
OTHER TOPICS IN HYPERTENSION
Chapter 5. Hypertensive Crisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Chapter 6. Resistant Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Chapter 7. Identiable (Secondary) Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Renal Parenchymal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Renovascular Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Primary Aldosteronism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Cushings Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Coarctation of the Aorta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Acromegaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Primary Hyperparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Additional Treatment for Other Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
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Chapter 5
Hypertensive Crisis
Hypertensive crisis is characterized by the presence of severe elevations in blood pressure
(e.g., diastolic BP > 120130 mmHg) that threaten end-organ function and prognosis without
immediate therapy. Hypertensive crisis is arbitrarily classied into hypertensive emergencies
and hypertensive urgencies. Hypertensive emergencies are conditions requiring acute blood
pressure lowering within minutes to hours with intravenous therapy in an intensive care unit.
Examples include hypertensive encephalopathy and extreme elevations in blood pressure
associated with acute pulmonary edema, dissecting aortic aneurysm, myocardial ischemia,
or intracerebral hemorrhage (Table 5.1). Hypertensive urgencies are conditions requiring
more gradual reductions in blood pressure with oral or parenteral therapy over a few hours.
Depending on clinical status, patients with hypertensive urgencies may require emergency
management. Hypertensive emergencies occur in fewer than 1% of patients with primary
(essential) hypertension and are more common in blacks.
Table 5.1. Hypertensive Emergencies
Accelerated-malignant hypertension with papilledema

Cerebrovascular conditions
Hypertensive encephalopathy
Atherothrombotic brain infarction with severe hypertension
Intracerebral hemorrhage
Subarachnoid hemorrhage
Head trauma
Cardiac conditions
Acute aortic dissection
Acute left ventricular failure
Acute or impending myocardial infarction
After coronary bypass surgery
Renal conditions
Acute glomerulonephritis
Renovascular hypertension
Renal crises from collagen-vascular diseases
Severe hypertension after kidney transplantation
Excess circulating catecholamines
Pheochromocytoma crisis
Food or drug interactions with monoamine oxidase inhibitors
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Chapter 5. Hypertensive Crisis 53
Table 5.1. Hypertensive Emergencies (cont'd)
Sympathomimetic drug use (cocaine)

Rebound hypertension after sudden cessation of antihypertensive drugs
Automatic hyperreexia after spinal cord injury
Eclampsia
Surgical conditions
Severe hypertension in patients requiring immediate surgery
Postoperative hypertension
Postoperative bleeding from vascular suture lines
Severe body burns
Severe epistaxis
Vascular damages caused by hypertensive emergencies are characterized by brinoid

necrosis, intravascular coagulation, and microangiopathic hemolytic anemia, and is more
closely related to the rapidity of rise in blood pressure than the absolute level per se. Hyperten-
sive encephalopathy can occur in previously normotensive individuals who develop an acute
rise in blood pressure to levels as low as 160/100 mmHg, as seen in pregnancy complicated
by eclampsia.
The initial goal of therapy is to decrease mean arterial pressure by 15%25% within min-
utes to a few hours (or to a diastolic BP of ~ 100110 mmHg); immediate restoration of blood
pressure to normal is not recommended. Drug therapy has improved 1-year survival from
25% to 90% and 5-year survival from 5%10% to 80%. Drugs used for treatment of hyper-
tensive emergencies are listed in Table 5.2. The choice of drug is in part dependent on the
medical setting. Nitroprusside requires constant supervision, whereas nicardipine, labetalol,
and cledipine can be used with less constant attention. Common oral agents used to treat
hypertensive crisis are shown in Table 5.3.
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Table 5.2. Parenteral Drugs for Treatment of Hypertensive Emergency
Duration
Adverse
Onset of Effectsb of
Druga Dose Action Action Side Effects Special Indications
Vasodilators
Nitroprusside 0.2510.00 g/kg/ Immediate 12 min Nausea, vomiting, muscle Not preferred for most
min IV twitching, thiocyanate hypertensive emergencies

and cyanide toxicity
Nitroglycerin 5100 g/min 25 min 510 min Headache, vomiting, Not preferred but may
methemoglobinemia, be useful with coronary
tolerance with ischemia
prolonged use
Fenoldopam 0.10.6 g/kg/ 45 min 1015 min Tachycardia, increased May be indicated with
(Corlopam) min IV intraocular pressure renal insufciency
Nicardipinec 515 mg/h 510 min 14 h Headache, nausea, Most hypertensive
(Cardene IV) ushing, tachycardia emergencies
Clevidipine 12 mg IV, rapidly 24 min 515 min Headache and ush Most hypertensive
(cleviprex) increasing dose to emergencies
Essentials
16 mg max
Hydralazine 520 mg IV 1020 min 14 h Tachycardia, ushing, Eclampsia. Not for aortic
1040 mg IM 2030 min 46 h headache, vomiting, dissection
aggravation of angina
9/29/09 12:20:35 PM
Adrenergic inhibitor
Phentolamine 515 mg IV 12 min 310 min Tachycardia, ushing, Catecholamine excess
headache
Esmolol 250500 g/kg/ 12 min 1020 min Hypotension, nausea Aortic dissection after
(Brevibloc) min for 4 min, then surgery
50300 g/ kg/
min IV
Labetalol 2080 mg IV bolus 510 min 36 h Vomiting, scalp tingling, Most hypertensive
(Normodyne, every 10 min2 mg/ burning in throat, emergencies except acute
Trandate) min I.V. infusion dizziness, nausea, heart failure
heart block, orthostatic
hypotension
Chapter 5. Hypertensive Crisis
a
In order of rapidity of action.
b
Hypotension may occur with any.
c
Intravenous formulations of other calcium channel blockers are also available.
55
9/29/09 12:20:35 PM
Table 5.3. Oral Drugs for Hypertensive Urgencies
Drug Class Dose Onset Duration, h

Captopril Angiotensin- 6.550.0 mg 15 min 46
converting enzyme
inhibitor
Clonidine Central -agonist 0.2 mg initially, then 0.52.0 h 68
0.1 mg/h, up to
0.8 mg total
Furosemide Diuretic 2040 mg 0.51.0 h 68
Labetalol - and b-Blocker 100200 mg 0.52.0 h 812
Nifedipine Calcium channel 510 mg 515 min 35
blocker
Propranolol -Blocker 2040 mg 1530 min 36
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Chapter 6. Resistant Hypertension 57
Chapter 6
Resistant Hypertension
Resistant hypertension is dened as the persistence of inadequate BP control (< 140/90 mmHg
in younger patients; < 160/90 mmHg in patients over age 65) despite adequate triple-drug
therapy, including a diuretic. Resistant hypertension occurs in ~ 10% of hypertensive patients
and can be caused by any of the possibilities listed in Table 6.1. The identiable hypertensions
are covered in Chapter 7.
Treatment depends largely on recognition of the cause(s) or resistance. The goal is to
move the patient beyond non-adherence to therapy. Volume overload resulting from once-a-
day furosemide is the next most common obstacle. Obstructive sleep apnea may be the most
frequently overlooked cause.
Guidelines to improve maintenance of antihypertensive therapy are shown in Table 6.2.
A new therapy for resistant hypertensionthe endothelium antagonist, darusentanmay
soon be available. See the Appendix (p. 71) for more information.
Table 6.1. Causes of Inadequate Responsiveness to Therapy

Pseudo-resistance
White coat or ofce elevations
Pseudohypertension in the elderly
Non adherence to therapy
Side effects or costs of medication
Lack of consistent and continuous primary care
Inconvenient and chaotic dosing schedules
Instructions not understood
Organic brain syndrome (e.g., memory decit)
Drug-related causes
Doses too low
Inappropriate combinations
Rapid inactivation (e.g., hydralazine)
Drug actions and interactions
NSAIDS
Sympathomimetics
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Table 6.1. Causes of Inadequate Responsiveness to Therapy (cont'd)
Nasal decongestants
Appetite suppressants
Cocaine and other street drugs
Caffeine
Oral contraceptives
Adrenal steroids
Licorice (as may be found in chewing tobacco)
Cyclosporine, tacrolimus
Erythropoietin
Associated conditions
Smoking
Increased obesity
Sleep apnea
Insulin resistance or hyperin sulinemia
Ethanol intake more than 1 ounce a day
Anxiety-induced hyperventilation or panic attacks
Chronic pain
Intense vasoconstriction (Raynaud phenomenon, arteritis)
Identiable causes of hypertension
Volume overload
Excess sodium intake
Progressive renal damage (nephrosclerosis)
Fluid retention from reduction of blood pressure
Inadequate diuretic therapy
Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC VI). 1997;157:24132446. Available at http://www.nhlbi.nih.gov/
guidelines/hypertension/. Accessed May 27, 2009.
Table 6.2. Guidelines to Improve Maintenance of Antihypertensive Therapy

