The Changing Paradigm of
Hypertension:
Victoria E. Judd M. D.
Objectives
• Define hypertension
• Discuss the diagnosis and evaluation of
hypertension
• List the management of hypertension
• List the complications of hypertension
Hypertension
• Most common disease of industrialized
world (>20% of adult population)
• Major risk factor for death from heart
attack, stroke, congestive heart
failure,kidney disease, retinopathy,
peripheral vascular disease
• Pathogenesis unknown
• Treatment inadequate
What is Hypertension?
• The Seventh Report of the Joint National
Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood
Pressure (JNC 7)
Definition of Hypertension
These definitions apply to:
• Adults
• On no antihypertensive
medications
• Who are not acutely ill
Definition of Hypertension
• If there is a disparity in category
between the systolic and diastolic
pressures, the higher value
determines the severity of the
hypertension.
Definition of Hypertension
• The systolic pressure is the greater
predictor of risk in patients over
the age of 50 to 60.
Definition of Hypertension
• Somewhat different definitions
were suggested by the European
Societies of Hypertension and
Cardiology, which published 2007
guidelines for the management of
arterial hypertension.
Definition of Hypertension
• Optimal blood pressure: systolic
<120 mmHg and diastolic <80
mmHg
• Normal: systolic 120-129 mmHg
and/or diastolic 80-84 mmHg
• High normal: systolic 130-139
mmHg and/or diastolic 85-89
mmHg
Definition of Hypertension
•
•
•
•
Hypertension:
Grade 1: systolic 140-159 mmHg
and/or diastolic 90-99 mmHg
Grade 2: systolic 160-179 mmHg
and/or diastolic 100-109 mmHg
Grade 3: systolic ≥180 mmHg and/or
diastolic ≥110 mmHg
Isolated systolic hypertension: systolic
≥140 mmHg and diastolic <90 mmHg
Resistant Hypertension
• Blood pressure that remains above goal
despite the concurrent use of 3
antihypertensive agents of 3 different
classes.
Definition of Malignant
Hypertension
• Malignant hypertension is marked
hypertension with retinal
hemorrhages, exudates, or
papilledema.
• Malignant hypertension is usually
associated with a diastolic pressure
above 120 mmHg.
Definitions
• Hypertensive encephalopathy can be
seen at diastolic pressures as low as
100 mmHg in previously normotensive
patients with acute hypertension due to
preeclampsia or acute
glomerulonephritis.
• In patients in whom autoregulation is
impaired may also develop hypertensive
injury at relatively mild degrees of
hypertension.
Diagnosis of Hypertension
• The optimal interval for screening for
hypertension is not known. The 2007 United
States Preventive Services Task Force (USPSTF)
guidelines on screening for high blood pressure
recommend screening every two years for persons
with systolic and diastolic pressures below 120
mmHg and 80 mmHg, respectively (normal BP in
JNC 7), and yearly for persons with a systolic
pressure of 120 to 139 mmHg or a diastolic
pressure of 80 to 89 mmHg.
Diagnosis of Hypertension
• Proper measurement and interpretation of
the blood pressure is essential in the
diagnosis and management of hypertension.
Diagnosis of Hypertension
• A recent study found no clinical difference
in blood pressure readings from a bare arm
compared to those measured over a sleeved
arm.
• A comparison of blood pressure measurement over a
sleeved arm versus a bare arm. Ma G; Sabin N; Dawes M;
CMAJ. 2008 Feb 26;178(5):585-9.
Diagnosis of Hypertension
• In the absence of end-organ
damage, the diagnosis of mild
hypertension should not be made
until the blood pressure has been
measured on at least three to six
visits, spaced over a period of
weeks to months.
Diagnosis of Hypertension
• Sequential studies have shown
that the blood pressure drops by
an average of 10 to 15 mmHg
between visits one and three in
patients who appear to have mild
hypertension on a first visit to a
new provider, with a stable value
not being achieved until more than
six visits in some cases.
Diagnosis of Hypertension
• Thus, many patients considered to
be hypertensive at the initial visit
are in fact normotensive.
• Confirming the diagnosis of mild hypertension.
Hartley RM; Velez R; Morris RW; D'Souza MF;
Heller RF; Br Med J (Clin Res Ed) 1983 Jan
22;286(6361):287-9.
Diagnosis of Hypertension
• Variation in cuff blood pressure in untreated
outpatients with mild hypertension-implications for initiating antihypertensive
treatment. Watson RD; Lumb R; Young MA;
Stallard TJ; Davies P; Littler WA; J Hypertens
1987 Apr;5(2):207-11.
Circumstances of BP
Measurements
• No caffeine during the hour preceding
the measurement and no smoking
during the preceding 30 minutes
• No exogenous adrenergic stimulants,
such as phenylephrine in decongestants
or eye drops for pupillary dilatation
• A quiet, warm setting
• Home readings should be taken upon
varying circumstances
Equipment for BP Measurement
Cuff size
• The length of the bladder should
be 80 percent and the width of the
bladder should be at least 40
percent of the circumference of the
upper arm.
BP Measurement
• Take at least two measurements
on each visit, separated by as
much time as possible; if
measurements vary by more than
5 mmHg, take additional
measurements until two
consecutive measurements are
close.
BP Measurement
• For the diagnosis of hypertension, take
three measurements at least one week
apart.
• Initially, take blood pressure in both
arms; if pressures differ, use the higher
arm.
• If the arm pressure is elevated, take
the pressure in one leg, particularly in
patients under age 30.
BP Measurement
• Inflate the bladder quickly to 20
mmHg above the systolic pressure
as estimated from loss of radial
pulse
• Deflate the bladder 3 mmHg per
second
BP Measurement
• Record the Korotkoff phase V
(disappearance) as the diastolic
pressure.
• If the Korotkoff sounds are weak,
have the patient raise the arm,
open and close the hand five to
ten times, and then inflate the
bladder quickly.
