Module 4
Hypertension Assignment
a. Epidemiology
The definition of hypertension changed with the 2017 ACC/AHA guideline
from a BP of ≥140/90 mm Hg to ≥130/80 mm Hg. Hence, the prevalence of
hypertension has increased considerably. Almost half (46%) of American adults age
20 years and older have hypertension according to the ACC/AHA definition.3
Although the overall prevalence has increased, only 1.9% would require additional
drug therapy as the majority of newly diagnosed patients would require
nonpharmacologic therapy only.
The overall incidence of hypertension is similar between men and women but
varies depending on age. The prevalence of high BP is higher in men than women
before the age of 65 and is similar between the ages 65 and 74. However, after the age
of 74, more women have high BP than men.1,4 Prevalence rates are highest in non-
Hispanic blacks (59% in men, 56% in women), followed by non-Hispanic whites
(47% in men, 41% in women), non-Hispanic Asians (45% in men, 36% in women),
and Hispanics (45% in men, 42% in women).
Blood pressure (BP) values naturally increase with age, and the prevalence of
hypertension, which is defined as persistently elevated BP values, is particularly
common among older individuals. This age-related increase in blood pressure is a
well-documented phenomenon and has significant implications for public health and
clinical practice. As individuals age, the elasticity of their arterial walls decreases,
leading to increased vascular resistance and, consequently, higher blood pressure
levels.
Hypertension is a major risk factor for various cardiovascular diseases,
including heart attack, stroke, heart failure, and peripheral artery disease. It is also
associated with other health issues such as chronic kidney disease and cognitive
decline. The lifetime risk of developing hypertension is remarkably high. Among
individuals who are 55 years of age and older and are currently normotensive, the risk
of eventually developing hypertension exceeds 90%. This statistic underscores the
importance of regular BP monitoring and early intervention to prevent the onset of
hypertension and its associated complications.
Most patients experience elevated blood pressure for several years before they
receive a formal diagnosis of hypertension. This pre-hypertensive stage is critical
because it provides a window of opportunity for early detection and management.
However, hypertension often goes unnoticed and undiagnosed during this period
because it typically does not cause noticeable symptoms. Consequently, many
individuals may be unaware that their blood pressure is gradually increasing to
unhealthy levels.
The diagnosis of hypertension tends to occur most frequently between the
third and fifth decades of life. During these years, individuals are often balancing
multiple stressors such as career demands, family responsibilities, and lifestyle factors
that can contribute to elevated blood pressure. It is during these decades that primary
prevention efforts can be particularly impactful. Health care providers should
emphasize the importance of lifestyle modifications, such as maintaining a healthy
diet, engaging in regular physical activity, reducing sodium intake, limiting alcohol
consumption, and managing stress, as these changes can significantly lower the risk of
developing hypertension.
Moreover, there are various stages of hypertension that clinicians use to
classify the severity of the condition, guiding treatment decisions. Stage 1
hypertension is defined as a systolic BP of 130-139 mmHg or a diastolic BP of 80-89
mmHg. Stage 2 hypertension is characterized by a systolic BP of 140 mmHg or higher
or a diastolic BP of 90 mmHg or higher. Hypertensive crisis, which requires
immediate medical attention, is diagnosed when systolic BP exceeds 180 mmHg or
diastolic BP exceeds 120 mmHg. These classifications help in stratifying risk and
tailoring interventions appropriately.
In addition to lifestyle changes, pharmacological treatments are often
necessary to manage hypertension effectively. A wide range of antihypertensive
medications is available, including diuretics, ACE inhibitors, angiotensin II receptor
blockers, calcium channel blockers, and beta-blockers. The choice of medication
depends on various factors, including the patient's overall health, presence of
comorbidities, and specific characteristics of their hypertension. It is not uncommon
for patients to require a combination of medications to achieve optimal blood pressure
control.
Regular follow-up and monitoring are crucial components of hypertension
management. Patients should be encouraged to monitor their BP at home using
validated devices, as this can provide valuable information about their BP patterns and
help identify white-coat hypertension or masked hypertension. Health care providers
should also schedule periodic office visits to assess BP control, review treatment
adherence, and make necessary adjustments to the management plan.
In conclusion, the increase in blood pressure with age and the high prevalence
of hypertension among older adults highlight the critical need for proactive and
comprehensive approaches to blood pressure management. With a lifetime risk of
developing hypertension exceeding 90% for individuals 55 years and older who are
currently normotensive, early detection, lifestyle modifications, and appropriate
pharmacological interventions are essential strategies to mitigate the risk and impact
of hypertension. Effective management requires a combination of patient education,
regular monitoring, and tailored treatment plans to improve health outcomes and
reduce the burden of hypertension-related complications.
b. Etiology
In most patients, hypertension results from unknown pathophysiologic
etiology (essential or primary hypertension). This form of hypertension cannot be
cured, but it can be controlled. A smaller most of these cases, renal dysfunction
resulting from severe chronic kidney disease (CKD) or renovascular disease is the
most common secondary cause. Certain agents (drugs or other products), either
directly or indirectly, can increase BP and cause or exacerbate hypertension.