Involve the patient in decision making to the extent desired
Assess attitudes and beliefs
Provide individual assessments of current risks and potential benets of control.
Inform the patient about the condition and its treatment
If patient agrees, involve family
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Chapter 6. Resistant Hypertension 59
Table 6.2. Guidelines to Improve Maintenance of Antihypertensive Therapy (cont'd)
Articulate the goal of therapy: to reduce blood pressure to near normotension with few or
no side effects
Be alert for signs of inadequate intake of medications, e.g., absence of blood pressure response
or expected effects, e.g., bradycardia with -blocker
Recognize and manage depression
Maintain contact with the patient
Encourage visits and calls to allied health personnel
Give feedback to the patient via home blood pressure readings
Make contact with patients who do not return
Keep care inexpensive and simple
Do the least workup needed to rule out secondary causes
Obtain follow-up laboratory data only yearly unless indicated more often
Encourage lifestyle changes if needed
Use home blood pressure readings
Use once-daily doses of long-acting drugs.Use generic drugs and break larger doses of
scored tablets in half
If appropriate, use combination tablets
Use calendar blister packs
Inspect all pill containers at each visit
If medications must be taken separately, provide clear, easily read instructions
Use clinical protocols monitored by nurses and assistants
Prescribe according to pharmacologic principles
Add one drug at a time
Start with small doses, aiming for 5- to 10-mmHg reductions at each step, unless more rapid
response is indicated
Have medication taken immediately on awakening in the morning. If morning surge of
blood pressure (above 160/100) persists, give at least some drugs at 6 PM or at bedtime
Provide feedback and validation of success
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Chapter 7
Identiable (Secondary) Hypertension
Identiable (or secondary) hypertension is dened as hypertension that can be ascribed to an
identiable cause, and affects 5%10% of the total hypertensive population. Indications for
work-up include: history, physical exam, and labs suggesting a secondary cause; a resistance
to triple drug therapy; BP worsening after a period of good control; accelerated or malig-
nant hypertension; and a negative family history with diastolic BP > 110 mmHg (Table 7.1).
Clinical features, diagnostic tests, and treatment recommendations for the various causes of
secondary hypertension are detailed in the pages to follow. Table 7.1 is a shorter version for
the most common. Table 7.2 provides a brief summary of the features of the major causes
of Identiable Hypertension. Table 7.3 lists the multiple chemical agents that can raise the
blood pressure.
Table 7.1. Features of Inappropriate Hypertension

Age of onset: < 20 or > 50 yr
Level of blood pressure: > 180/110 mmHg
Organ damage
Funduscopy grade II or beyond
Serum creatinine > 1.5 mg/dL
Cardiomegaly or left ventricular hypertrophy as determined by electrocardiography
Presence of features indicative of secondary causes
Unprovoked hypokalemia
Abdominal bruit
Variable pressures with tachycardia, sweating, tremor
Family history of renal disease
Poor response to generally effective therapy
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Chapter 7. Identiable (Secondary) Hypertension 61
Table 7.2. Most Common Causes of Secondary Hypertension

A. Renal Parenchymal Disease
Prevalence Most common cause of secondary hypertension (excluding obesity and

alcohol abuse). Responsible for 2%5% of all cases of hypertension.
Etiology Most commonly associated with chronic glomerulonephritis, hypertensive
nephrosclerosis, and diabetic nephropathy. Hypertension is primarily due to
volume overload.
Diagnosis Renal ultrasound (bilateral small scarred kidneys), renal biopsy. Laboratory
ndings include estimated glomerular ltration rate < 30 mL/min,
proteinuria, abnormal urinary sediment.
Treatment Drug therapy: Loop diuretics (may require multiple daily high doses)
or metolazone (may be effective as once-daily dosing). Nonresponders
should be treated with an ACE inhibitor, ARB, and/or calcium
antagonist. If needed, follow with an -blocker and/or labetalol or a
-blocker. Minoxidil is often useful when further therapy is required.
Hemodialysis or renal transplantation may be required for
hypertensive control in end-stage renal disease.
Avoid nonsteroidal anti-inammatory drugs (inhibit the production of
vasodilatory renal prostaglandins), potassium-sparing diuretics, and
potassium supplements.
B. Renovascular Hypertension
Prevalence Occurs in 1% of hypertensive patients. Responsible for 20% of resistant or

accelerated-malignant hypertension in non-blacks (less common in blacks).
Etiology Atherosclerosis is the cause in 80%90% of cases, is more common in
older men, and usually involves the ostium and proximal third of the renal
artery. Fibromuscular dysplasia is responsible for about 10% of cases,
is more common in young females, and usually involves the distal two-
thirds of the renal artery and branches. Bilateral disease is not uncommon
(Textor, 2008).
Presentation Suspect the diagnosis in hypertensive patients with:
Onset of hypertension < 30 years of age or rapid onset after
50 years
Resistance to 3-drug therapy
Deterioration in renal function after administration of ACE inhibitors or
ARBs
Uncontrolled hypertension after a period of good control
Malignant hypertension
Recurrent acute pulmonary edema
Sudden worsening of renal function in a hypertensive patient
Epigastric, subcostal, or ank bruit
Extensive atherosclerosis elsewhere
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Table 7.2. Most Common Causes of Secondary Hypertension (Cont'd)
B. Renovascular Hypertension
Screen Captopril renography: Isotopic renography after captopril

demonstrates a decrease in renal blood ow or GFR by > 20% with
a > 10% difference between the two sides. If the post-captopril study
is abnormal, renography should be repeated without captopril to ensure
that the difference is vascular and not parenchymal in origin.
Renal duplex sonography is a useful screening test if performed by an
experienced sonographer.
MRA angiography is usually used in patients with renal insufciency.
Diagnosis Renal arteriography is needed to demonstrate the anatomical lesion.
In patients with unilateral disease, a positive captopril-challenge isotopic
renogram is usually adequate to conrm the functional signicance
of a lesion.
Treatment For atherosclerotic renovascular hypertension, three forms of therapy are
available. The response to each is partly dependent on the location of
the lesion(s), the degree of renal damage, and the age of the patient. In
limited trials, medical therapy and angioplasty both are associated with a
70%80% improvement in renal perfusion and reduction in systemic blood
pressure. However, only now is there a properly controlled trial comparing
the two therapies being performed: the Cardiovascular Outcomes for
Renal Atherosclerotic Lesions (CORAL) trial, with results hopefully available
by 2010.
Surgery is now recommended only for those who fail to respond to
medical therapy or angioplasty or who require surgery for other vascular
causes.
Angioplasty with stenting is likely as successful as medical therapy, but
is being performed, often without evidence that an identied lesion
is responsible for the hypertension. This usually occurs when renal
angioplasty is performed as a yby exam during arteriography. ACE
inhibitors and ARBs are very effective at controlling blood pressure
but may cause acute renal failure if bilateral renal artery stenosis or
unilateral renal artery stenosis of a solitary kidney is present or develops.
Even when blood pressure is adequately controlled on medical therapy,
renal dysfunction and loss of renal mass may develop. Therefore, renal
function and size should be followed every 36 months.
Fibromuscular dysplasia: Balloon angioplasty with stenting is the
treatment of choice (high success rate, low restenosis rate).
C. Primary Aldosteronism
Prevalence Present in < 1% of patients with hypertension, although reported to be

more common when patients are screened by plasma aldoster one-to-renin
ratios (ARR) (Kaplan, 2007).
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C. Primary Aldosteronism
Etiology Adrenal adenoma (60%), bilateral adrenal hyperplasia (40%) in

classical disease. Bilateral adrenal hyperplasia is more common in early,
normokalemic patients identied by ARR.
Presentation Hypertension with hypokalemia, which may rst become evident during
treatment with diuretics. Others manifestations include muscle pain,
cramping or weakness, polyuria, polydipsia, metabolic alkalosis.
Screen Plasma renin activity (PRA) < 1 ng/mL/hr and plasma aldosterone
> 15 mg/dL. (Many essential hypertensives with normal PA levels have
high ARR because of low renin levels.)
24-hour urine potassium (Uk) while patient is hypokalemic, ingesting
a normal sodium intake (urinary sodium excretion > 100 mEq/day), and
not receiving supplemental potassium or diuretics. If UK is < 30 mEq/day,
primary aldosteronism is essentially excluded; if > 30 mEq/day, continue
workup.
Diagnosis If PRA is low and plasma aldosterone high, primarily (autonomous)
hyperaldosteronism must be identied by either an intravenous saline
or three days of oral sodium loading. To do this, discontinue diuretics
and replenish normal body stores and serum levels of potassium to
within normal range (may take weeks to months). Then administer
either a high sodium diet for three days or IV normal saline (2 liters over
4 hours). Primary aldosteronism is diagnosed if either urinary aldosterone
exceeds 14 ng/dL on a high sodium diet, or if recumbent serum
aldosterone exceeds 10 ng/dL following an IV saline load.
An abdominal CT or MRI may be helpful if a large solitary adrenal
adenoma is identied. However, these procedures often give incorrect
evidence. Therefore, adrenal venous sampling is required to correctly
identify the type of lesion (Taylor, 2008).
Treatment Bilateral adrenal hyperplasia: Potassium-sparing diuretic (eplerenone,
spironolactone, amiloride, triamterene) calcium antagonist.
Adrenal adenoma: Preoperative therapy with spironolactone followed
by surgical resection. 60% of patients are cured.
D. Cushings Syndrome
Prevalence Present in < 1% of patients with hypertension.

Etiology Excessive pituitary ACTH, usually caused by a pituitary adenoma, is
responsible for 70% of cases and results in bilateral adrenal hyperplasia.
Other causes include adrenal adenoma or carcinoma (15%) and ACTH-
producing extra-adrenal tumors (15%).
Presentation Manifestations include truncal obesity, moon facies, ecchymosis, muscle
atrophy, edema, striae, acne, hirsutism, osteoporosis, glucose intolerance,
hypokalemia.
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D. Cushings Syndrome
Screen 24 hour urinary free cortisol levels > 100 g suggest the diagnosis.
Overnight dexamethasone suppression test: 1 mg of
dexamethasone at midnight followed by plasma cortisol at 8:00 AM. If
level > 7 g/dL, proceed with prolonged dexamethasone suppression
test (below).
Diagnosis Measure basal plasma ACTH levels and perform a prolonged
dexamethasone suppression test: Administer 0.5 mg every 6 hours
2 days followed by 2 mg every 6 hours 2 days. Measure urinary free
cortisol and plasma cortisol on the second day of each dose.
Adrenal tumor: Failure to suppress on low or high dose; ACTH
undetectable.
Ectopic ACTH syndrome: Failure to suppress on low or high dose; ACTH
very elevated.
Cushings disease (excess pituitary ACTH with bilateral adrenal
hyperplasia): Failure to suppress on low dose but suppressed to < 50%
of control value on high dose; ACTH normal to elevated.
Treatment Pituitary adenoma: Transphenoidal microsurgery improves signs and
symptoms in ~ 80%. Heavy-particle irradiation is also of value. Bilateral
adrenalectomy is generally reserved for disabling symptoms unresponsive
to other therapy. Ketoconazole and mitotane inhibit adrenal cortisol
secretion.
Ectopic ACTH syndrome: Remove tumor when feasible.
Ketoconazole, metapyrone, aminoglutethimide, alone or in combination,
for medical therapy.
Adrenal adenoma or carcinoma: Surgical resection. Mitotane for
residual or nonresectable tumor.
Drugs should not be considered primary therapy, although they may be
of adjunctive value (diuretic plus spironolactone).
E. Pheochromocytoma
Prevalence Present in < 1% of patients with hypertension.