Hypertensive Response to Visit
•
Increase in systolic pressure, determined by continuous intraarterial
monitoring, in 30 hypertensive patients as the blood pressure is taken with a
sphygmomanometer by an unfamiliar doctor or nurse. A new doctor's visit
raised the systolic pressure by a mean of 22 mmHg within the first few
minutes, an effect that attenuated within five to 10 minutes and that was less
pronounced with a nurse's visit. The alerting effect of the new physician's visit
persisted for four daily visits in this study, but typically diminished with
increasing familiarity. A similar pattern was seen with the diastolic pressure,
with the peak increase being 13 mmHg during a physician's visit. Data from
Mancia, G, Parati, G, Pomidossi, G, et al, Hypertension 1987; 9:209.
BP Measurement
Recordings
• Note the pressure, patient
position, arm, and cuff size: e.g.,
140/90, seated, right arm, large
adult cuff
BP Overestimated
•
•
•
•
•
•
Arm below heart
Small cuff
Talking
Cold temperature
Alcohol
Tobacco
BP Underestimated
•
•
•
•
Arm above heart
Cuff too large
Supine
Provider bias
ABPM
• ABPM is determined using a device
worn by the patient that takes
blood pressure measurements over
a 24 to 48 hour period, usually
every 15 to 20 minutes during the
daytime and every 30 to 60
minutes during sleep.
ABPM
• These blood pressures are
recorded on the device, and the
average day (diurnal) or night
(nocturnal) blood pressures are
determined from the data by a
computer.
ABPM
• The percentage of blood pressure
readings exceeding the upper limit
of normal can also be calculated.
• This is considered to provide a
better measure of systolic and
diastolic blood pressure load than
an individual blood pressure
measurement.
ABPM
• However, ABPM is not available in many
clinicians' offices. This is probably due
to a combination of factors, including
lack of knowledge regarding its utility,
its expense, and minimal
reimbursement by third-party payers.
• In addition, ABPM is still only a onetime measure of a variable factor that
must be followed over time.
Definition of Hypertension by
ABPM
• A 24-hour average above 135/85
mmHg
• Daytime (awake) average above
140/90 mmHg
• Nighttime (asleep) average above
125/75 mmHg
ABPM
• In two separate community based
studies, with 1700 and 5292
participants, multivariate analysis
demonstrated that only ambulatory
blood pressures (and not office blood
pressures) were significant predictors of
cardiovascular and all-cause mortality
after a mean follow-up of over eight
years.
ABPM
• Ambulatory blood pressure and mortality: a populationbased study. Hansen TW; Jeppesen J; Rasmussen S; Ibsen
H; Torp-Pedersen C; Hypertension 2005 Apr;45(4):499504. Epub 2005 Mar 7.
• Superiority of ambulatory over clinic blood pressure
measurement in predicting mortality: the Dublin outcome
study. Dolan E; Stanton A; Thijs L; Hinedi K; Atkins N;
McClory S; Den Hond E; McCormack P; Staessen JA;
O'Brien E. Hypertension 2005 Jul;46(1):156-61. Epub
2005 Jun 6.
ABPM
• Some, but not all, data suggest
that measurement of nighttime
blood pressure may yield
additional prognostic data in terms
of all cause mortality and
cardiovascular events.
ABPM
• A cohort study of 7458 patients in six
countries from Europe, Asia, and South
America found that both daytime and
nighttime blood pressure predicted all
cardiovascular events.
• Nighttime blood pressure, adjusted for day
time blood pressure, predicted total,
cardiovascular, and noncardiovascular
mortality.
• In contrast, daytime blood pressure, adjusted
for blood pressure measured during sleep,
only predicted noncardiovascular mortality.
ABPM
• Similar findings were noted in a
second cohort of 3957 patients
who underwent ambulatory
monitoring.
• Blood pressures obtained during
sleep were more predictive of allcause mortality than those
obtained during waking hours.
When to Get ABPM
• Suspected white coat hypertension
• Suspected episodic hypertension (e.g.,
pheochromocytoma)
• Hypertension resistant to increasing
medication
• Hypotensive symptoms while taking
antihypertensive medications
• Autonomic dysfunction
Home BPM
• In view of the cost and limited
availability of ambulatory
monitoring, increasing attention is
being given to home monitoring
with inexpensive semi-automatic
devices.
Home BPM
• Such self-recorded casual blood
pressure measurements taken at
home or work correlate more
closely with the results of 24-hour
or daytime ambulatory monitoring
than with blood pressure taken in
the physician's office.
Home BPM
• Home blood pressure
measurements may be more
predictive of adverse outcomes
(e.g., stroke, ESRD) than clinic
blood pressures.
Home BPM
• Patient self-monitoring of blood
pressure may improve blood
pressure control.
• A systematic review found a 4
mmHg reduction in systolic blood
pressure among patients
instructed to measure blood
pressure themselves.
Home BPM
• The potential problems with outpatient
BP measurements can be minimized by
providing adequate training, and
periodically checking the machine for
accuracy.
• These can be tested by having the
patient or their partner take the BP in
the office with their home monitor at
the same time that a medical person
measures the BP in the other arm.
Home BPM
• As with ambulatory monitoring, the BP
taken by the patient varies widely
during the day, being influenced by
factors such as stress (particularly at
school, work), smoking, caffeine intake,
natural circadian variation, and
exercise.
• Thus, multiple readings should be taken
to determine the average level.
Home BPM
• The timing of antihypertensive medication
must also be considered. With short-acting
drugs, the BP may fall to normal or even
below normal one to two hours after therapy
and then gradually increase to elevated levels
until the next dose is taken.
• This problem can be minimized by having the
outpatient BP measured 30 to 60 minutes
before taking medications, preferably in the
early morning to assess for possible
inadequate overnight BP control.
Evaluation of Hypertension
• To rule out identifiable and often
curable causes of hypertension.
• To determine the extent of target
organ damage.
• To assess the patient's overall
cardiovascular risk status.