When managing a patient with hypertension or another medical condition
where a secondary cause is identified, it is crucial to address this underlying factor as
a primary strategy. The identification of a secondary cause means that the elevated
blood pressure or other symptoms are likely being driven by another condition or
external agent. In such cases, the first step in management should be to remove or
mitigate the offending agent whenever feasible. This approach can be more effective
than merely treating the symptoms, as it targets the root cause of the problem,
potentially leading to a more definitive resolution.
For example, certain medications are known to cause secondary hypertension.
These include nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives,
decongestants, corticosteroids, and some antidepressants. If a patient's hypertension is
suspected to be medication-induced, the clinician should review the patient's
medication history in detail. Discontinuing or substituting the offending medication, if
clinically appropriate, can often result in a significant improvement or normalization
of blood pressure. This requires close collaboration between the patient and their
healthcare provider to ensure that the substitution or discontinuation does not
adversely affect the management of the underlying condition for which the medication
was originally prescribed.
In addition to medications, certain lifestyle factors and substances can
contribute to secondary hypertension. Excessive alcohol consumption, illicit drug use
(such as cocaine or amphetamines), and even high intake of caffeine can elevate blood
pressure. Addressing these factors involves comprehensive patient education and
support to reduce or eliminate the use of these substances. For instance, patients may
benefit from counseling services, support groups, or referral to substance abuse
programs as part of their treatment plan.
Another category of secondary causes includes endocrine disorders such as
primary aldosteronism, Cushing's syndrome, pheochromocytoma, and thyroid
disorders. These conditions can significantly affect blood pressure regulation.
Effective management involves treating the underlying endocrine disorder, which may
require medications, surgical interventions, or other specialized treatments. For
example, primary aldosteronism often requires the use of mineralocorticoid receptor
antagonists or surgical removal of aldosterone-producing adenomas, while
pheochromocytomas are typically managed with surgical resection following
preoperative medical stabilization.
Renal conditions are also common secondary causes of hypertension. Chronic
kidney disease, renal artery stenosis, and glomerulonephritis can all lead to elevated
blood pressure. Management strategies for these conditions focus on improving renal
function or relieving renal artery obstruction. Angioplasty with or without stenting
may be considered for significant renal artery stenosis, while chronic kidney disease
management might involve optimizing blood pressure control, using renin-
angiotensin-aldosterone system inhibitors, and managing associated comorbidities
like diabetes.
Sleep apnea is another condition frequently associated with secondary
hypertension. Obstructive sleep apnea (OSA) can lead to intermittent hypoxia and
sympathetic nervous system activation, resulting in elevated blood pressure.
Management of OSA typically involves the use of continuous positive airway
pressure (CPAP) therapy, weight loss, and other interventions to improve airway
patency during sleep. Treating sleep apnea not only helps in reducing blood pressure
but also improves overall cardiovascular health and quality of life.
In cases where an offending agent or secondary cause is not easily removed or
treated, management may involve controlling the contributing condition as effectively
as possible while concurrently treating the hypertension or related symptoms. This
might involve using a combination of pharmacological and non-pharmacological
strategies tailored to the individual patient’s needs.
It is also important to consider that some patients may have multiple
contributing factors, necessitating a multifaceted approach to management.
Comprehensive care plans should be developed that address all potential secondary
causes, optimize primary disease control, and incorporate lifestyle modifications.
Regular monitoring and follow-up are essential to assess the effectiveness of
interventions and make necessary adjustments.
In summary, when a secondary cause of a medical condition such as
hypertension is identified, the primary focus should be on removing the offending
agent or treating the underlying comorbid condition. This approach not only addresses
the root cause but can also lead to more effective and lasting management of the
patient’s overall health. Such strategies require a thorough evaluation, patient
education, and a collaborative, multidisciplinary approach to care.
c. Pathophysiology
Multiple physiologic factors control BP and abnormalities of these factors are
potential contributing components in the development of essential hypertension.
These include malfunctions in either humoral (ie, the renin–angiotensin–aldosterone
system [RAAS]) or vasodepressor mechanisms, abnormal neuronal mechanisms,
defects in peripheral autoregulation, and disturbances in sodium, calcium, and
natriuretic hormones. Many of these factors are cumulatively affected by the
multifaceted RAAS, which ultimately regulates arterial BP. It is probable that no one
factor is solely responsible for essential hypertension.
Arterial BP is the pressure in the arterial wall measured in millimeters of
mercury (mm Hg). The two arterial BP values are systolic BP (SBP) and diastolic BP
(DBP). SBP represents the peak value, which is achieved during cardiac contraction.
DBP is achieved after contraction when the cardiac chambers are filling, and
represents the nadir value. The absolute difference between SBP and DBP is called the
pulse pressure and is a measure of arterial wall tension. Mean arterial pressure (MAP)
is the average pressure throughout the cardiac contraction cycle. It can be used
clinically to represent overall arterial BP, especially in hypertensive emergency.
During a cardiac cycle, two-thirds of the time is spent in diastole and one-third in
systole.