Etiology More than 80% are single, benign, norepinephrine-producing tumors
of the adrenal medulla. 10% of tumors are malignant, 10% are bilateral,
and 10% are familial (associated with multiple endocrine neoplasia Type
2A [medullary carcinoma of thyroid, parathyroid hyperplasia] and IIB
[mucosal neuroma syndrome]).
Presentation Hypertension is persistent in 50%, paroxysmal in 50%, and a few patients
are normotensive. May also present with episodic palpitations, headache,
sweating, orthostatic hypotension, weight loss, glucose intolerance.
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E. Pheochromocytoma
Screen Plasma metanephrine > 0.5 nmol/L or normetanephrine > 0.9 nmol/L
(Young, 2007).
24 hour urinary total metanephrines > 1.3 mg. False-positive tests are
much more likely if the patient is taking sympathomimetic drugs, MAO
inhibitors, or labetalol. False-negative results have been seen after x-ray
contrast media containing methylglucamine.
Diagnosis Clonidine suppression test: After resting for 30 minutes after
placement of an indwelling venous catheter, obtain basal plasma
catecholamines, then give 0.3 mg clonidine orally and obtain samples at
2 and 3 hours. Failure to suppress basal catecholamine levels
by > 50% is considered a positive test.
Tumor localization: CT scan is able to localize 90% of tumors > 1
cm in diameter. I-MIBG scan or selective arteriography with regional
catecholamine levels can also be used.
Treatment Immediate treatment of severe hypertension: Phentolamine (IV).
Long-term therapy: Surgical resection is the treatment of choice. Pre-
operative -receptor blockade (phenoxybenzamine or doxazosin until
normotensive 5210 days) is often recommended. Post-operative
hypoglycemia and hypotension may occur. Long-term clinical follow-up is
important to identify late recurrences.
If surgical resection is not possible, chronic medical therapy with
phenoxybenzamine (oral -blocker) or -methyl-tyrosine (oral
inhibitor of catechol synthesis) is recommended.
F. Coarctation of the Aorta
Prevalence Present in 0.1%1% of patients with hypertension.

Etiology Congenital narrowing of the aorta beyond origin of left subclavian artery,
distal to insertion site of ligamentum arteriosum. May involve long or short
segments and can be partial or complete.
Presentation May complain of cold feet and leg claudication. Findings on physical
exam include arm BP > leg BP, thrill in suprasternal notch, systolic ow
murmur (best heard in left posterior thorax), and absent femoral pulses in
most. Chest x-ray may demonstrate rib notching (increased collateral ow
through intercostal arteries) and indentation of the aortic knob (gure 3
sign). One-third of patients have bicuspid aortic valves. Complications
include congestive heart failure, endocarditis, stroke.
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F. Coarctation of the Aorta
Natural history Without corrective surgery, 80% ultimately die prematurely from
complications of hypertension. In a series of 200 patients who died prior
to the availability of surgical treatment, the majority of deaths occurred in
the second, third, and fourth decades. Causes of death included cardiac
(50%), cerebral hemorrhage (13%; spontaneous or 2 to ruptured cerebral
aneurysm), and rupture of the aorta (> 20%).
Diagnosis Aortography, transesophageal echo with Doppler, MRI
Treatment Surgical repair or angioplasty is the treatment of choice.
Transient worsening of hypertension may develop postoperatively but
can usually be prevented by the prophylactic use of a -blocker.
Drug therapy: ACE inhibitor or calcium antagonist.
G. Acromegaly
Prevalence Present in < 0.1%0.2% of patients with hypertension.

Etiology Usually due to a growth hormone-secreting pituitary adenoma.
Presentation Soft tissue swelling, extremity enlargement, joint pains, glucose
intolerance, macroglossia. Cardiovascular manifestations include
hypertension, cardiomegaly, premature coronary disease, arrhythmias,
cardiomyopathy. Heart failure develops in 10%20%.
Screen Increased levels of insulin-like growth factor (somatomedin C). Once
diagnosed, it is important to assess the integrity of other pituitary
hormones: If hypertension is present, exclude pheochromocytoma
(p. 65) or an aldosterone-producing adenoma (p. 63); if sinus tachycardia
or atrial brillation is present, exclude hyperthyroidism.
Diagnosis Glucose suppression test: Failure to suppress growth hormone levels to <
2 ng/mL 2 hours after oral administration of 100 grams of glucose.
Treatment Transphenoidal resection of the tumor is the mainstay of therapy.
Drug therapy (bromocriptine [dopaminergic agonist], octreotide [long-acting
somatostatin analog]) and radiation therapy are often used as adjuncts.
H. Primary Hyperparathyroidism
Prevalence Present in < 0.1%0.2% of patients with hypertension.

Etiology Solitary adenoma (85%), hyperplasia of all 4 glands (10%; usually familial
and occurs in association with multiple endocrine neoplasia Types 1 and 2),
carcinoma (< 5%).
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H. Primary Hyperparathyroidism
Presentation Patients are frequently asymptomatic: 10%20% of cases are rst

diagnosed after routine chemical screening. The rst manifestation may
be hypercalcemia after initiating therapy with thiazide diuretics.
Other manifestations include fatigue, weakness, renal symptoms in 50%
(polyuria, nocturia, renal stones, nephrocalcinosis), proximal muscle
weakness, nonspecic joint/back symptoms.
Diagnosis Elevated levels of serum calcium and parathyroid hormone (hypercalcemia
normally suppresses parathyroid hormone levels).
Treatment Surgical parathyroidectomy is the treatment of choice. Although
hypertension often persists (Taylor et al., 2008), surgery generally halts
the formation of renal stones and allows skeletal remineralization in
those with bone disease. Post-op hypocalcemia is not uncommon;
acute treatment with IV calcium and long-term therapy with vitamin D
and oral calcium may be needed.
For elderly patients and those with mild elevations of serum calcium
only, optimal therapy is controversial (i.e., surgery vs. conservative
medical follow-up). When medical therapy is chosen, thiazide diuretics
should be avoided (may further increase serum calcium).
Additional Treatment for Other Causes

Glucocorticoids Treat with diuretics spironolactone. Prevent by intermittent
therapy (prednisone every other day)
Licorice Also present in some chewing tobaccos. Treat with diuretics
spironolactone. Hypertension should disappear after licorice
ingestion is stopped.
Sympatho-mimetics Present in diet pills and street drugs. Treat with labetalol.
NSAIDs NSAIDs inhibit the production of vasodilatory prostaglandins.
Treat by substituting acetaminophen for NSAID or increasing
the dose of the antihypertensive drug.
Alcohol Etiology in up to 10% of young males with hypertension.
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Additional Treatment for Other Causes
Oral contraceptives (OCP) 5% develop hypertension within 5 years of use, which usually
manifests as a small persistent increase in systolic blood
pressure (5 mmHg) and diastolic blood pressure (2 mmHg)
then returns to baseline within 3 months of discontinuation.
All patients receiving OCP should have their blood pressure
checked after 36 months of use. If blood pressure is
elevated, other forms of contraception should be considered.
When medical therapy is required, a diuretic-spironolactone
combination is often effective.
Cocaine, amphetamines Cocaine stimulates the release and inhibits neuronal re-uptake
of norepinephrine. In addition to hypertension, patients may
present with arrhythmias, seizures, Ml, dilated pupils, mental
status changes and stroke, usually within one hour of drug use.
Acute renal failure from rhabdomyolysis may also occur. Treat
with phentolamine for hypertension and b-blockers for
arrhythmias. Nonselective -blockers may cause a paradoxical
increase in blood pressure due to unopposed b-receptor
simulation caused by excess catecholamines.
Cyclosporine or tacrolimus Treat with calcium antagonist, labetalol, or an ACEI. Drugs that
increase cyclosporine levels, including diltiazem, nicardipine,
and verapamil, may reduce the cost of immunosuppression.
Chemical agents Table 7.3
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Table 7.3. Hypertension Induced by Chemical Agents
Mechanism Examples
Expansion of uid volume

Increased sodium intake Antacids; processed foods
Mineralocorticoid effects Licorice; cortisone; anabolic steroids
Stimulation of renin-angiotensin Estrogens (oral contraceptives;
Inhibition of prostaglandins NSAIDs
Stimulation of sympathetic nervous

activity
Sympathomimetic agents Caffeine; cocaine; ephedrine;
methylenedioxymethamphetamine
(MDMA, ecstasy); methylphenidate
(Ritalin); nicotine; phencyclidine (Sernulan);
phenylpropanolamine
Interactions with monoamine oxidase Foods with high tyramine content (e.g., red
inhibitors wines, aged cheese)
Anesthetics Ketamine
Ergot alkaloids Ergotamine
Dopamine receptor agonist Bromocriptine
Antidopaminergic Metoclopramide
Sandostatin analogue Sandostatin LAR
Interference with antihypertensive drugs