History
Duration of hypertension
• Last known normal blood pressure
• Course of the blood pressureincreasing, decreasing, stable
History
Prior treatment of hypertension
• Drugs: types, doses, side effects
History
Intake of agents that may cause
hypertension
• Estrogens
• Adrenal steroids
• Cocaine
• Sympathomimetics; i.e.
amphetamines
• Excessive sodium
History
Family history
• Hypertension
• Premature cardiovascular disease
or death
• Familial diseases:
pheochromocytoma, renal disease,
diabetes
History
Symptoms of secondary causes
• Muscle weakness
• Spells of tachycardia, sweating,
tremor
• Thinning of the skin
• Flank pain
History
Symptoms of target organ damage
• Headaches
• Transient weakness or blindness
• Loss of visual acuity
• Chest pain
• Dyspnea
• Claudication
History
Presence of other risk factors
• Smoking
• Diabetes
• Dyslipidemia
• Physical inactivity
History
Dietary history
• Sodium
• Alcohol
• Saturated fats
History
Psychosocial factors
• Support structure
• Work status
• Educational stressors
History
Features of sleep apnea
• Early morning headaches
• Daytime somnolence
• Loud snoring
• Erratic sleep
Physical Exam
• Accurate measurement of blood
pressure
Physical Exam
General appearance
• Distribution of body fat
• Skin lesions
• Muscle strength
• Alertness
Physical Exam
Fundoscopy
• Hemorrhage
• Papilledema
• Cotton-wool spots
Physical Exam
Neck
• Palpation and auscultation of
carotids
• Thyroid
• Neck circumference in inches
Physical Exam
Heart
• Size
• Rhythm
• Sounds
Physical Exam
Lungs
• Rhonchi
• Rales
Physical Exam
Abdomen
• Renal masses
• Bruits over aorta or renal arteries
• Femoral pulses
Physical Exam
Extremities
• Peripheral pulses
• Edema
Physical Exam
Neurologic assessment
• Visual disturbance
• Focal weakness
• Confusion
Laboratory
• Complete blood count, routine blood
chemistries (hemolysis,
thrombocytopenia, acute renal failure)
• Lipid profile (Should be done fasting)
• Urinalysis (proteinuria, hematuria)
• Electrocardiogram (myocardial
ischemia, hypertrophy)
Laboratory
• Additional tests may be indicated
in certain settings.
Hypertension
• Primary (essential) 95%
• Secondary 5% (has a demonstrable cause)
Secondary Hypertension is
Suggested By
• Severe or refractory hypertension.
• An acute rise in blood pressure over a
previously stable value.
• Proven age of onset before puberty.
• Age less than 30 years in non-obese,
non-black patients with a confirmed
negative family history of hypertension.
Renovascular
Hypertension
• Renovascular hypertension is the
most common correctable cause of
secondary hypertension.
Renovascular
Hypertension
• The following are settings in which
renovascular hypertension or
another cause of secondary
hypertension should be suspected:
Renovascular
Hypertension
• Proven age of onset before puberty
or above age 50.
• Negative family history for
hypertension.
Renovascular
Hypertension
• A systolic-diastolic abdominal bruit that
lateralizes to one side. This finding has a
sensitivity of approximately 40 percent (and is
therefore absent in many patients) but has a
specificity as high as 99 percent.
• Systolic bruits alone are more sensitive but
less specific.
• The patient should be supine, moderate
pressure should be placed on the diaphragm
of the stethoscope, and auscultation should be
performed in the epigastrium and all four
abdominal quadrants.
Other Causes of Identifiable Hypertension
• Pheochromocytoma should be
suspected if there are paroxysmal
elevations in blood pressure (which
may be superimposed upon stable
chronic hypertension), particularly
if associated with the triad of
headache (usually pounding),
palpitations, and sweating.
Other Causes of Identifiable Hypertension
• Cushing's syndrome (including that
due to corticosteroid
administration) is usually
suggested by the classic physical
findings of cushingoid facies,
central obesity, ecchymoses, and
muscle weakness.
Other Causes of Identifiable Hypertension
• Coarctation of the aorta is
characterized by decreased or
lagging peripheral pulses and a
vascular bruit over the back.
Components of cardiovascular risk factors
in patients with hypertension
Major risk factors
•
•
•
•
•
Cigarette smoking
Obesity (BMI >30 kg/m2)
Physical inactivity
Dyslipidemia
Diabetes mellitus
Components of cardiovascular risk factors
in patients with hypertension
• Microalbuminuria or estimated GFR <60
mL/min
• Age >55 years for men, >65 years in
women
• Family history of premature coronary
disease; Men - <55 years,Women - <65
years
Target Organ Damage
•
•
•
•
Heart disease
Left ventricular hypertrophy
Angina or prior myocardial infarction
Prior coronary revascularization
Heart failure
Stroke or transient ischemic attack
Chronic kidney disease
Peripheral arterial disease
Retinopathy
Why Treat
• In clinical trials, antihypertensive
therapy compared to placebo has
been associated with significant 20
to 25 percent reduction in the
incidence of major cardiovascular
events (e.g., stroke, heart failure,
and myocardial infarction).
Why Treat
• The cardiovascular benefit may be
even greater with optimal control
to below 130/80 mmHg, which is
currently recommended in patients
with diabetes, coronary disease, or
a coronary equivalent.
Why Treat
• Preventing heart disease by controlling hypertension:
impact of hypertensive subtype, stage, age, and sex.
Wong ND; Thakral G; Franklin SS; L'Italien GJ; Jacobs
MJ; Whyte JL; Lapuerta P. Am Heart J 2003
May;145(5):888-95.
Recommendation
Maintain normal body weight (BMI, 18.5 to 24.9
kg/m2)
Consume a diet rich in fruits, vegetables, and
low-fat dairy products with a reduced content of
saturated and total fat
Reduce dietary sodium intake to no more than
100 meq/day (2.4 g sodium or 6 g sodium
chloride)
Engage in regular aerobic physical activity such
as brisk walking (at least 30 minutes per day,
most days of the week)
Limit consumption to no more than 2 drinks per
day in most men and no more than 1 drink per
day in women and lighter-weight persons
Approximate systolic
BP reduction,
range*
5-20 mmHg per 10kg weight loss
8 to 14 mmHg
2 to 8 mmHg
4 to 9 mmHg
2 to 4 mmHg
Who Should be Treated?
• There should be clear evidence of
likely benefit before
antihypertensive drugs are begun.
• Such evidence is now available for
most degrees of hypertension
(diastolic pressure persistently
≥90 mmHg and systolic pressure
≥140 mmHg).