The classification of BP in adults (age 18 years and older) is based on the
average of two or more properly measured BP values from two or more clinical
encounters. According to ACC/AHA, there are four BP categories: normal, elevated,
stage 1 hypertension, and stage 2 hypertension. Elevated BP is not a disease category,
but is associated with an increased CV risks compared to patients with normal BP.6 It
identifies patients whose BP is likely to progress to hypertension in the future, and
thus for whom lifestyle modifications should be enacted to attenuate this progression.
Hypertensive crises are clinical situations where patients have extreme BP elevations,
typically >180/120 mm Hg. They are categorized as either hypertensive emergency or
hypertensive urgency. Hypertensive emergencies are extreme BP elevations that are
accompanied by acute or progressing end-organ damage. Hypertensive urgencies are
extreme BP elevations without acute or progressing end-organ injury.
Epidemiologic data demonstrate a strong correlation between BP and CV
morbidity and mortality.7 Risk of hypertensionassociated complications (eg, stroke,
myocardial infarction [MI], angina, heart failure [HF], kidney failure, early death
from a CV causes) is directly correlated with BP. Starting at a BP of 115/75 mm Hg,
the risk of CV disease doubles with every 20/10 mm Hg increase.1 Even patients with
elevated BP have an increased risk of CV disease. Treating patients with hypertension
with antihypertensive drug therapy provides significant clinical benefits. Evidence
from large-scale placebo-controlled clinical trials has repeatedly shown that the
increased risks of CV events and death associated with elevated BP are reduced
substantially by antihypertensive drug therapy.
The RAAS is a complex endogenous system that is involved with most
regulatory components of arterial BP. Activation and regulation are primarily
governed by the kidney. The RAAS regulates sodium, potassium, and blood volume.
Therefore, this system significantly influences vascular tone and sympathetic nervous
system activity, and is the most influential contributor to the homeostatic regulation of
BP. Renin is an enzyme that is stored in the juxtaglomerular cells, which are located
in the afferent arterioles of the kidney. The release of renin is modulated by several
factors: intrarenal factors (eg, renal perfusion pressure, catecholamines, angiotensin
II) and extrarenal factors (eg, sodium, chloride, potassium).
Juxtaglomerular cells function as a baroreceptor-sensing device. Decreased
renal artery pressure and kidney blood flow are sensed by these cells and stimulate
secretion of renin. A decrease in sodium and chloride delivered to the distal tubule
stimulates renin release. Catecholamines increase renin release probably by directly
stimulating sympathetic nerves on the afferent arterioles that in turn activate the
juxtaglomerular cells. Renin catalyzes the conversion of angiotensinogen to
angiotensin I in the blood. Angiotensin I is then converted to angiotensin II by
angiotensin-converting enzyme (ACE). After binding to specific receptors (classified
as either angiotensin II type 1 [AT1 ] or angiotensin II type 2 [AT2 ] subtypes),
angiotensin II exerts biologic effects in several tissues. The AT1 receptor is located in
the brain, kidneys, myocardium, peripheral vasculature, and the adrenal glands. These
receptors mediate most responses that are critical to CV and kidney function. The AT2
receptor is located in adrenal medullary tissue, uterus, and brain. Stimulation of the
AT2 receptor does not influence BP regulation.
Circulating angiotensin II can elevate BP through pressor and volume effects.
Pressor effects include direct vasoconstriction, stimulation of catecholamine release
from the adrenal medulla, and centrally mediated increases in sympathetic nervous
system activity. Angiotensin II also stimulates aldosterone synthesis from the adrenal
cortex, leading to sodium and water reabsorption that increases plasma volume, TPR,
and ultimately BP. Aldosterone also has a deleterious role in the pathophysiology of
other CV diseases (eg, HF, MI, kidney disease) by promoting tissue remodeling
leading to myocardial fibrosis and vascular dysfunction. Clearly, any disturbance in
the body that leads to activation of the RAAS could explain chronic hypertension. The
heart and brain contain a local RAAS. In the heart, angiotensin II is also generated by
angiotensin I convertase (human chymase). This enzyme is not blocked by ACE
inhibition. Activation of the myocardial RAAS increases cardiac contractility and
stimulates cardiac hypertrophy. In the brain, angiotensin II modulates the production
and release of hypothalamic and pituitary hormones and enhances sympathetic
outflow from the medulla oblongata.
Natriuretic hormone inhibits sodium and potassium ATPase and thus interferes
with sodium transport across cell membranes. Inherited defects in the kidney’s ability
to eliminate sodium can cause increased blood volume. A compensatory increase in
the concentration of circulating natriuretic hormone theoretically could increase
urinary excretion of sodium and water. However, this hormone might block the active
transport of sodium out of arteriolar smooth muscle cells. The increased intracellular
sodium concentration ultimately increases vascular tone and BP.
Central and autonomic nervous systems are intricately involved in the
regulation of arterial BP. Many receptors that either enhance or inhibit norepinephrine
release are located on the presynaptic surface of sympathetic terminals. The α and β
presynaptic receptors play a role in negative and positive feedback to the
norepinephrine-containing vesicles. Stimulation of presynaptic α-receptors (α2 )
exerts a negative inhibition on norepinephrine release. Stimulation of presynaptic β-
receptors facilitates norepinephrine release. Sympathetic neuronal fibers located on
the surface of effector cells innervate the α- and β-receptors. Stimulation of
postsynaptic α-receptors (α1 ) on arterioles and venules results in vasoconstriction.
