Beruflich Dokumente
Kultur Dokumente
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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Section 1
DIAGNOSIS, EVALUATION, AND TREATMENT
OF HYPERTENSION
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.
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).
HEREDITY-ENVIRONMENT
Age
PRE-HYPERTENSION 0 30
ESTABLISHED HYPERTENSION 30 50
UNCOMPLICATED COMPLICATED
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.
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
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)
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)
Chapter 2
Evaluation of 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.
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
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.
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
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]).
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).
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
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)
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
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.
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.
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
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).
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
(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.
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.
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
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
77883_CH03_print.indd 22
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
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
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
77883_CH03_print.indd 23
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
Chapter 3. Treatment of Essential Hypertension
9/29/09 10:52:37 AM
Table 3.1. Treatment of Essential Hypertension (Cont'd)
77883_CH03_print.indd 24
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
24 H y p e r t e n s i o n
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
77883_CH03_print.indd 25
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.
Chapter 3. Treatment of Essential Hypertension
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Table 3.1. Treatment of Essential Hypertension (Cont'd)
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
77883_CH03_print.indd 26
The HYVET trial demonstrated that combination
treatment based on a non-thiazide diuretic and an
26 H y p e r t e n s i o 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
77883_CH03_print.indd 27
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.
Chapter 3. Treatment of Essential Hypertension
9/29/09 10:52:37 AM
Table 3.1. Treatment of Essential Hypertension (Cont'd)
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
77883_CH03_print.indd 28
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
28 H y p e r t e n s i o n
(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
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-
77883_CH03_print.indd 29
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
Chapter 3. Treatment of Essential Hypertension
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Table 3.1. Treatment of Essential Hypertension (Cont'd)
77883_CH03_print.indd 30
antagonists and labetalol are widely used outside the
U.S. ACE inhibitors, ARBs, and direct renin inhibitors are
30 H y p e r t e n s i o n
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
77883_CH03_print.indd 31
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.
Chapter 3. Treatment of Essential Hypertension
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
Table 3.1. Treatment of Essential Hypertension (Cont'd)
77883_CH03_print.indd 32
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).
32 H y p e r t e n s i o n
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.
77883_CH03_print.indd 33
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.
Chapter 3. Treatment of Essential Hypertension
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
34 H y p e r t e n s i o n Essentials
Chapter 4
Antihypertensive Drug Classes: Mechanism of Action
and Selected Features
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).
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).
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).
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
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
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.
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
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
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.
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
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.
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
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).
-1 ADRENERGIC BLOCKERS
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.
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.
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.
77883_CH04_print.indd 49
peripheral
vasodilation
Side effects Weakness, palpitations Postural dizziness Bronchospasm; Cough; Flushing; local edema;
Overt fatigue; prolong angioedema constipation
hypoglycemia (verapamil)
Cautions Diabetes mellitus; gout; Congestive heart Peripheral vascular Renal insufciency; Heart failure
digitalis toxicity failure disease; insulin- renovascular
Chapter 4. Antihypertensive Drug Classes
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
77883_CH04_print.indd 50
Cough from ACE inhibitor ARB Depression CCB (non-DHP)
Cyclosporine-induced CCB Dyslipidemia Central a-agonists
50 H y p e r t e n s i o n
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
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.
Duration
Adverse
Onset of Effectsb of
Druga Dose Action Action Side Effects Special Indications
77883_CH05_print.indd 54
Vasodilators
Nitroprusside 0.2510.00 g/kg/ Immediate 12 min Nausea, vomiting, muscle Not preferred for most
54 H y p e r t e n s i o n
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
77883_CH05_print.indd 55
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
56 H y p e r t e n s i o n Essentials
Table 5.3. Oral Drugs for Hypertensive Urgencies
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.
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.
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
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.
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
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
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
Paradoxical response to
antihypertensive drugs
Withdrawal, followed by catechols Clonidine
Unopposed -adrenergic vasoconstriction -blockers
Intrinsic sympathomimetic activity Pindolol
Combination - and -blocker Propranolol plus clonidine
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.
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
Benazepril-Amlodipine Benazepril-Hydrocholothiazide
Group Group
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.
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.
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).
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
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.
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).
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.
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
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.
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%).
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:
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:
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).
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.
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.
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.
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.
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.
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.
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
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.
Title: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in
hypertension study (LIFE): A randomised trial against atenolol.
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.
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:
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.
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.
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
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.
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.
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.
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.
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.
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.
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
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
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