Cardiovascular Benefit of
Treating Mild Hypertension
Cardiovascular Benefit of
Treating Mild Hypertension
• Reduced incidence of fatal and total coronary heart disease
(CHD) events and strokes following antihypertensive therapy
in 17 controlled studies involving almost 48,000 patients with
mild to moderate hypertension. The number of patients
having each of these events is depicted, with active treatment
lowering the incidence of coronary events by 16 percent and
stroke by 40 percent. However, the absolute benefit - as
shown, in percent, by the numbers at the top of the graph was much less. Treatment for approximately 4 to 5 years
prevented a coronary event or a stroke in two percent of
patients (0.7 + 1.3), including prevention of death in 0.8
percent.
•
Data from Hebert, PR, Moser, M, Mayer, J, et al, Arch Intern Med
1993; 153:578.
Who Should be Treated?
• There are controversial data
suggesting that treatment of
prehypertension may lower the
risk of developing sustained
hypertension. (TROPHY trial).
Who Should be Treated?
• In general, epidemiologic studies of
treated and untreated patients reveal
that there is a gradually increasing
incidence of coronary disease and
stroke and cardiovascular mortality as
the blood pressure rises above 110/75
mmHg, with some notable differences
in risk based upon age and underlying
comorbid conditions.
Who Should be Treated?
• The Framingham Heart Study also reported an
increased incidence of poor outcomes as the
blood pressure rises, even with values within
the "normal" range.
• This study examined the risk of cardiovascular
disease at 10 year follow-up among subjects
with "high-normal" blood pressure at baseline
examination, which was defined as a systolic
blood pressure of 130 to 139 mmHg, a
diastolic pressure of 85 to 89 mmHg, or both,
and with "normal" blood pressure, which was
defined as a systolic blood pressure of 120 to
129 mmHg, a diastolic pressure of 80 to 84
mmHg, or both.
Who Should be Treated?
• Cumulative incidence of cardiovascular events over time in
6859 men and women in the Framingham Heart Study who
were initially free of hypertension or cardiovascular
disease. The patients were put into one of three BP
categories: optimal blood pressure (BP 120/ 80), normal
BP (120 to 129/80-84), and high-normal BP (130-139/8589 mmHg). If the systolic and diastolic pressures were
discordant, the higher of the two categories was used.
High-normal BP, compared to optimal BP, was associated
with an adjusted hazard ratio for cardiovascular disease of
1.6 in men and 2.5 in women. Data from Vasan, RS,
Larson, MG, Leip, EP, et al, N Engl J Med 2001;
345:1291.
Treatment
• In the Women's Health Initiative study
involving over 60,785 postmenopausal
women who were followed for 7.7
years, women with prehypertension,
compared to normotensive individuals,
had an increased risk of cardiovascular
death (HR 1.76, 95% CI 1.40 to 2.2),
myocardial infarction (1.93, 95% CI
1.49 to 2.50) and stroke (1.36, 95% CI
1.05 to 1.77).
Treatment
• Prehypertension and cardiovascular disease risk in the
Women's Health Initiative. Hsia J; Margolis KL; Eaton
CB; Wenger NK; Allison M; Wu L; LaCroix AZ; Black
HR. Circulation. 2007 Feb 20;115(7):855-60.
Who Should be Treated?
• The Medical Research Council Mild
Hypertension Trial found a close
correlation between cardiovascular risk
and the systolic pressure measured
three months after entry into the trial.
In contrast, a transient increase in
systolic pressure at entry due to a white
coat response was not associated with
increased risk.
Who Should be Treated?
• Antihypertensive medications
should generally be begun if the
systolic pressure is persistently
≥140 mmHg and/or the diastolic
pressure is persistently ≥90 mmHg
in the office and at home despite
attempted nonpharmacologic
therapy.
Who Should be Treated?
• In patients with diabetes, chronic
kidney disease, or known
cardiovascular disease,
antihypertensive therapy is
indicated when the systolic
pressure is persistently above 130
mmHg and/or the diastolic
pressure is above 80 mmHg.
Who Should be Treated?
• 5 to 20 percent of patients with normal
office readings have been found to have
elevated out-of-the office readings by
24 hour automatic ambulatory blood
pressure monitoring.
• These patients with "masked"
hypertension appear to have an
increased cardiovascular risk similar to
those with elevated office and
ambulatory readings.
Treatment
• Although recommendations for
initiating medical therapy in
essential hypertension have been
proposed, there is no uniform
agreement on which
antihypertensive agent should be
given for initial therapy.
Treatment
• A variety of different classes of
drugs can be used in this setting.
These include the thiazide
diuretics, angiotensin converting
enzyme (ACE) inhibitors,
angiotensin II receptor blockers
(ARB’s), calcium channel blockers,
and beta blockers.
Treatment
• The choice among the different
antihypertensive drugs has not
generally been made on the basis
of efficacy, since each of these
agents is roughly equally effective,
producing a good antihypertensive
response in 30 to 50 percent of
cases.
Treatment
• An increasing number of trials
have provided evidence that, at
the same level of blood pressure
control, most antihypertensive
drugs provide the same degree of
cardiovascular protection,
particularly cardiovascular
morbidity and mortality.
Treatment
• The 2007 American Heart Association statement
on the treatment of blood pressure in ischemic
heart disease, the 2007 European Society of
Hypertension/European Society of Cardiology
guidelines on the management of hypertension,
and a 2008 meta-analysis concluded that the
amount of blood pressure reduction is the major
determinant of reduction in cardiovascular risk in
patients with hypertension, not the choice of
antihypertensive drug.
Treatment
•
•
Effects of different regimens to lower blood pressure on major cardiovascular
events in older and younger adults: meta-analysis of randomised trials.
Turnbull F; Neal B; Ninomiya T; Algert C; Arima H; Barzi F; Bulpitt C;
Chalmers J; Fagard R; Gleason A; Heritier S; Li N; Perkovic V; Woodward M;
MacMahon S. BMJ. 2008 May 17;336(7653):1121-3. Epub 2008 May 14.
Treatment of hypertension in the prevention and management of ischemic
heart disease: a scientific statement from the American Heart Association
Council for High Blood Pressure Research and the Councils on Clinical
Cardiology and Epidemiology and Prevention. Rosendorff C; Black HR;
Cannon CP; Gersh BJ; Gore J; Izzo JL Jr; Kaplan NM; O'Connor CM; O'Gara
PT; Oparil S. Circulation. 2007 May 29;115(21):2761-88. Epub 2007 May 14.