There are two types of postsynaptic β-receptors, β1 and β2 . Both are present in all
tissues innervated by the sympathetic nervous system. However, in some tissues β1 -
receptors predominate (eg, heart), and in other tissues β2 -receptors predominate (eg,
bronchioles). Stimulation of β1 -receptors in the heart increases heart rate
(chronotropy) and force of contraction (inotropy), whereas stimulation of β2 -
receptors causes vasodilation in arteries and veins.
The baroreceptor reflex system is the major negative feedback mechanism that
controls sympathetic activity. Baroreceptors are nerve endings lying in the walls of
large arteries, especially in the carotid arteries and aortic arch. Changes in arterial BP
rapidly activate baroreceptors that then transmit impulses to the brain stem through
the ninth cranial nerve and vagus nerve. In this reflex system, a decrease in arterial BP
stimulates baroreceptors, causing reflex vasoconstriction, increased heart rate, and
increased force of cardiac contraction. Baroreceptor reflex mechanisms may be less
responsive in older patients and those with diabetes. Stimulation of specific areas
within the central nervous system (eg, nucleus tractus solitarius, vagal nuclei,
vasomotor center, area postrema) can either increase or decrease BP. For example, α2
- adrenergic stimulation within the central nervous system decreases BP through
inhibitory effects on the vasomotor center. However, angiotensin II increases
sympathetic outflow from the vasomotor center, which increases BP. The purpose of
these neuronal mechanisms is to regulate BP and maintain homeostasis. Pathologic
disturbances in any of the four major components (autonomic nerve fibers, adrenergic
receptors, baroreceptors, central nervous system) could chronically elevate BP. These
systems are physiologically interrelated. A defect in one component may alter normal
function in another. Therefore, cumulative abnormalities may explain the
development of essential hypertension.
Abnormalities in renal or tissue autoregulatory systems could cause
hypertension. Renal defects in sodium excretion may develop, which can then cause
resetting of tissue autoregulatory processes resulting in a higher BP. The kidney
usually maintains a normal BP through a volume–pressure adaptive mechanism.
When BP drops, the kidneys respond by increasing retention of sodium and water,
which leads to plasma volume expansion that increases BP. Conversely, when BP
rises above normal, renal sodium and water excretion are increased to reduce plasma
volume and CO. Local autoregulatory processes maintain adequate tissue
oxygenation. When tissue oxygen demand is normal to low, the local arteriolar bed
remains relatively vasoconstricted. However, increased metabolic demand triggers
arteriolar vasodilation that lowers peripheral vascular resistance (PVR) and increases
blood flow and oxygen delivery.
Intrinsic defects in renal adaptive mechanisms could lead to plasma volume
expansion and increased blood flow to peripheral tissues, even when BP is normal.
Local tissue autoregulatory processes that vasoconstrict would then be activated to
offset the increased blood flow. This effect would result in increased PVR and, if
sustained, would also result in thickening of the arteriolar walls. This
pathophysiologic component is plausible because increased TPR is a common
underlying finding in essential hypertension.
Vascular endothelium and smooth muscle play important roles in regulating
blood vessel tone and BP. Regulating functions are mediated by vasoactive substances
that are synthesized by endothelial cells. It has been postulated that a deficiency in
local synthesis of vasodilating substances (eg, prostacyclin and bradykinin) or excess
vasoconstricting substances (eg, angiotensin II and endothelin I) contributes to
essential hypertension, atherosclerosis, and other CV diseases. Nitric oxide is
produced in the endothelium, relaxes the vascular epithelium, and is a very potent
vasodilator. The nitric oxide system is an important regulator of arterial BP. Patients
with hypertension may have an intrinsic nitric oxide deficiency, resulting in
inadequate vasodilation.
Excess sodium intake is associated with hypertension. Populationbased studies
demonstrate that high-sodium diets are associated with a high prevalence of stroke
and hypertension. Conversely, lowsodium diets are associated with a lower prevalence
of hypertension. Clinical studies have shown that dietary sodium restriction lowers BP
in many (but not all) patients with elevated BP. The exact mechanisms by which
excess sodium leads to hypertension are not known. Alterations in calcium and
potassium may also play an important role in the pathogenesis of hypertension. A lack
of dietary calcium hypothetically can disturb the balance between intracellular and
extracellular calcium, resulting in an increased intracellular calcium concentration and
alterations in vascular smooth muscle function. Dietary potassium intake is inversely
related to BP, and may blunt the effect of sodium on BP.1 Potassium depletion may
also increase PVR, but the clinical significance of small serum potassium
concentration changes in relation to BP is unclear. While altered calcium and
potassium may play a role in the development of hypertension, data demonstrating
reduced CV risk with supplementation are very limited.
d. Clinical Presentation
Hypertension is called the silent killer because most patients do not have
symptoms. The primary physical finding is persistently elevated BP. The diagnosis of
hypertension cannot be made based on one elevated BP measurement. The average of
two or more BP measurements taken during two or more clinical encounters is
required to diagnose hypertension.