Inhibition of prostaglandin synthesis NSAIDs
Inhibition of neuronal uptake Tricyclic antidepressants; sibutramine
Paradoxical response to
antihypertensive drugs
Withdrawal, followed by catechols Clonidine
Unopposed -adrenergic vasoconstriction -blockers
Intrinsic sympathomimetic activity Pindolol
Combination - and -blocker Propranolol plus clonidine
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Table 7.3. Hypertension Induced by Chemical Agents (Cont'd)
Mechanism Examples
Unknown mechanisms
Heavy metal poisoning Lead; Mercury thallium
Chemicals Carbon disulde; arsenic; methyl chloride;
polychlorinated biphenyl
Insecticides Parathion
Insect bites Spider; scorpion
Diagnostic agents Indigo carmine; pentagastrin; thyrotropin-
releasing hormone
Therapeutic agents Cyclosporine; clozapine; disulram
erythropoietin; herbal remedies;
indinavir; lithium
Alcohol Alcohol
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Appendix. Clinical Trials 71
APPENDIX. CLINICAL TRIALS
Trial: ACCOMPLISH
Title: Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. (The
Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hyperten-
sion Trial)
Publication: Jamerson K, Weber MA, Bakris GL, et al. N Engl J Med 2008;359:24172428.
Summary: The objective of this study was to evaluate the effectiveness of two combinations of
antihypertensive drugs to reduce cardiovascular events in a high-risk hypertensive population.
Participants: 11,506 patients from 5 countries (U.S., Sweden, Norway, Denmark, Finland), age 55
years or older, diagnosed with hypertension and at high risk for cardiovascular events, were enrolled
starting in 2003.
Randomization: Patients were randomized to either benazepril 20 mg plus hydrocholorothiazide

12.5 mg (n = 5762) or benazepril 20 mg plus amlodipine 5 mg (n = 5744). After 1 month of treat-
ment, benazepril was increased to 40 mg qd in both groups, plus hydrocholorothiazide up to 25 mg
and amlodipine up to 10 mg (in respective groups) to reach target BP of < 140/90 mmHg.
Length of trial: Patients were randomized between October 2003 and May 2005. The trial was
terminated after a mean follow-up of 36 months, when the boundary of the prespecied stopping
rule was exceeded.
Applicability of data: Approximately 70% of study participants were enrolled in the United States.
The self-reported race/ethnicity of participants was a somewhat fair representation of the U.S. popu-
lation (83.5% white, 12.3% black, 5.4% Hispanic). Average age of participants was 68.4 6.86 (SD)
years old at entry. More men than women were enrolled (60.0% vs. 40.0%).
Primary end points: Composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke,
hospitalization for angina, resuscitation after sudden cardiac arrest, or coronary revascularization.
Secondary end points: Death from cardiovascular causes, nonfatal MI, and nonfatal stroke.
Results: At termination of the study, mean blood pressures after dose adjustment were
131.6/73.3 mmHg in the benazepril-amlodipine group and 132.5/74.4 mmHg in the benazepril-
hydrocholorothiazide group. There were fewer primary outcome events in the benazepril-amlodipine
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group (552) than in the benazepril-hydrocholorothiazide group (679). Statistical analysis is as
follows:
Benazepril-Amlodipine Benazepril-Hydrocholothiazide
Group Group
Primary outcome event 552 pts (9.6%) 679 pts (11.8%)

occurrence
Absolute risk reduction 2.2 percentage points
Relative risk reduction 19.6% (HR, 0.80; P < 0.001)
Primary event rates per 1000 32.3 39.7
patient-years
Conclusion: Findings from the ACCOMPLISH trial indicate that the combination of an ACEI and a
CCB reduced cardiovascular morbidity and mortality beyond that seen with the combination of an
ACEI and low-dose thiazide diuretic.

Trial: ALLHAT
Title: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting

enzyme inhibitor or calcium channel blocker vs. diuretic. The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT).
Publication: The ALLHAT Ofcers and Coordinators for the ALLHAT Collaborative Research Group.
JAMA 2002;288:29812997.
Summary: ALLHAT was the largest study to compare three major classes of medications to treat
high blood pressure. It was designed to determine whether treatment of hypertensive patients with
an ACE inhibitor or a CCB would lower incidence of CHD or other CVD events versus treatment with
a diuretic as an initial therapy.
Participants: 33,357 men and women age 55 years, with hypertension and at least one other
CHD risk factor, were enrolled between February 1994 and January 1998.
Randomization: Patients were randomized to receive chlorthalidone 12.5 to 25 mg/d (n = 15,255);

lisinopril 10 to 40 mg/d (n = 9054); or amlodipine 2.5 to 10 mg/d (n = 9048).
Length of trial: Patients were followed for an average of 4.9 years.
Applicability of data: There are several concerns regarding applicability of the data. First, blood
pressure reduction was not equivalent between groups, especially for the chlorthalidone/lisinopril
comparison. Second, results of the study were driven to a large extent by the experience of black
patients, who fared far worse than non-blacks. Third, the stepped-care protocol restricted patients
in the lisinopril and amlodipine groups from receiving contemporary combination therapy (ACE
inhibitor or calcium antagonist plus a diuretic, ACE inhibitor plus a calcium antagonist).
Primary end points: Combined fatal CHD or nonfatal MI.
Secondary end points: All-cause mortality, stroke, combined CHD (primary outcome, coronary
revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke,
treated angina without hospitalization, heart failure, and peripheral arterial disease).
Results: The primary outcome occurred in 2,956 patients, with no difference between treatments.
Likewise, all-cause mortality did not differ between groups.
Versus Chlorthalidone
Drugs (Patients) 6-Year Event Rate Relative Risk (95% CI) P Value
Chlorthalidone 11.5%
(n = 15,255)
Amlodipine 11.3% 0.98 (0.901.07) 0.65
(n = 9,048)
Lisinopril (n = 9,054) 11.4% 0.99 (0.911.08) 0.81

Conclusion: Results of the ALLHAT study generated international comment, given the size and
scope of the study and controversy over interpretation of the data. Investigators concluded that
diuretics are superior to CCBs and ACE inhibitors as rst-line treatment in preventing $ 1 form
of CVD in hypertensive patients. However, given the important limitations of this study, a subset-
specic approach to the management of hypertension is warranted (i.e., blacks, diabetics).

Trial: ANBP2
Title: A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for
hypertension in the elderly. (The Second Australian National Blood Pressure Study Trial)
Publication: LMH Wing, CM Reid, P Ryan, et al. N Engl J Med 2003;348:583592.
Summary: The ANBP2 trial was conducted to test the benets of antihypertensive treatment with
an ACE inhibitor-based regimen versus a diuretic-based regimen in elderly (> 60 years) patients with
regard to cardiovascular event outcome.
Participants: 6,083 hypertensive men and women, age 65 to 84 years, were enrolled over a three-
year period.
Randomization: Patients were randomized to either an ACE inhibitor (n = 3044) or a thiazide
diuretic (n = 3039). Specic drugs could be chosen by treating physician; however, enalapril or HCTZ
were the recommended treatments, respectively. Supplemental therapy to reach target BP goal
could be a -blocker, CCB, or -adrenoreceptor antagonist in the ACE-based regimen, or a -blocker,
CCB, or adrenoreceptor antagonist in the diuretic-based regimen.
Length of trial: Participants were followed for a median of 4.1 years. The trial was stopped due to
limited resources and achievement of required number of total observed end-point events.
Applicability of data: Participants were entirely from Australia and were 95% white.
Primary end points: All cardiovascular events or all-cause mortality.
Results: There were fewer observed cardiovascular events in the ACE inhibitor treatment group.
Gender differences were noted regarding reduction of cardiovascular events in male subjects. No
signicant difference in blood pressure reduction was noted.
Male Female
ACE Subjects, Subjects,
Inhibitor Diuretic Hazard Both Both
Treatment Treatment Ratio Treatment Treatment
Group Group (95% CI) P Value Groups Groups
First 490 529 0.89 0.06
cardiovascular (0.791.01)
event or all-cause
mortality
All-cause 195 210 0.90 0.27
mortality (0.751.09)
Combined 695 736 0.89 0.05
primary end (0.791.00)
points (all cardio
events + all-cause
mortality)

Male Female
ACE Subjects, Subjects,
Inhibitor Diuretic Hazard Both Both
Treatment Treatment Ratio Treatment Treatment
Group Group (95% CI) P Value Groups Groups
All cardiovascular 907 524
events events; events;
17% rate HR 1.00
reduction, (95% CI,
HR 0.83 0.831.21);
(95% CI, P = 0.98
0.710.97);
P = 0.02
Conclusion: Study results showed an advantage for cardiovascular event outcomes for elderly
hypertensive patients treated with an ACE inhibitor versus a diuretic agent, but only among males.

Trial: ASCOT
Title: Prevention of cardiovascular events with an antihypertensive regimen of amlodipine add-

ing perindopril as required versus atenolol adding bendro umethiazide as required, in the Anglo-
Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre
randomised controlled trial.
Publication: Dahlof B, Sever PS, Poulter NR, et al. Lancet 2005;366:895906.
Summary: The ASCOT trial was designed to study the effect of antihypertensive treatment with
a CCB (amlodipine) plus an ACE inhibitor versus the standard treatment regimen of a -blocker
(atenolol) plus a diuretic.
Participants: 19,257 men and women, age 4079 years old, with documented hypertension
( 160/100 mmHg untreated or 140/90 mmHg treated) were enrolled between February 1998
and May 2000. In addition, all patients had 3 cardiovascular risk factors (i.e., cigarette smoking,
hx of cerebral vascular or peripheral vascular disease, microalbuminuria).
Randomization: Patients were randomized to either amlodipine 510 mg perindopril 48 mg or

atenolol 50100 mg bendroumethiazide 1.252.5 mg + K. Further antihypertensive treatment
was added as needed to reach target BP of 140/90 mmHg. Patients with a total cholesterol of
6.5 mmol/L were further randomized to receive either atorvastatin 10 mg or placebo daily
(ASCOT-LLA: lipid-lowering arm).
Length of trial: The trial was stopped in 2004 after a median patient follow-up of 5.5 years, due to
signicant differences in rates of all-cause mortality (lower rates in the CCB-based regimen group).
Applicability of data: ASCOT was the largest European study of hypertensive patients to date.
Patients were not recruited from the Americas, Asia, or any African countries, thus making applicabil-
ity of the data limited to those with European ancestry.
Primary end points: Nonfatal MI and fatal coronary heart disease.
Secondary end points: Fatal and nonfatal stroke, nonfatal MI, all-cause mortality, total cardiovas-
cular events and procedures, total coronary end points, and cardiovascular mortality.
Results: At the time the trial was stopped, results showed a 10% reduction in the primary endpoint
of nonfatal MI and fatal CHD, although this did not reach statistical signicance as there was a short-
age of 220 events necessary to reach the threshold. Trial results, however, did show an advantage
toward the amlodipine-based treatment in preventing all-cause mortality, total coronary endpoints,
fatal and nonfatal stroke, and cardiovascular mortality. Blood pressure was reduced by a mean of
2.9/1.8 mmHg in the amlodipine-based treatment group; however, blood pressures were nearly
equivalent in both groups by the end of the study.