Treatment
•
•
2007 Guidelines for the management of arterial hypertension: The Task Force for the
Management of Arterial Hypertension of the European Society of Hypertension (ESH)
and of the European Society of Cardiology (ESC). Mancia G; De Backer G; Dominiczak
A; Cifkova R; Fagard R; Germano G; Grassi G; Heagerty AM; Kjeldsen SE; Laurent S;
Narkiewicz K; Ruilope L; Rynkiewicz A; Schmieder RE; Struijker Boudier HA;
Zanchetti A; Vahanian A; Camm J; De Caterina R; Dean V; Dickstein K; Filippatos G;
Funck-Brentano C; Hellemans I; Kristensen SD; McGregor K; Sechtem U; Silber S;
Tendera M; Widimsky P; Zamorano JL; Kjeldsen SE; Erdine S; Narkiewicz K; Kiowski
W; Agabiti-Rosei E; Ambrosioni E; Cifkova R; Dominiczak A; Fagard R; Heagerty AM;
Laurent S; Lindholm LH; Mancia G; Manolis A; Nilsson PM; Redon J; Schmieder RE;
Struijker-Boudier HA; Viigimaa M; Filippatos G; Adamopoulos S; Agabiti-Rosei E;
Ambrosioni E; Bertomeu V; Clement D; Erdine S; Farsang C; Gaita D; Kiowski W; Lip
G; Mallion JM; Manolis AJ; Nilsson PM; O'brien E; Ponikowski P; Redon J; Ruschitzka
F; Tamargo J; van Zwieten P; Viigimaa M; Waeber B; Williams B; Zamorano JL . Eur
Heart J. 2007 Jun;28(12):1462-536. Epub 2007 Jun 11.
Treatment
• In the absence of a specific
indication, there are three main
classes of drugs that are used for
initial monotherapy: thiazide
diuretics, long-acting calcium
channel blockers (most often a
dihydropyridine), and ACE
inhibitors or angiotensin II
receptor blockers.
Treatment
• It is the attained blood pressure, not
the specific drug(s) used, that is the
primary determinant of outcome.
• Beta blockers are not commonly used
for initial monotherapy in the absence
of a specific indication, since they may
have an adverse effect on some
cardiovascular outcomes, particularly in
older patients.
Treatment
• Beta blockers as initial therapy? —
It is unclear whether beta blockers
offer the same degree of cardiovascular
protection as other antihypertensive
drugs in patients with essential
hypertension who have no specific
indications for their use (e.g., resting
tachycardia, angina pectoris, or a
recent myocardial infarction).
Treatment
• There may be some differences in
selected outcomes, such as stroke,
or in noncardiovascular outcomes
such as the development of
diabetes, and differences based on
patient characteristics, such as
presence of diabetes and race.
Treatment
• These observations led to a general
consensus, including 2007 guidelines
from the American Heart Association
and European Society of
Hypertension/European Society of
Cardiology, that the amount of BP
reduction is the major determinant of
reduction in cardiovascular risk, not the
choice of antihypertensive drug.
Treatment
• However, based upon the results of
the ACCOMPLISH trial, this
conclusion about equivalent
efficacy of the different drugs may
not apply to combination therapy.
Treatment
• ACCOMPOLISH: Avoiding
Cardiovascular Events in
Combination Therapy in
Patients Living with Systolic
Hypertension
Treatment
ALLHAT: The Antihypertensive and LipidLowering Treatment to Prevent Heart
Attack Trial
ALLHAT
• ALLHAT was designed to evaluate
whether the incidence of adverse
cardiovascular outcomes differed
among those randomly assigned to
chlorthalidone (12.5 to a maximum of
25 mg/day, the equivalent dose of of
hydrochlorothiazide is 1.5 to 2.0 times
higher) compared to one of three other
antihypertensive drugs: amlodipine (a
calcium channel blocker), lisinopril (an
ACE inhibitor), or doxazosin (an alphaadrenergic blocker).
ALLHAT
• The doxazosin arm was terminated
prematurely because of a significantly
increased risk of heart failure compared
to chlorthalidone (relative risk 2.0 after
adjusting for a 3 mmHg higher in-trial
systolic pressure with doxazosin) noted
during an interim analysis and a smaller
increase in stroke and all cardiovascular
events.
ALLHAT
• The incidence of the primary
outcome (fatal coronary heart
disease and nonfatal myocardial
infarction), and all-cause mortality
were the same for all three agents.
ALLHAT
• A higher rate of heart failure was
observed with amlodipine
compared with chlorthalidone
(10.2 versus 7.7 percent, RR 1.38,
95% CI 1.25-1.52)
ALLHAT
• Compared with chlorthalidone,
lisinopril had higher rates of
combined cardiovascular disease
outcomes (33.3 versus 30.9
percent, RR 1.10), stroke (6.3
versus 5.6 percent, RR 1.15), and
heart failure (8.7 versus 7.7
percent, RR 1.19).
ALLHAT
• The principal finding of ALLHAT is that
chlorthalidone, amlodipine, and
lisinopril provided similar protection
from coronary heart disease death and
nonfatal myocardial infarction among
patients with hypertension and risk
factors for cardiovascular disease, a
result consistent with CAPPP, STOP
Hypertension 2, and other trials.
ALLHAT
• Unlike the smaller trials previously
reviewed, the large number of
participants in ALLHAT provided
the power to detect that a thiazide
diuretic may actually be superior
to a calcium channel blocker and
an ACE inhibitor in preventing
some adverse cardiovascular
outcomes.
ALLHAT
• One possible explanation for this
unexpected result is that lisinopril
provided relatively less blood
pressure control than
chlorthalidone, as the first two
years of the trial were associated
with a 3 to 4 mmHg higher blood
pressure with the ACE inhibitor.
Chlorthalidone versus
Hydrochlorothiazide
• Chlorthalidone at the same dose is
approximately 1.5 to 2.0 times as
potent as hydrochlorothiazide.
Thus, 12.5 mg/day of
chlorthalidone is equivalent to 19
to 25 mg/day of
hydrochlorothiazide.