Inaccuracies with indirect measurements result from inherent biologic
variability of BP, errors related to incorrect technique, and the white coat effect.11
Variations in BP occur with environmental temperature, the time of day and year,
meals, physical activity, posture, alcohol, nicotine, and emotions. In the clinic setting,
standard BP measurement procedures (eg, appropriate rest period, correct technique,
right cuff size) are often not followed, which results in poor estimation of true BP. In
addition, variations may occur between individuals measuring BP. Due to these
factors, use of oscillometric devices is generally preferred. Approximately 15% to
20% of patients have white coat hypertension, where BP values rise in a clinical
setting but are normal in nonclinical environments as measured with home or
ambulatory BP (ABP) monitors.
Interestingly, the rise in BP dissipates gradually after leaving the clinical
setting. It may or may not be precipitated by other stresses in the patient’s daily life.
This is in contrast to masked hypertension, where a decrease in BP occurs in the
clinical setting.12 With masked hypertension, home BP is much higher than the
inoffice BP measurement. This situation may lead to undertreatment or lack of
treatment for hypertension. While white coat hypertension is associated with a
minimal increase in CV events, masked hypertension increases the risk similar to
those with sustained hypertension. Moreover, patients with either white coat or
masked hypertension are at higher risk of progressing to sustained hypertension.
Pseudohypertension is a falsely elevated BP measurement. It may be seen in
older patients, those with long-standing diabetes, or those with CKD due to rigid,
calcified brachial arteries.11 In these patients, the true arterial BP when measured
directly with intraarterial measurement (the most accurate measurement of BP) is
much lower than that measured using the indirect cuff method. The Osler’s maneuver
has been proposed as a method to test for pseudohypertension. In this maneuver, the
BP cuff is inflated above peak SBP. If the radial artery remains palpable, the patient
has a positive Osler’s sign (rigid artery), which may indicate pseudohypertension.
However, the diagnostic accuracy and reliability of this maneuver is questionable, and
therefore is not recommended.
Older patients with a wide pulse pressure may have an auscultatory gap that
can lead to underestimated SBP or overestimated DBP measurements. In this
situation, as the cuff pressure falls from the true SBP value, the Korotkoff sound may
disappear (indicating a false DBP measurement), reappear (a false SBP measurement),
and then disappear again at the true DBP value. When an auscultatory gap is present,
Korotkoff sounds are usually heard when pressure in the cuff first starts to decrease
after inflation. This may be eliminated by raising the arm overhead by 30 seconds
before bringing it to the proper position and inflating the cuff. This maneuver
decreases the intravascular volume and improves inflow thereby allowing Korotkoff
sounds to be heard.
Neither ABP nor home BP monitoring is needed for the diagnosis of
hypertension, but they are recommended. These modalities can enhance the ability to
identify patients with white coat and masked hypertension.1 In addition, ABP
monitoring may be a stronger predictor of all-cause and CV mortality than clinic
measurements. The 2017 ACC/AHA guideline recommends out-of-office
measurements for diagnostic confirmation and to assist in titrating antihypertensive
medication.1 ABP monitoring may be helpful for patients with apparent drug
resistance, hypotensive symptoms while on antihypertensive therapy, episodic
hypertension (eg, white coat hypertension), autonomic dysfunction, and in identifying
“nondippers” whose BP does not decrease by >10% during sleep and who may
portend an increased risk of hypertension-associated complications. Limitations of
ABP and home BP measurements include the complexity of use, costs, and lack of
prospective outcome data describing normal ranges for these measurements. Although
home BP monitoring is less complicated and less costly than ambulatory monitoring,
patients may omit or fabricate readings, or have poor technique (eg, not resting for an
adequate period, improper placement, wrong cuff size). Therefore, patients should be
educated on appropriate selection of a home BP device (eg, validated machine, ideally
has a memory feature, correct cuff size) and how to use it correctly.
Frequently, the only sign of essential hypertension is elevated BP. The rest of
the physical examination may be completely normal. However, a complete medical
evaluation (including a comprehensive medical history, physical examination, and
laboratory and/or diagnostic tests) is recommended after diagnosis to (a) identify
secondary causes, (b) identify other CV risk factors or comorbid conditions that may
define prognosis and/or guide therapy, and (c) assess for the presence or absence of
hypertension-associated complications. All patients with hypertension should have the
tests described in the "CLINICAL PRESENTATION: HYPERTENSION" box prior to
initiating antihypertensive drug therapy.1 For patients without a history of
atherosclerotic cardiovascular disease (ASCVD), left ventricular dysfunction, or
diabetes, it is also important to estimate future risk of ASCVD. The 10-year clinical
ASCVD (defined as coronary death or nonfatal myocardial infarction, or fatal or
nonfatal stroke) risk calculator is based on the Pooled Cohort Equations and lifetime
risk prediction.