Amlodipine-Based Atenolol-Based
Treatment Group Treatment Group Statistical Analysis
Mean blood pressure 136.1/79.2 mmHg 137.7/77.4 mmHg

(at study end)
Primary endpoint 429 474 Unadjusted HR 0.90,
event 95% CI 0.791.02,
P = 0.1052
Incidence of fatal and 327 422 HR 0.77, 95% CI
nonfatal stroke 0.660.89,
P = 0.0003
Incidence of all-cause 738 820 HR 0.89, 95% CI
mortality 0.810.99, P = 0.025
Conclusion: While the trial was stopped earlier than anticipated, results from ASCOT-BPLA indicate
that a CCB/ACE-inhibitor combination treatment regimen may confer results beyond lowering blood
pressure, specically decrease in all-cause mortality, fatal and nonfatal stroke, and cardiovascular
mortality.

Trial: CONVINCE
Title: Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints
(CONVINCE) trial.
Publication: Black HR, Elliott WJ, Grandits G, et al. JAMA 2003;289:20732082. [Note: It was
unprecedented for JAMA to publish the results of an aborted clinical trial.]
Summary: The objective of this international study was to assess equivalence of initial therapy with
controlled-onset extended-release (COER) verapamil and standard therapy with physicians choice of
either atenolol or hydrochlorothiazide (HCTZ) in preventing cardiovascular disease-related events.
Participants: 16,602 patients from 15 countries, age 55 years or older and diagnosed with hyper-
tension and 1 additional risk factor for CVD, were enrolled between 1996 and 1998.
Randomization: Patients were randomized to either COER verapamil 180 mg or physicians choice
of atenolol 50 mg or hydrochlorothiazide 12.5 mg.
Length of trial: Originally planned for 5-year follow-up, the CONVINCE trial was sponsor-terminated
two years prematurely for business considerations.
Applicability of data: Approximately 70% of study participants were enrolled in the Americas.
The self-reported race/ethnicity of participants generally represented that of the country of origin
(in the U.S. 74.2% were white, 13.9% black, 10.9% Hispanic, and 0.6% were Asian). Average age
of participants was 65.6 7.4 (SD) years old at entry. More women than men were enrolled (56.0% vs.
44.0%).
Primary end points: Stroke, MI, or cardiovascular disease-related death.
Secondary end points: Expanded cardiovascular disease end point (hospitalization for angina, car-
diac revascularization or transplant, heart failure, TIA or carotid endarterectomy); all-cause mortality;
cancer; hospitalization for bleeding (excluding hemorrhagic stroke); and incidence of primary end
points occurring between 6 AM and noon.
Results: At termination of the study, systolic blood pressure was reduced by 13.6 mmHg for
participants in the COER verapamil group and by 13.5 mmHg in the atenolol or hydrochlorothiazide
group. Diastolic blood pressure was reduced by 7.8 mmHg for participants in the COER verapamil
group and by 7.1 mmHg in the atenolol or HCTZ group. A total of 364 primary CVD-related events
occurred in the COER verapamil group versus 365 in the atenolol or HCTZ group. Statistical analysis
is as follows:
CVD-Related Fatal or Nonfatal Fatal or CVD-Related

Events Stroke Nonfatal MI Death
Hazard ratio 1.02 1.15 .82 1.09

P value with (95% CI), (95% CI), (95% CI), (95% CI),
Condence 0.881.18; 0.901.48; 0.651.03; 0.871.37;
Interval P = .77 P = .26 P = .09 P = .47

Conclusion: The CONVINCE clinical trial was stopped prematurely by the sponsor, before results
were unblinded. This decision was extremely controversial in the medical community and many
considered it unethical, as there was no recommendation from the DSMB to stop the trial. Still,
the principal investigator indicated that although equivalence was not established in the given
timeframe, it likely would have emerged if the trial had continued.

Trial: DORADO DAR 311
Title: Darusentan in Resistant Hypertension.
Publication: In press. Lancet, 2009.
Summary: The objective of this multi-center, international study was to assess safety and efcacy
of darusentan, an oral endothelin receptor antagonist, in combination with other antihypertensive
medications in reducing blood pressure (both systolic and diastolic) in patients with resistant hyper-
tension.
Participants: 379 male and female patients, between ages 35-80 (mean age 62), diagnosed with
resistant hypertension and following a regimen of 3 or more antihypertensive medications, including
a diuretic.
Randomization: Patients were randomized to darusentan 50 mg qd, 100 mg qd, 300 mg qd, or
placebo.
Length of trial: DORADO was a 14-week clinical trial, with two extension arms: DORADO-EX and
DORADO-AC.
Primary end points: Coprimary endpoints were change in trough sitting systolic blood pressure
and change in trough sitting diastolic blood pressure from baseline to week 14, as measured by
sphygmomanometry.
Secondary end points: Change from baseline in mean 24-hour systolic blood pressure and diastolic
blood pressure, and percent of patients reaching SBP goal.
Results: Reduction in blood pressure, both systolic and diastolic, was shown in all groups receiving
doses of darusentan. Results were statistically signicant (P < 0.001) when compared to the placebo
group. The most common adverse effect was peripheral edema (occurring in approximately 1/3 of
those taking darusentan).
Results are as follows:
Reduction in Blood Pressure at 14 Weeks
Trough Sitting Ambulatory Blood Pressure

Blood Pressure Monitoring
SBP DBP SBP DBP
50 mg 16.5 mmHg 10.1 mmHg 9.0 mmHg 7.8 mmHg
Darusentan
Darusentan
Darusentan
Placebo 8.6 mmHg 5.3 mmHg 1.1 mmHg 0.7 mmHg
P < 0.001 for each group vs. placebo

Conclusion: Reduction in baseline blood pressure was shown when darusentan was added to an
existing regimen in a population with treatment-resistant hypertension.

Trial: Exforge-HCT
Title: Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: A ran-
domized clinical trial.
Publication: Calhoun DA, Lacourciere Y, Chiang YT, Glazer RD. Hypertension. 2009;54:32-39.
Summary: The objective of this study was to assess safety and efcacy of triple therapy with amlo-
dipine (Aml), valsartan (Val), and hydrochlorothiazide (HCTZ) for reduction of moderate or severe
hypertension when compared to each of the dual therapy components (Val/HCTZ, Aml/Val, and Aml/
HCTZ).
Participants: 2271 male and female patients, between ages 18-85, with moderate or severe hyper-
tension (only 2060 patients completed the study).
Randomization: Patients were randomized to Aml/Val/HCTZ 10/320/25 mg qd (n = 571), Val/

HCTZ 320/25 mg qd (n = 553), Aml/Val 10/320 mg qd (n = 558), or Aml/HCTZ 10/25 mg qd
(n = 554) with a gradually increased titration to full dose.
Length of trial: Eight weeks, with a placebo run-in period of 1 week.
Primary end points: Change in mean sitting systolic blood pressure (MSSBP) and mean sitting
diastolic blood pressure (MSDBP) from baseline to end point.
Secondary end points: Change from baseline to weeks 5, 7, and 9 in MSSBP and MSDBP, SBP
control, DBP control, and overall BP control rates at end point and at weeks 5, 7, and 9.
Results: The maximum dose of Exforge HCT (Aml/Val/HCTZ 10/320/25 mg) demonstrated signi-
cantly greater reductions in SBP and DBP (39.68 mmHg and 24.74 mmHg) than that of all dual com-
binations of its components at the same doses. The reductions in systolic/diastolic blood pressure
with Exforge HCT were 7.6/5.0 mmHg greater than with valsartan/hydrochlorothiazide, 6.2/3.3
mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/
hydrochlorothiazide.
Achievement of Blood SBP Least Square

Pressure Control Means Change DBP Least Square
(< 140/90 mmHg) at End from Baseline Means Change from
Point (% of participants) (mmHg) Baseline (mmHg)
Aml/Val/HCTZ
70.8% 39.7 24.7
(Exforge HCT)
Val/HCTZ 48.3% 32.0 19.7
Aml/Val 54.1% 33.5 21.5
Aml/HCTZ 44.8% 31.5 19.5
P < 0.0001 for all categories

Conclusion: This was the rst randomized, double-blind study to assess the efcacy and safety of
combination treatment with a calcium channel blocker (amlodipine), angiotensin receptor blocker
(valsartan), and a diuretic (hydrochlorothiazide). Exforge HCT (which combines all three drugs into
one pill) demonstrated signicantly greater reductions in SBP and DBP than the dual combinations
of its components. Exforge HCT was well-tolerated during this clinical trial.