Chlorthalidone versus
Hydrochlorothiazide
• Based on the above observations,
experts suggest that
chlorthalidone (12.5 to 25 mg/day)
is the low-dose thiazide diuretic of
choice.
• However, the choice may vary with
the clinical setting.
Chlorthalidone versus
Hydrochlorothiazide
• A possibly more important
difference than potency is the
longer duration of action of
chlorthalidone (24 to 72 hours
versus 6 to 12 hours with
hydrochlorothiazide).
Chlorthalidone versus
Hydrochlorothiazide
• Given the lower potency of
hydrochlorothiazide at the same
dose and its shorter duration of
action, one cannot conclude in the
absence of evidence that 12.5
mg/day of hydrochlorothiazide will
produce the same benefit as 12.5
mg/day of chlorthalidone.
Chlorthalidone versus
Hydrochlorothiazide
• Furthermore, the evidence
supporting the efficacy of thiazide
diuretics in the management of
hypertension comes primarily from
trials using chlorthalidone, such as
ALLHAT.
Chlorthalidone versus
Hydrochlorothiazide
• There is little if any evidence that
hydrochlorothiazide alone in a
dose of 12.5 to 25 mg/day reduces
cardiovascular events and the
blood pressure may not be as wellcontrolled overnight.
Chlorthalidone versus
Hydrochlorothiazide
• In addition, in the ACCOMPLISH
trial, which compared combination
therapy with benazepril plus either
hydrochlorothiazide (12.5 to 25
mg/day) or amlodipine,
cardiovascular outcomes were
worse in the benazeprilhydrochlorothiazide group.
Chlorthalidone versus
Hydrochlorothiazide
Jamerson, K. et al. Benazepril plus amlodipine or
hydrochlorothiazide for hypertension in high-risk
patients. N. Engl. J. Med. 359, 2417–2428 (2008).
Treatment
• Single agent therapy does not control
the blood pressure in some patients at
diagnosis (particularly those more than
20/10 mmHg above goal) and, over
time, in an increasing proportion of
patients who were initially controlled
with monotherapy (e.g., approximately
40 percent at five years in the ALLHAT
trial compared to approximately 30
percent at one year).
What to Use?
• Thiazide-type diuretics
• Angiotensin converting enzyme (ACE)
inhibitors/angiotensin II receptor
blockers (ARBs)
• Calcium channel blockers
• Beta blockers, which are now used less
often for initial therapy in the absence
of a specific indication for their use
Antihypertensive response to
different drugs in whites
Antihypertensive response to different
drugs in whites
•
Response rates to single drug therapy for hypertension in whites under the age
of 60. There were no significant differences in response, except that
hydrochlorothiazide (HCTZ) appeared to be least effective. A response was
defined as a diastolic pressure below 90 mmHg at the end of the titration phase
and below 95 mmHg at one year. The pattern of response was similar but the
success rate for each drug was reduced by five to 15 percent if goal diastolic
pressure were less than 90 mmHg at one year. There were between 30 and 39
patients in each group. Data from Materson, BJ, Reda, DJ, Cushman, WC, et
al, N Engl J Med 1993; 328:914. Correction and additional data: Am J
Hypertens 1995; 8:189.
Antihypertensive response
to different drugs in blacks
Antihypertensive response
to different drugs in blacks
•
Response rates to single drug therapy for hypertension in blacks over the age
of 60 years. The highest response was seen with diltiazem and
hydrochlorothiazide (HCTZ) and the lowest with captopril. A response was
defined as a diastolic pressure below 90 mmHg at the end of the titration phase
and below 95 mmHg at one year. The pattern of response was similar but the
success rate for each drug was reduced by five to 15 percent if goal diastolic
pressure were less than 90 mmHg at one year. There were between 42 and 53
patients in each group. Data from Materson, BJ, Reda, DJ, Cushman, WC, et
al, N Engl J Med 1993; 328:914. Correction and additional data: Am J
Hypertens 1995; 8:189.
Choice of Thiazide Diuretics
• In most patients not previously treated
with a thiazide diuretic, it is suggest to
use low-dose chlorthalidone, rather
than hydrochlorothiazide.
• However, among frail older patients who
are less than 10 mmHg above goal
blood pressure, some consider low-dose
hydrochlorothiazide a reasonable
alternative.
Choice of Thiazide Diuretics
• Chlorthaloidone is not available in all
formularies and pharmacies.
• There is no 12.5 mg tablet. Thus, 25 mg
tablets of generic chlorthalidone need to be
cut in half. There is a more expensive 15 mg
brand name preparation (Thalitone®).
• This preparation has greater bioavailability
than generic chlorthalidone, and clinical
studies suggest that its antihypertensive
efficacy is closer to 25 mg of generic
chlorthalidone.
Choice of Thiazide Diuretic
• Low-dose hydrochlorothiazide (12.5 to a
maximum of 25 mg/day) is widely used and,
after publication of the ALLHAT trial, was
recommended as initial monotherapy in most
patients with mild essential hypertension by
JNC 7 and others.
• However, hydrochlorothiazide is less effective
and has a shorter duration of action than
chlorthalidone, and there is little, if any,
evidence that low-dose hydrochlorothiazide
alone reduces cardiovascular events as
opposed to the evidence with chlorthalidone.
Thiazide Diuretic
Risks of;
• Hypokalemia
• Glucose intolerance
• New onset diabetes mellitus
Dose-dependence of thiazide-induced side
effects
Dose-dependence of thiazide-induced side
effects
• Metabolic complications induced by bendrofluazide in
relation to daily dose (multiply by 10 to get equivalent
doses of hydrochlorothiazide). Increasing the dose led
to progressive hypokalemia and hyperuricemia and a
greater likelihood of a mild elevation in the fasting blood
glucose (FBG), all without a further reduction in the
systemic blood pressure. Each treatment group
contained approximately 52 patients. Data from
Carlsen, JE, Kober, L, Torp-Pedersen, C, Johannsen, P,
BMJ 1990; 300:975.
Treatment
• Younger patients respond best to
angiotensin converting enzyme
(ACE) inhibitors or angiotensin-II
receptor blockers (ARBs).