A complete medical evaluation should provide clues for identifying secondary
hypertension. Patients with secondary hypertension might have signs or symptoms
suggestive of the underlying disorder. Patients with pheochromocytoma may have a
history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of
these patients suffer from episodes of orthostatic hypotension. In primary
hyperaldosteronism, symptoms related to hypokalemia usually include muscle cramps
and muscle weakness. Patients with Cushing’s syndrome may complain of weight
gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscular weakness
and have several classic physical features (eg, moon face, buffalo hump, hirsutism).
Patients with coarctation of the aorta may have higher BP in the arms than in legs and
diminished or even absent femoral pulses. Patients with renal artery stenosis may
have an abdominal systolic–diastolic bruit. Laboratory tests may also help identify
secondary hypertension. Baseline hypokalemia may suggest mineralocorticoid-
induced hypertension. Protein, red blood cells, and casts in the urine may indicate
renovascular disease. Some laboratory tests are used specifically to diagnose
secondary hypertension. These include plasma norepinephrine and urinary
metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations
for primary hyperaldosteronism, and plasma renin activity, captopril stimulation test,
renal vein renin, and renal artery angiography for renovascular disease.
The onset of hypertension is usually preceded by increased BP values that are
in the elevated BP category. BP values may fluctuate between elevated and normal
levels for a period of time. As the disease progresses, PVR increases, and BP
elevation becomes chronic. Several complications can result as a consequence of high
BP in patients with hypertension (see "CLINICAL PRESENTATION:
HYPERTENSION" box). CV events (eg, MI, cerebrovascular events, kidney failure)
are the primary causes of CV morbidity and mortality in patients with hypertension.
The probability of CV events and CV morbidity and mortality in patients with
hypertension is directly correlated with the severity of BP elevation.
Hypertension accelerates the development of atherosclerosis and stimulates
left ventricular and vascular dysfunction. These pathologic changes are thought to be
secondary to both a chronic pressure overload and a variety of nonhemodynamic
stimuli. Several nonhemodynamic disturbances have been implicated in these effects
(eg, the adrenergic system, RAAS, increased synthesis and secretion of endothelin I,
decreased production of prostacyclin and nitric oxide). Atherosclerosis in
hypertension is accompanied by the proliferation of smooth muscle cells, lipid
infiltration into the vascular endothelium, and enhancement of vascular calcium
accumulation. Cerebrovascular disease is a consequence of hypertension. Either gross
neurologic deficits or a slight hemiparesis with some incoordination and hyperreflexia
are indicative of cerebrovascular disease. Stroke can result from lacunar infarcts
caused by thrombotic occlusion of small vessels or intracerebral hemorrhage resulting
from ruptured microaneurysms. Transient ischemic attacks secondary to
atherosclerosis in the carotid arteries can also develop in patients with hypertension.
Retinopathies can occur in hypertension and may manifest as a variety of
different findings. A funduscopic examination can detect hypertensive retinopathy,
which manifests as arteriolar narrowing, focal arteriolar constrictions, arteriovenous
crossing changes (nicking), retinal hemorrhages and exudates, and disk edema. Focal
arteriolar narrowing, retinal infarcts, and flame-shaped hemorrhages usually are
suggestive of an accelerated or malignant phase of hypertension (seen in some
hypertensive emergencies). Papilledema (swelling of the optic disk) is usually only
present in hypertensive emergencies. Heart disease is a commonly identified
complication of hypertension. A thorough cardiac and pulmonary examination can
identify cardiopulmonary abnormalities. Clinical manifestations include LVH,
coronary artery disease (angina, prior MI, and prior coronary revascularization), and
HF. These complications may lead to cardiac arrhythmias, angina, MI, and sudden
death. Coronary artery disease (also called coronary heart disease) and associated CV
events are the most common causes of death in patients with hypertension.
The kidney damage caused by hypertension is characterized pathologically by
hyaline arteriosclerosis, hyperplastic arteriosclerosis, arteriolar hypertrophy, fibrinoid
necrosis, and atheroma of the major renal arteries. Glomerular hyperfiltration and
intraglomerular hypertension are early stages of hypertensive nephropathy. Persistent
albuminuria is followed by a gradual decline in renal function. The primary renal
complication in hypertension is nephrosclerosis, which is secondary to
arteriosclerosis. Atheromatous disease of a major renal artery may give rise to renal
artery stenosis. Overt kidney failure is an important cause of end-stage kidney disease,
especially in African Americans, Hispanics, and Native Americans. The peripheral
vasculature is a target organ affected by hypertension. Physical examination of the
vascular system can detect evidence of atherosclerosis, which may present as arterial
bruits (aortic, abdominal, or peripheral), distended veins, diminished or absent
peripheral arterial pulses, or lower extremity edema. Peripheral arterial disease (PAD)
is a clinical condition that can result from atherosclerosis. Other CV risk factors (eg,
smoking) can increase the likelihood of PAD as well as all other complications.
Although hypertension is one of the most common medical conditions, BP
control rates are poor. Clinical inertia in hypertension is defined as an office visit for
which no therapeutic move was made to lower BP in a patient with uncontrolled
hypertension.27 Clinical inertia is not the entire reason why many patients with
hypertension do not achieve goal BP values. However, it is certainly a major reason
that can be remedied simply through more aggressive antihypertensive drug therapy.
This strategy can include initiating, titrating, or changing drug therapy.