Trial: HYVET
Title: Treatment of hypertension in patients 80 years of age or older. (The Hypertension in the Very
Elderly Trial)
Publication: Beckett NS, Peters R, Fletcher AE, et al. N Engl J Med 2008;358:18871898.
Summary: The objective of this international study was to investigate prevention of strokes in
very elderly hypertensive patients. The benet-to-risk ratio of treating the very elderly had not been
previously established.
Participants: 3,845 very elderly patients (dened as age 80 or older) from 13 countries in Western
and Eastern Europe, China, Australasia, and North Africa. Patients had baseline sustained systolic BP
of 160 mmHg, and diastolic BP < 110 mmHg.
Randomization: Patients were randomized to either active treatment (n = 1933) or placebo

(n = 1912). Active treatment was a diuretic (indapamide 1.5 mg SR) plus an ACE inhibitor if required
(perindopril 24 mg) to reach target BP of < 150/80 mmHg.
Length of trial: Median follow-up was 1.8 years. Originally planned for completion in 2008, the
trial was halted early due to the recommendation from an independent data monitoring committee
based on early results. Evidence showed that active treatment signicantly reduced incidence of fatal
and non-fatal stroke.
Applicability of data: Participants were primarily from Eastern Europe (n = 2144) and China
(n = 1526). Age range at entry was 80105 yrs, with 73.0% of patients 80 to 84 years of age.
Females comprised 60.7% of participants randomized to active treatment and 60.3% of participants
randomized to placebo. Although ethnicity may not be reective of the U.S. population, this
landmark trial provides valuable data for the elderly population.
Primary end points: Fatal or non-fatal total stroke.
Secondary end points: Total mortality, cardiovascular mortality, cardiac mortality, and stroke
mortality.
Results: At termination of the study, active treatment was associated with a 30% reduction in fatal
and non-fatal stroke, total mortality reduced by 21%, and stroke mortality reduced by 39%.
Death From
Fatal or Non-CV/
Nonfatal Death From Death From Unknown Death From
Stroke Stroke Any Cause Causes CV Cause
N(%)
Active 12.4 (51) 6.5 (27) 47.2 (196) 23.4 (97) 23.9 (99)
treatment
group [Rate per
1,000 pt-yr
(# of events)]

Death From
Fatal or Non-CV/
Nonfatal Death From Death From Unknown Death From
Stroke Stroke Any Cause Causes CV Cause
Placebo group 17.7 (69) 10.7 (42) 59.6 (235) 28.9 (114) 30.7 (121)
[Rate per
1,000 pt-yr
(# of events)]
Statistical HR 0.70 0.61 0.79 0.81 0.77
analysis (0.491.01); (0.380.99); (0.650.95); (0.621.06); (0.601.01);
(95% CI) P = 0.06 P = 0.046 P = 0.02 P = 0.12 P = 0.06
Conclusion: The HYVET clinical trial is a landmark trial in its focus on the very elderly. Treatment
of hypertensive elderly patients was shown to be benecial for fatal and non-fatal stroke. An unex-
pected result (and cause of the trials earlier than expected end) was the reduction of mortality from
any cause, thus encouraging the medical community to pursue hypertensive treatment with the
combination of indapamide and perindopril for this population.

Trial: INVEST
Title: A calcium antagonist vs. a noncalcium antagonist hypertension treatment strategy for patients
with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A random-
ized controlled trial.
Publication: Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. JAMA 2003;290:28052816.
Summary: The INVEST trial was designed to compare mortality and morbidity outcomes of calcium
antagonist regimens versus non-calcium antagonist regimens in ambulatory hypertensive patients
with CAD. The study utilized a multidrug strategy, as older hypertensive patients tend to need more
than one medication to adequately control blood pressure.
Participants: 22,576 participants from 14 countries, age 50 or older, with documented hyperten-
sion and coexisting CAD were enrolled starting in September 1997.
Randomization: Patients were randomized to verapamil SR 240 mg + trandolapril 2-mg prn

to achieve target BP (n = 11,267) or atenolol 50 mg + HCTZ 25-mg prn to achieve target BP
(n = 11,309). In both groups, titration () of trandolapril or HCTZ was allowed per physician recom-
mendation. Additional hypertensive medications were allowed to further achievement of target
BP and/or minimize adverse effects, provided patients randomized to verapamil did not receive a
-blocker and those randomized to atenolol did not receive a calcium agonist.
Length of trial: Mean follow-up with patients was 2.7 years.
Applicability of data: Patients were recruited from 14 countries (including the U.S.) and included a
large proportion of elderly, Hispanic (36%), diabetic, and female patients (52%).
Primary end points: First occurrence of all-cause mortality, nonfatal MI, or nonfatal stroke.
Secondary end points: Cardiovascular death, angina, newly diagnosed diabetes, BP control.
Results: With regard to primary outcome events, there was no statistical signicance between the
two treatment groups. Likewise, blood pressure control was achieved at similar rates.
Calcium Antagonist Non-Calcium Antagonist

Group (Verapamil) Group (Atenolol)
Conrmed primary outcome 1119 (9.93%); [RR] 0.98; 1150 (10.17%); [RR] 0.98;
events 95% CI, 0.901.06; P =.57 95% CI, 0.901.06; P = .57
All-cause death 873 (7.75%); [RR] 0.98; 893 (7.90%); [RR] 0.98;
95% CI, 0.901.07 95% CI, 0.901.07
Nonfatal MI 151 (1.34%) [RR] 0.99; 153 (1.35%); [RR] 0.99;
95% CI, 0.791.24 95% CI, 0.791.24

Calcium Antagonist Non-Calcium Antagonist

Group (Verapamil) Group (Atenolol)
Nonfatal stroke 131 (1.16%) [RR] 0.89; 95% 148 (1.31%); [RR] 0.89;
CI, 0.701.12 95% CI, 0.701.12
Achievement of target systolic 65% 64%
blood pressure
Achievement of diastolic 88.5% 88.1%
blood pressure
Conclusion: Findings of the INVEST trial showed no clinically signicant difference between a
calcium antagonist-based treatment regimen and a non-calcium antagonist-based treatment regimen
for hypertensive patients with coexisting CAD. Both regimens were well-tolerated by participants.
This suggests that equivalent efcacy can be achieved in a verapamil-trandolapril-based strategy as
with an atenolol-hydrochlorothiazide based strategy.

Trial: LIFE
Title: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in
hypertension study (LIFE): A randomised trial against atenolol.
Publication: Dahlof B, Devereux RB, Kjeldsen SE, et al. Lancet 2002;359:9951003.
Summary: LIFE was designed to test the hypothesis that blocking angiotensin II would improve LVH
(a leading indicator of cardiovascular complications) in hypertensive patients, as compared to current
standard treatment of hypertension with -blockers + diuretics.
Participants: 9,193 hypertensive patients from 8 countries (Denmark, Finland, Iceland, Norway,
Sweden, U.K, and U.S.), age 5580 years, with ECG-conrmed left ventricular hypertrophy, were
enrolled between June 1995 and May 1997.
Randomization: Patients were randomized to either losartan 50 mg qd (n = 4,298) or atenolol 50

mg qd (4,182), with the addition of HCTZ 12.5 mg if necessary to achieve BP lowering. Thereafter,
trial drugs were increased to 100 mg qd (HCTZ to 25 mg), with additional antihypertensive medica-
tion (CCB or other medications, exclusive of angiotensin II receptor antagonists, -blockers, or ACE
inhibitors) as needed to reach target BP of < 140/90 mmHg.
Length of trial: Participants were followed for 4.8 1.0 years.
Applicability of data: Participants were primarily enrolled from Denmark and the United States,
making study results most applicable to U.S. and Danish populations.
Primary end points: First occurrence of cardiovascular event: death due to cardiovascular causes;
fatal or nonfatal MI; or fatal or nonfatal stroke.
Secondary end points: Cardiovascular death, stroke, MI, all-cause mortality, hospitalization for
heart failure, new-onset diabetes.
Results: BP reduction was similarly achieved in both trial groups, with the losartan-based regimen
provided increased benet in reduction of cardiovascular events (death, stroke, MI). Statistical analy-
sis is as follows:
Losartan-Based Regimen Atenolol-Based Regimen
Occurrence of primary end point 508 (23.8 per 1000 pt-yrs) 588 (27.9 per 1000 pt-yrs)
Blood pressure reduction 30.2/16.6 (SD 18.5/10.1) 29.1/16.8 (SD 19.2/10.1)
Occurrence of new onset AF 150 pts [RR] 0.67, 95% 221 pts [RR] 0.67, 95% CI
CI 0.550.83, P < 0.001 0.550.83, P < 0.001
Conclusion: Losartan-based treatment showed signicant reduction of new onset atrial brilla-
tion and prevention of MI or stroke, as compared to atenolol-based treatment, with similar blood
pressure reduction. The study authors thus assumed that losartan provides benets beyond blood
pressure reduction. The big nding was a 25% stroke advantage to losartan, which is the basis for an
indication for this drug. Also, the benets of losartan were not seen in black patients, an unexpected
nding that has not been explained.