Treatment
• Support for this differential antihypertensive
response in younger patients is supported by a
study of 56 young (22 to 51 years) white
hypertensive patients who were treated in a
crossover rotation with the four main classes
of antihypertensive drugs: ACE inhibitor,
thiazide diuretic, long-acting dihydropyridine
CCB, and beta blocker.
• Significantly greater responses in both systolic
and diastolic blood pressure levels were noted
with the ACE inhibitor and beta blocker than
with the CCB or diuretic.
Treatment
• Optimisation of antihypertensive treatment by crossover
rotation of four major classes. Dickerson JE; Hingorani
AD; Ashby MJ; Palmer CR; Brown MJ. Lancet 1999 Jun
12;353(9169):2008-13.
Treatment
• Each of the recommended first-line
agents will normalize the BP in 30 to 50
percent of patients with mild
hypertension.
• A patient who is relatively unresponsive
to one drug has an almost 50 percent
likelihood of becoming normotensive on
a second drug.
Treatment: ACE Risks
Hypotension
• dizziness
• syncope
• weakness
Treatment: ACE Risks
Acute Renal Failure
• A decline in renal function, that is
usually modest but may be severe, may
be observed in some patients with
bilateral renal artery stenosis,
hypertensive nephrosclerosis,
congestive heart failure, polycystic
kidney disease, or chronic renal failure.
Treatment: ACE Risks
Hyperkalemia
In pregnant women or women who
may become pregnant, ACE
inhibitors are associated with
increased teratogenic risk to the
fetus.
Treatment: ACE Risks
Cough
• It usually begins within one to two
weeks of instituting therapy, but can be
delayed up to six months.
• Women are affected more frequently
than men.
• Chinese, at least in Hong Kong, have a
high prevalence that approaches 50
percent.
Treatment: ACE Risks
Cough
• It typically resolves within one to four
days of discontinuing therapy, but can
take up to four weeks.
• It generally recurs with rechallenge,
either with the same or a different ACE
inhibitor.
• It does not occur more frequently in
asthmatics than in nonasthmatics but it
may be accompanied by bronchospasm.
Treatment: ACE Risks
• Treatment consists of lowering the dose
or discontinuing the drug, which will
lead to resolution of the cough.
• Improvement often begins within four
to seven days but may persist for three
to four weeks or more in some patients.
• Readministration of an ACE inhibitor is
associated with a high rate of recurrent
cough (67 percent in a randomized
trial).
Treatment:ARBs Risks
Cough
• The incidence of cough is lower in
patients treated with ARBs.
ARBs should not be given to
pregnant women or those who
may become pregnant.
Treatment: ARBs Risks
Angioedema
• The risk of angioedema appears to
be lower with ARBs than ACE
inhibitors.
Treatment:ARBs Risks
Hypotension
• Hypotension appears to be more
common with ARBs than ACE
inhibitors.
Treatment Risks
• Nifedipine and related drugs induce the most
prominent direct vasodilation, an effect that
can lead to dizziness, headache, flushing, and
peripheral edema.
• In comparison, decreased cardiac contractility,
reduced cardiac conduction, and constipation
are most likely to be seen with verapamil.
• Diltiazem has an intermediate effect on these
parameters and appears to be associated with
the lowest incidence of adverse effects.
Treatment Effects on Lipids
• High doses (50 mg/day or more)
of thiazide diuretics produce an
initial five to 10 percent elevation
in total and LDL-cholesterol and a
lesser increase in triglycerides.
Treatment Effect on Lipids
• The hyperlipidemic effect of thiazide
diuretics is dose-dependent.
• There is, for example, little or no effect
on lipid metabolism with a daily dose of
12.5 mg of hydrochlorothiazide or its
equivalent, a dose which may have as
great an antihypertensive effect as
higher doses.
Treatment Effect on Lipids
• The ACE inhibitors appear to have
no important effect on plasma
lipids and may minimize or prevent
the rise in lipids induced by
diuretic therapy (via an unknown
mechanism).
Treatment Effect on Lipids
• The calcium channel blockers
appear to have either a neutral or
mildly beneficial effect on the lipid
profile.
Treatment Effects on Lipids
• The effect of beta blockers on serum lipids
varies with their pharmacologic characteristics,
and may be more prominent among smokers.
• Nonselective and beta-1-selective beta
blockers have little effect on cholesterol levels
but lead to an approximate 10 percent fall in
cardioprotective HDL-cholesterol and,
particularly with nonselective agents, a 20 to
40 percent rise in triglycerides.
• In contrast, lipid levels are relatively
unaffected by labetalol (a combined alphaand beta-blocker) and beta blockers with
intrinsic sympathomimetic activity.
Treatment Effect on Lipids
• Newer beta blockers may have a more
favorable metabolic profile; carvedilol, a
combined nonselective beta and alpha-1
blocker, also prevents lipid peroxidation.
• One study evaluated 45 patients with noninsulin-dependent diabetes mellitus and
hypertension who were randomly assigned to
therapy with metoprolol or carvedilol.
Carvedilol was associated with a significantly
greater fall in total cholesterol and lesser rise
in triglycerides than metoprol.
Specific Indications
• Thiazide diuretics are particularly
useful in black and elderly
patients, while loop diuretics are
typically used in patients with
heart failure or other edematous
state.
Specific Indications
•
•
•
•
•
Beta blocker
Resting tachycardia (usually reflecting
an increase in beta-adrenergic tone)
Heart failure due to diastolic
dysfunction and some cases of systolic
dysfunction
Migraine headaches
Glaucoma
Those with a previous myocardial
infarction or angina pectoris
Specific Indications
•
•
•
•
Contraindications to Beta Blocker
Asthma or chronic obstructive
pulmonary disease,
Severe peripheral vascular disease,
Raynaud phenomenon
Bradycardia, second or third degree
heart block
Hypoglycemia-prone diabetics in whom
the early warning symptoms of
hypoglycemia may be masked
Specific Indications
ACE inhibitors have a variety of
advantages in the treatment of
hypertension.
• They are broadly effective in all patient
groups (even in patients with relatively
low plasma renin levels), lack the
adverse lipid and glycemic effects of
high doses of thiazides and ß-blockers,
and have few toxic side effects.