The choice of initial antihypertensive drug therapy depends on the degree of
BP elevation and presence of compelling indications. A single first-line
antihypertensive drug should be started as an initial therapy in most patients with
newly diagnosed hypertension presenting with stage 1 hypertension. Combination
drug therapy, preferably with two firstline antihypertensive drugs, should be started as
an initial therapy in patients with newly diagnosed hypertension presenting with more
severe BP elevation (stage 2 hypertension). This general approach to an initial. There
are several compelling indications where specific antihypertensive drug classes have
evidence showing unique benefits in patients with hypertension. Under these
circumstances, selection of antihypertensive drug therapy should follow an evidence-
based order.
All patients with elevated blood pressure and hypertension should be
prescribed lifestyle modifications. However, they should never be used as a
replacement for antihypertensive drug therapy for patients with hypertension who are
not at goal BP. Recommended modifications that have been shown to lower BP
Lifestyle modifications can provide smallto-moderate reductions in SBP. Aside from
reducing BP in patients with known hypertension, strict adherence to lifestyle
modification can decrease the progression to hypertension in patients with elevated
BP values. A sensible dietary program is one that is designed to reduce weight
gradually (for overweight and obese patients) and restricts sodium intake with only
moderate alcohol consumption (for patients who consume alcohol). Successful
implementation of dietary and lifestyle modifications by patients requires aggressive
promotion by clinicians through patient education, encouragement, and continued
reinforcement. Weight loss, as little as 5% of body weight, can decrease BP
significantly in overweight or obese patients. Diets rich in fruits and vegetables and
low in saturated fat have been shown to lower BP in patients with hypertension. Most
people experience BP lowering with sodium restriction.
The Dietary Approaches to Stop Hypertension (DASH) eating plan is a diet
that is rich in fruits, vegetables, and low-fat dairy products with a reduced content of
saturated and total fat. It is recommended as a reasonable and feasible diet that has
proven to lower BP. Intake of sodium should be minimized as much as possible,
ideally to 1.5 g/day, although an interim goal of a 1 g/day reduction may be
reasonable considering the challenges in achieving low sodium intake. Patients should
be aware of the multiple sources of dietary sodium (eg, processed foods, soups, table
salt) so that they may implement restriction. Potassium intake should be encouraged
through fruits and vegetables with high content (ideally 3.5-5 g/day) in those with
normal kidney function or without impaired potassium excretion. Excessive alcohol
use can either cause or worsen hypertension. Patients with hypertension who drink
alcoholic beverages should restrict their daily intake.
An ACEi, ARB, CCB, or a thiazide are the preferred first-line antihypertensive
agents for most patients.1 These agents should be used to treat the majority of patients
with hypertension because of evidence demonstrating CV event reduction. Several of
these medications have subclasses where significant differences in mechanism of
action, clinical use, side effects, or evidence from outcome studies exist. β-Blocker
therapy should be reserved to either treat a specific compelling indication or used in
combination with one or more of those mentioned above first-line antihypertensive
agents for patients without a compelling indication. Other antihypertensive drug
classes are considered alternative drug classes that may be used in select patients after
implementing first-line agents.
Landmark placebo-controlled clinical trials demonstrate that thiazide therapy
irrefutably reduces the risk of CV morbidity and mortality. The Systolic Hypertension
in the Elderly Program (SHEP),9 Swedish Trial in Old Patients with Hypertension
(STOPHypertension),8 and Medical Research Council (MRC) studies showed
significant reductions in stroke, MI, all-cause CV disease, and mortality with thiazide-
based therapy versus placebo. These trials used β-blockers as an add-on therapy for
BP control. Agents such as an ACEi, an ARB, and a CCB were not available at the
time of these studies. However, subsequent clinical trials have compared these
antihypertensive agents with a thiazide and have demonstrated similar long-term
benefits.
The results of the ALLHAT were the deciding evidence that the JNC7 used to
justify thiazide therapy as a first-line therapy.28 It was designed to test the hypothesis
that newer antihypertensive agents (an α-blocker, an ACEi, or a dihydropyridine
CCB) would be superior to thiazide-based therapy. The primary objective was to
compare the combined end point of fatal CHD and nonfatal MI. Other hypertension-
related complications (eg, HF, stroke) were evaluated as secondary end points. This
was the largest prospective hypertension trial ever conducted and included 42,418
patients aged 55 and older with hypertension and one additional CV risk factor. This
double-blind trial randomized patients to chlorthalidone-, amlodipine-, doxazosin-, or
lisinoprilbased therapy for a mean of 4.9 years.
The doxazosin treatment arm was terminated early when a significantly higher
risk of HF versus chlorthalidone was observed.35 The other arms were continued as
scheduled and no significant differences in the primary endpoint were seen between
the chlorthalidone and lisinopril or amlodipine treatment groups at the end of the trial.