Trial: ONTARGET
Title: Telmisartan, ramipril, or both in patients at high risk for vascular events. (The Ongoing Telm-
isartan Alone and in Combination with Ramipril Global Endpoint Trial)
Publication: ONTARGET Investigators, Yusuf S, Teo KK, et al. N Engl J Med 2008;358(15):
15471559.
Summary: The objective of this study was to clarify whether an ARB (specically telmisartan), an
ACE inhibitor (ramipril), or a combination of both, best reduces incidence of proteinuria in high-risk
patients with normal or controlled blood pressure.
Participants: 25,620 patients from 41 countries, age 55 years or older, with established atheroscle-
rotic vascular disease or diabetes with end-organ damage, were enrolled starting in 2001.
Randomization: Patients were randomized to ramipril 10 mg (n = 8576), telmisartan 80 mg

(n = 8542), or a combination of both (n = 8502).
Length of trial: The trial ran from November 2001 to June 2007.
Applicability of data: ONTARGET was the largest clinical trial of its kind, with patients enrolled from
700 sites worldwide. In the United States, participants were enrolled at sites in 44 of the 50 states.
Primary end points: Primary composite end point was rst occurrence of any dialysis, renal trans-
plantation, doubling of serum creatinine, or death.
Secondary end points: Composite of any dialysis and doubling of serum creatinine, components
of primary end point, changes in eGFR, and changes in proteinuria.
Results: Frequency of composite end points (dialysis, doubling of serum creatinine, or death) was
similar with telmisartan and ramipril, but increased with combination therapy (death was the most
common component of the primary composite). Likewise, secondary end points were similar with
telmisartan and ramipril, but showed more frequent occurrence with combination therapy. Statistical
analysis is as follows:
Combination:
Telmisartan
Telmisartan Ramipril + Ramipril
Primary composite n = 1147 n = 1150 n = 1233
(dialysis, serum (13.4%) HR 1.00, (13.5%) HR 1.00, (14.5%) HR 1.09,
creatinine doubling, 95% CI, 0.921.09 95% CI, 0.921.09 95% CI, 1.011.18;
death) P = 0.037
Secondary n = 189 n = 174 n = 212
endpoints (2.21%) HR 1.09; (2.03%) HR 1.09; (2.49%) HR 1.24,
(dialysis or doubling 95% CI, 0.891.34 95% CI, 0.891.34 95% CI, 1.011.51,
of serum creatinine) P = 0.038

Conclusion: The ONTARGET clinical trial is the largest trial ever undertaken to explore the benets
of combination treatment (ARB + ACE inhibitor) versus single therapy treatment. Results showed
that while treatment with telmisartan showed similar effects to that with ramipril, combination
treatment was more likely to adversely affect renal functioning in this population.
Authors Note: The increase of end-points in those on combination therapy likely was caused by
hypotension and reduced renal perfusion from the full doses of both drugs. To ascertain the rationale
for combination of an ACEI and an ARB, the doses of each should have been reduced to half.

Trial: Tekturna HCT
Title: Renin inhibition with aliskiren provides additive antihypertensive efcacy when used in combi-
nation with hydrochlorothiazide.
Publication: Villamil A, Chrysant SG, Calhoun D, et al. J Hypertension. 2007 Jan; 25(1):21726.
Summary: Tekturna HCT is a single-tablet combination of a renin inhibitor, aliskiren (Tekturna), and
a diuretic, hydrochlorothiazide (HCTZ). This clinical trial was designed to evaluate the safety, efcacy,
and tolerability of Tekturna HCT in a range of doses as compared to monotherapy with Tekturna or
hydrochlorothiazide alone.
Participants: 2,762 male and female patients, age 18 years or older, with mild-to-moderate primary
hypertension participated in a multicenter, randomized, double-blind, placebo-controlled, parallel
group, 15-arm factorial trial.
Randomization: Patients were randomized to receive once daily doses of one of the following:
placebo; aliskiren monotherapy (75, 150, or 300 mg); HCTZ monotherapy (6.25, 12.5, or 25 mg); or
a combination of aliskiren and HCTZ (every dose combination except aliskiren/HCTZ 300/6.25 mg)
in a factorial design.
Length of trial: 8 weeks, after a 1-week washout period followed by up a 4-week placebo run-in
phase.
Primary end points: Change in mean seated diastolic blood pressure (MSDBP) from baseline to
week 8.
Secondary end points: Change in mean seated systolic blood pressure (MSSBP) from baseline to
week 8. Also, assessment of the dose-response efcacy for all treatment groups; the proportion of
patients showing a successful response to therapy (MSDBP < 90 mmHg and/or 10 mmHg reduc-
tion from baseline); the proportion of patients achieving BP control (MSDBP < 90 mmHg and MSSBP
< 140 mmHg); the safety and tolerability of aliskiren alone and in combination with HCTZ; and the
effects of treatment on plasma renin activity and renin concentration.
Results: Reduction in mean seated DBP was greater in patients receiving combination treatment
than those receiving monotherapy.
Mean Change from Baseline in

MSDBP (mmHg) P value vs. placebo
Placebo 6.9
Aliskiren 75 mg 8.7 P < 0.05
Aliskiren 150 mg 8.9 P < 0.05
Aliskiren 300 mg 10.3 P 0.0001

Mean Change from Baseline in

MSDBP (mmHg) P value vs. placebo
HCTZ 6.25 mg 9.1 P < 0.05
HCTZ 12.5 mg 10.1 P 0.0001
HCTZ 25 mg 9.4 P < 0.05
Combination 10.8 P 0.0001
A 75 mg
H 6.25 mg
A 75 mg
H 12.5 mg
A 75 mg
H 25 mg
A 150 mg
H 6.25 mg
A 150 mg
H 12.5 mg
A 150 mg
H 25 mg
A 300 mg
H 12.5 mg
A 300 mg
H 25 mg
Conclusion: The combination of aliskiren (Tekturna) and hydrochlorothiazide (HCTZ) resulted in sig-
nicant blood pressure reduction when compared to monotherapy with either drug alone. Although
not indicated as an initial therapy, Tekturna HCT may be used if monotherapy fails.

Trial: VALUE
Title: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based
on valsartan or amlodipine: The VALUE (Valsartan Antihypertensive Long-term Use Evaluation)
randomized trial.
Publication: Julius S, Kjeldsen SE, Weber M, et al. Lancet 2004;363:20222931.
Summary: The VALUE trial was conducted to test the hypothesis that treatment with an ARB
(specically, valsartan) would be more effective than that with a CCB (amlodipine) for hypertensive
patients at high risk for cardiovascular events.
Participants: 15,245 men and women from 31 countries (largest numbers from Germany, Italy,
and U.S.), age 50 years or older, diagnosed with hypertension (treated or untreated) and at high
risk for cardiovascular complications due to co-existing diseases (hx of MI or TIA, peripheral vascular
disease) or risk factors (cigarette smoking, hypercholesterolemia, diabetes), were enrolled between
September 1997 and November 1999.
Randomization: Patients were randomized to either amlodipine 5 mg (n = 7649) or valsartan

80 mg (n = 7596), followed by uptitration to 10 mg and 160 mg, respectively. The addition of
hydrochlorothiazide (HCTZ) 12.525.0 mg was permitted at physician discretion to achieve blood pres-
sure control at < 140/90 mmHg. Additional antihypertensive medications were likewise permitted,
exclusive of ARBs, ACE inhibitors, and CCBs.
Length of trial: Duration of treatment was event-driven; patients were followed up for a mean
of 4.2 years.
Applicability of data: Although a large number of patients were recruited in the United States,
ethnic diversity of the study population was not fully representative of the U.S. population. Study
participants self-reported ethnicity was white (89.3%), black (4.2%), Asian (3.5%), and no reported
percentage of Hispanic participants. Mean age was 67.2 years.
Primary end points: Primary composite end point of cardiac morbidity and mortality dened
as: sudden cardiac death, fatal or nonfatal MI, emergency thrombolytic/brinolytic treatment and/
or emergency revascularization to avoid MI, death during/after revascularization, new or chronic
heart failure requiring hospitalization, or heart failure death.
Secondary end points: Fatal/nonfatal MI, stroke, or heart failure.
Results: Results showed no difference with respect to occurrence of primary composite end point
in either group. While overall blood pressure was reduced in study participants, the noted effects
of the amlodipine-based treatment were more pronounced (from start to end of trial, mean blood
pressure in the amlodipine group fell by 17.3/9.9 mmHg, while only by 15.2/8.2 in the valsartan
group). Statistical analysis is as follows:

Valsartan Amlodipine
Primary composite endpoint 10.6%; HR 1.04, 95% CI 10.4%; HR 1.04, 95% CI

occurrence 0.941.14, P = .49 0.941.14, P = .49
All-cause death 11.0%; HR 1.04, 95% CI 10.8%; HR 1.04, 95% CI
0.941.14, P = .45 0.941.14, P = .45
Fatal and nonfatal MI 4.8%; HR 1.19, 95% CI 4.1%; HR 1.19, 95% CI
1.021.8, P = .02 1.021.8, P = .02
Fatal and nonfatal stroke 4.2%; HR 1.15, 95% CI 3.7%; HR 1.15, 95% CI
0.981.35, P = .08 0.981.35, P = .08
Hospitalization or death from 4.6%; HR 0.89, 95% CI 5.3%; HR 0.89, 95% CI
heart failure 0.771.03, P = .12 0.771.03, P = .12
Conclusion: Both treatment regimens in the VALUE trial effectively lowered blood pressure of
participants; however, there was no signicant difference regarding primary composite cardiac end
point between the two groups. The trial did not show signicant benet to treating hypertensive
patients at risk for cardiovascular events with an ARB (specically, valsartan) instead of a CCB
(amlodipine).