Specific Indications
ACE inhibitors
• Heart failure
• Postmyocardial infarction
• Diabetes mellitus
• Proteinuric chronic renal disease,
since these agents may slow the
rate of disease progression
Specific Indications
• Underlying diseases that are relative
indications for the use of an ARB are
the same as those described above for
ACE inhibitors, although an ACE
inhibitor is most often used first.
• Patients who cannot tolerate an ACE
inhibitor (usually due to cough) can be
switched to an ARB.
Specific Indications
• ARBs, like ACE inhibitors, also
regress left ventricular
hypertrophy more rapidly than
beta blockers, and slow the rate of
progression of diabetic
nephropathy.
Specific Indications
• Long-acting calcium channel blockers
share many of the advantages of the
ACE inhibitors as vasodilatory agents.
• They are effective antihypertensive
agents that do not produce
hyperlipidemia or insulin resistance and
do not interfere with sympathetic
function.
• These agents are particularly effective
in older patients or those with a low
plasma renin activity
Specific Indications
• Calcium channel blockers tend to
moderately increase sodium excretion
and, in contrast to most other
antihypertensive agents, their efficacy
is usually not significantly enhanced by
dietary salt restriction.
• As a result, a calcium channel blocker
may be particularly effective in
hypertensive patients who do not
comply with dietary salt restriction.
Specific Indications
• Calcium channel blockers may also be
preferred in patients concurrently being
treated with a nonsteroidal antiinflammatory
drug (NSAID).
• The NSAIDs, by diminishing the production of
vasodilator prostaglandins, often produce a
moderate elevation in blood pressure in
patients treated with most antihypertensive
drugs; calcium channel blockers appear to be
an exception, as their antihypertensive
efficacy is not blunted in this setting.
Specific Indications
• In the large Anglo-Scandinavian Cardiac
Outcomes Trial (ASCOT), amlodipinebased therapy reduced blood pressure
more than atenolol-based therapy.
• This likely explains the greater
prevention of cardiovascular events
with the calcium channel blocker
Specific Indications
• There is also evidence that calcium
channel blockers reduce the
incidence of new-onset diabetes. A
2007 network meta-analysis
reported that, compared with
diuretics, the odds ratio for
incident diabetes was 0.75 (95%
CI of 0.62 to 0.90) for calcium
channel blockers.
Specific Indications
• A calcium channel blocker should
not be used as routine first line
treatment of hypertension, except
perhaps in black or elderly
patients, and then in combination
with a thiazide diuretic.
Specific Indications
•
•
•
•
•
•
Diseases that can also be treated by a
calcium channel blocker include:
Angina pectoris
Recurrent supraventricular tachycardia
(verapamil),
Raynaud phenomenon
(dihydropyridines)
Migraine headaches
Heart failure due to diastolic
dysfunction
Esophageal spasm
Case 1
• A 21 year old student presents to the clinic
for a complete physical exam for dental
school.
• Medical History is unremarkable
• BP 162/90
• Physical Exam is normal
• What do you do?
Case 1
• BP 158/96 one month later in the clinic
Home BP measurements:
• 150/80
• 162/84
• 158/88
• 162/82
• 156/86
Case 1
•
•
•
•
•
•
How should you proceed?
Labs
ECG
Life style modifications
Home BP measurements
Return to clinic in 6 months
Case 1
• The patient returns 1 year later and the BP is
164/90
• The patient has gained 2 pounds.
• Labs and ECG were normal.
• What is the BP goal?
• 140/90
Case 1
•
•
•
•
Reinforce lifestyle changes
Motivate to control BP
Start Medication
Evaluate for secondary causes
Case 2
• A 28 year old graduate student comes in for
fatigue.
• Recently had a URI. Still with nasal
congestion.
• Social Hx.-Binge drinker, occ tobacco, occ
marijuana, lives with roommate
• Family history negative
Case 2
• BP 162/90
• HR 108, tachycardia
• Pupils 5 mm. Nares red with clear
rhinorrhea.
• Rest of exam is normal.
Case 2 Assessment
•
•
•
•
•
Hypertensive
Tachycardia
Mydriasis
Rhinorrhea
Poly substance use/? abuse
Case 2
What to do?
• Ask about other substance use, medications,
secondary causes of hypertension
• Get ECG
• Discuss life style modification
Case 2
• He is on a over the counter cold/sinus tablet
• He admits to inhaling his roommates Ritalin
over the past few days while studying for
exams
• ECG sinus tachy, otherwise normal
Case 2
• Diagnosis is likely drug induced
hypertension
• Stop over the counter cold/sinus and Ritalin
• Recheck BP in one week
Case 2
• One week later BP 156/84
• Look for secondary causes
Case 3
• A 19 year old student comes fin for a STI
check
• Patient nervous about recent sexual contact
• Medical history unremarkable
• BP 160/92
• Rest of exam is normal
• STI labs drawn/ Patient counseled/ Patient
will return in one week for results of labs
Case 3
One week later
• STI labs are negative
• BP 148/96
• Ask the patient to return to clinic in one
month
Case 3
One month later
• BP158/96
• ECG normal
• Ask the patient to take BP at clinic several
times over the next month
Case 3
•
•
•
•
One month later:
BP 133/84, 130/78, 132/82, 128/78
Diagnosis pre-hypertension, white coat
hypertension
Discuss life style changes
RTC in one year
Case 4
• A 56 year old student comes in for a PAP
smear
• ROS. Arthritis, type 2 diabetes controlled
with diet and exercise
• Other history is unremarkable
• Takes ibuprofen daily for arthritis
Case 4
• BP160/92, similar on previous 2 visits
• Arthritis of hands
• Rest of exam unremarkable
Case 4 Assessment
•
•
•
•
56 year old
Stage 2 hypertension
Arthritis of hands
Type 2 diabetes
Case 4
•
•
•
•
•
•
What labs do you want?
CBC
Fasting lipid panel
Chem 7
ECG
UA
Hgb A1c ( not a hypertension lab)
Case 4
•
•
•
•
•
•
UA 1+ protein, 2+ glucose
Cr 1.2
Now what?
Start treatment for secondary hypertension
ACE for kidney protection
Avoid NSAID’s use acetaminophen
Case 4
•
•
•
•
•
Life style changes:
DASH diet
Weight reduction
Exercise
Low sodium diet
Decrease ETOH
Case 4
What is BP goal?
• 130/80