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INDEX
ARBs, see Angiotensin II Chemical agents,

ACE inhibitors, see receptor blockers hypertension
Angiotensin-converting Arrhythmia . . . . . . . . . . . 21 induced by . . . 6970
enzyme inhibitors Atherosclerosis . . . . . . . . 61 Chronic kidney disease . . . 31
Acromegaly . . . . . . . . . . . 66
Atherosclerotic renovascular Clevidipine . . . . . . . . . . . 54
Aerobic physical activity,
hypertension . . . . . 62 Cleviprex . . . . . . . . . . . . . 54
increase of . . . . . . 15
Atrioventricular (AV) Clonidine suppression
Aldosterone blockers . . . . 36
block . . . . . . . . . . 21 test . . . . . . . . . . . . 65
Aldosteronism,
Coarctation of
primary . . . . . 6263 Benign prostatic aorta . . . . . . . 6566
Alpha-1 adrenergic hypertrophy . . . . . . 21 Cocaine . . . . . . . . . . . . . . 68
blockers . . . . . 4546 Beta-blockers Combination drug
Ambulatory monitoring of mechanism of therapy . . . . . . 1718
blood pressure . . 89 action . . . . . . . . . . . 42 Corlopam . . . . . . . . . . . . 54
Angina . . . . . . . . . . . . . . 21 pharmacologic Coronary heart
Angioplasty . . . . . . . . . . . 62 properties of . . . 42, 43 disease, rate of . . . 13
Angiotensin II receptor vasodilating . . . . . . . . 44 Cushings syndrome . . . 6364
blockers Blood pressure
(ARBs) . . . . . . 3841
vs. ACE inhibitors . . . . 40
ambulatory D
iabetes . . . . . . . . . 2325
monitoring . . . . . 89 Direct renin
Angiotensin-converting follow-up schedule of . . . 7 inhibitors (DRI) 4142
enzyme (ACE) goals to control . . . . . 14 Direct vasodilators . . . . . . 47
inhibitors . . 3638, 41 measurement . . . . . . 58 Diuretics . . . . . . . . . . 3436
characteristics of . . . . . 39 stages . . . . . . . . . . . . . . 9
Drug therapy
vs. ARBs . . . . . . . . . . . 40 Brevibloc . . . . . . . . . . . . . 55 combination . . . . . 1718
Antihypertensive drugs initial . . . . . . . . . . . . . 15
characteristics of . . . 4950 C alcium channel blockers intensication of . . . 17
compelling indications (CCBs) . . . . . . 4445 Drugs
for . . . . . . . . . . . . 48 cardiovascular events for hypertensive
considerations for with . . . . . . . . . . . 46 emergencies . . . 5455
individualizing Captopril renography . . . 62 for hypertensive
therapy . . . . . . . . . 50 Cardiovascular urgencies. . . . . . . . 56
Antihypertensive therapy disease . . . . . . 11, 13
improving maintenance Cardiovascular risk E
smolol . . . . . . . . . . . . . 55
of . . . . . . . . . . 5859 factors . . . . . . . . . 13 Etiology . . . . . . . . . . . . . . . 2
improving patient CCBs, see Calcium
adherence to . . .1819 channel blockers F
enoldopam . . . . . . . . . 54
Aorta, coarctation Central alpha-adrenergic Fibromuscular
of . . . . . . . . . . 6566 agents . . . . . . . . . 46 dysplasia . . . . . 61, 62
77883_IDXx_print.indd 100 9/30/09 11:45:03 AM

Index 101
Pulmonary
Glucose suppression Labetalol . . . . . . . . . . . . 55 hypertension . . . . . 30
test . . . . . . . . . . . . . 66 Left ventricular hypertrophy
Gout . . . . . . . . . . . . . . . . 26 (LVH) . . . . . . . . . . 28
Liver disease . . . . . . . . . . 28
Renal parenchymal
H eart failure . . . . . . 2627 Loop diuretics . . . . . . . . . 36
disease . . . . . . . . . 61
Renin-angiotensin
Hydralazine . . . . . . . . . . . 54
Hyperparathyroidism, M yocardial infarction . . 28
system . . . . . . 36, 38
Renovascular
primary . . . . . . 6667
hypertension . . . 6162
Hypertensive crisis, N icardipine . . . . . . . . . . 54 Resistant
classication . . . . . 52 Nitroglycerin . . . . . . . . . . 54
hypertension . . . 5759
Hypertensive Nitroprusside . . . . . . . . . . 54 causes of . . . . . . . 5758
emergencies . . . . . 52 Non-steroidal anti-
dened . . . . . . . . . . . . 57
drugs for . . . . . . . 5455 inammatory drugs Risk stratication . . . . 1214
Hypertensive patient (NSAIDs) . . . . . . . . 67
clinical evaluation of
for cardiovascular
Normodyne . . . . . . . . . . . 55 Secondary hypertension
causes of . . 1112, 6168
disease . . . . . . . . . 11 O steoporosis . . . . . . . . 29 denition of . . . . . . . . 60
by laboratory testing 10 detection of . . . . . . . . 11
by physical P athophysiology. . . . . . . . 2 treatment for . . . . 6768
examination . . . . . 10 Patient compliance, Sphygmomanometer
for target organ optimizing . . . . . . 18 recordings, factors
damage . . . . . . . . 11 Peripheral vascular affecting accuracy
risk stratication disease . . . . . . . . . 29 of . . . . . . . . . . . . . . 6
high-risk group . . . . . 14 Phentolamine . . . . . . . . . 55 Stepdown drug
intermediate-risk Pheochromocytoma . . . 6465 therapy . . . . . . . . . . 18
group . . . . . . . . . . 13 Pituitary adenoma . . . . . . 64 Stroke . . . . . . . . . . . . . . . 29
low-risk group . . . . . 13 Plasma renin Systolic hypertension . . . . 32
Hypertensive urgencies . . 52 activity (PRA) . . . . . 63
drugs for . . . . . . . . . . 56 Potassium-sparing Target organ damage . . 13
Hypertrophic obstructive diuretics . . . . . 3436 assessment of . . . . . . . 11
cardiomyopathy . . . 27 Pregnancy treatment . . . . 30 Therapeutic lifestyle
Preoperative changes (TLC) . . . . 15
I dentiable hypertension, hypertension . . . . . 30 Thiazides . . . . . . . . . . . . . 36
see Secondary Prevention of Trandate . . . . . . . . . . . . . 55
hypertension hypertension . . . . 34 Treatment, hypertension
Inappropriate hypertension, Primary angina . . . . . . . . . . . . 21
features of . . . . . . 60 aldosteronism 6263 arrhythmia . . . . . . . . . 21
Initial drug therapy . . . . . 15 Primary asthma . . . . . . . . . . . . 22
intensication of . . . . . 17 hyperparathyroidism black . . . . . . . . . . . . . 22
Initial hypertension . . . . . . . . . . . . 6667 chronic kidney
treatment . . . . . . . 14 Pseudohypertension . . . . . 8 disease . . . . . . . . . . 31

by combination smokers . . . . . . . . . . . 31 INVEST . . . . . . . . . 8788

drug therapy . . 1718 by stepdown drug LIFE . . . . . . . . . . . . . . 89
diabetes . . . . . . . . 2326 therapy . . . . . . . . . 18 ONTARGET . . . . . . 9091
gout . . . . . . . . . . . . . . 26 valve disease . . . . . . . . 32 Tekturna HCT . . . . 9293
heart failure . . . . . 2627 women . . . . . . . . . . . . 33 VALUE . . . . . . . . . 9495
high cholesterol . . . . . 27 Trials
hypertrophic obstructive
cardiomyopathy . . . 27
ACCOMPLISH . . . . 7172
ALLHAT . . . . . . . . 7374
V alve disease . . . . . . . . 32
Vascular
induced by chemical ANBP2 . . . . . . . . . 7576
damages . . . . . . . . 53
agents . . . . . . 6970 ASCOT . . . . . . . . . 7778
Vasodilating beta
by initial drug CONVINCE . . . . . . 7980
blockers . . . . . . . . 44
therapy . . . . . . 15, 17 DORADO DAR 311
liver disease . . . . . . . . 28 . . . . . . . . . . . . 8182
osteoporosis . . . . . . . . 29 Exforge-HCT . . . . . 8384 W eight reduction . . . . 15
pregnancy . . . . . . . . . 30 HYVET . . . . . . . . . 8586 White-coat hypertension . . . 8

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Hypertension

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Copyright 2010 by Jones and Bartlett Publishers, LLC

Printed in the United States of America

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Norman Kaplan, MD, is clinical professor of internal medicine

Michael A. Weber, MD, is professor of medicine at the SUNY

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SECTION 1. DIAGNOSIS, EVALUATION, AND Mechanism of Action ............................. 36

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ACC American College of EPA eicosapentaenoic acid

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NHLBI National Heart, Lung, and qh every hours

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Chapter 1. Overview of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

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E. Pathophysiology. Essential hypertension is caused by increased vascular reactivity, the

F. Approach to Diagnosis and Treatment. As shown in Figure 1.2, management of

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Normotension EARLY HYPERTENSION 20 40

Accelerated- CARDIAC LARGE CEREBRAL RENAL

Figure 1.1. Natural History of Hypertension

H. Awareness, Treatment, and Control. Hypertension is grossly underdiagnosed and

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Evaluate the Patient Clinically

Figure 1.2. Approach to Diagnosis and Treatment of Hypertension

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STEP 1. CONFIRM AND STAGE HYPERTENSION

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Examinee Examinee Examinee

Adapted from: JAMA 1995;273:12111218.

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< 120 < 80 Recheck in 2 years

7. Wait 12 minutes and repeat the measurement. A third reading should be

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pressure measurements. These instruments provide more consistent readings

B. Exclude White-Coat Hypertension and Pseudohypertension. It is important to

2. Pseudohypertension. Pseudohypertension occurs when the blood pressure cuff

D. Ambulatory Blood Pressure Monitoring. Home readings should be considered in

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Table 2.3. Blood Pressure Stages

Normal < 120 and < 80

Compared to treatment based on conventional monitoring, antihypertensive treatment

STEP 2. EVALUATE THE PATIENT CLINICALLY

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B. Assessment of Target Organ Damage. Risk stratication plays an important role in

C. Detection of Secondary Hypertension. Hypertension that can be ascribed to an

Table 2.5. Causes of Secondary Hypertension (Chapter 7)

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STEP 3. RISK STRATIFICATION

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treatment of hypertension. The following is such an approach: Hypertensive patients can

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High-normal (130 Lifestyle modication Lifestyle modication Drug therapy

STEP 4. INITIATE TREATMENT AND OPTIMIZE COMPLIANCE

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B. Approach to Treatment. The choice of initial drug therapy is based on patient

C. Therapeutic Lifestyle Changes. Lifestyle modications should be initiated either

Lose weight if overweight. Weight reduction (~ 10 lb.) reduces blood pressure in

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Begin or Continue Lifestyle Modifications

Not at Blood Pressure Goal

Initiate Drug Therapy