However, chlorthalidone had statistically fewer secondary endpoints than amlodipine
(HF) and lisinopril (combined CV disease, HF, and stroke). The study conclusions
were that chlorthalidonebased therapy was superior in preventing one or more major
forms of CV disease and was less expensive than amlodipine- or lisinoprilbased
therapy. The ALLHAT was designed as a superiority study with the hypothesis that
amlodipine, doxazosin, and lisinopril would be better than chlorthalidone.36 It did not
prove this hypothesis. Several subgroup analyses of specific populations (eg, black
patients, CKD, diabetes) from the ALLHAT have been conducted to assess response
in certain unique patient populations.
Surprisingly, none of these analyses demonstrated superior CV event
reductions with lisinopril or amlodipine versus chlorthalidone. Overall, thiazides
remain unsurpassed in their ability to reduce CV morbidity and mortality in most
patients. Like the JNC7 guideline, the 2017 ACC/AHA high BP guideline
recommends a thiazide as a first-line therapy for most patients.1 However, an ACEi,
an ARB, and a CCB are also comparable first-line options. Contrary to the historical
preference to use a thiazide as preferred for treating most patients with hypertension,
they are simply one of four first-line drug therapy options.
Clinical trial data cumulatively demonstrate that ACEi-, CCB-, and ARB-
based antihypertensive therapy reduce CV events. These agents are first-line options
for patients without a compelling indication. The Blood Pressure Lowering Treatment
Trialists’ Collaboration has evaluated the incidence of major CV events and death
among different antihypertensive drug classes from 29 major randomized trials in
162,341 patients.40 In placebo-controlled trials, major CV events were significantly
lower with ACEi- and CCB-based regimens versus placebo. Although there were
minor differences in the incidence of certain CV events in some comparisons, there
were no differences in total major CV events when an ACEi, a CCB, or a thiazide was
compared with each other. In studies evaluating ARB-based therapy to control
regimens, the incidence of major CV events was lower with ARB-based therapy.
However, the control regimens used in these comparisons included both
antihypertensive drug therapies and placebo. These results were largely consistent
with the network meta-analysis conducted for the 2017 ACC/AHA guideline, which
found that an ACEi, an ARB, a CCB, and a thiazide were all similar as first-line
treatment for hypertension.
Data from meta-analyses that incorporate high-quality randomized controlled
trials provide more robust data than any single trial alone. High-quality meta-analyses
provide clinically useful data that support using ACEi-, CCB-, or ARB-based
treatment for hypertension as first-line antihypertensive agent. Clinicians should use
meta-analyses data as supporting evidence when selecting a firstline antihypertensive
regimen for hypertension in most patients. Other major consensus guidelines
recommend several firstline drug therapy options for treating hypertension in most
patients. The 2013 European Society of Hypertension/European Society of
Cardiology guidelines and the 2011 UK’s National Institute for Health and the
Clinical Excellence guidelines recommend an ACEi, an ARB, a CCB, or a thiazide as
first-line treatment.41,42 The European Society of Hypertension/European Society of
Cardiology guidelines are founded on the principle that CV risk reduction is a
function of BP control that is largely independent of specific antihypertensives.41 The
UK guideline stratifies patients based on age and race; they recommend an ACEi or
ARB first-line for patients under the age of 55 years, and a CCB first-line for patients
age 55 years or older or for black patients.
Clinical trial data and meta-analyses cumulatively suggest that treatment with
a β-blocker may not reduce CV events to the extent that an ACEi, an ARB, a CCB, or
particularly a thiazide does.1 In the systematic review and network analysis conducted
for the 2017 ACC/AHA guideline, β-blockers were less effective for the prevention of
stroke and CV events than diuretics.19 Meta-analyses data evaluating β-blockers and
their ability to reduce CV events have limitations. Most studies that were included in
these analyses used atenolol as the β-blocker studied. Therefore, it is possible that
atenolol is inferior and is the only β-blocker that does not reduce CV events as much
as other first-line antihypertensive drug classes. A recent network meta-analysis
comparing the effects of different β-blockers found a decreased risk of mortality and
CV events with lipophilic agents (metoprolol, propranolol, and oxprenolol) compared
to hydrophilic agents (atenolol).43 However, due to challenges in the interpretation of
meta-analyses of β-blockers compared to other first-line agents (eg, trials conducted at
different times, use of different beta-blockers, changes in the efficacy of agents, etc.),
most guideline recommendations do not differentiate between the β-blocker drug
class.41,42 In the absence of a compelling indication, the 2011 UK guideline
recommends a β-blocker as a fourth-line therapy, only after other first-line
antihypertensive agents (ACEi or ARB, CCB, thiazide) have been used.42 These
findings also call into question the validity of results from prominent prospective,
controlled clinical trials evaluating antihypertensive drug therapy that used β-blocker–
based therapy, especially atenolol, as the primary comparator.30,32 These studies
used once-daily atenolol, which in addition to being hydrophilic, may have been
inadequately dosed based on the short half-life of this agent.
β-Blocker–based antihypertensive therapy does not increase the risk of CV
events; β-blocker–based therapy reduces the risk of CV events compared with no
antihypertensive therapy. Using a β-blocker as a first-line antihypertensive agent is an
option when an ACEi, an ARB, a CCB, or a thiazide cannot be used. β-Blockers also
have an important role as an add-on therapy to first-line agents to reduce BP in
patients with hypertension but without compelling indications. Many of the clinical
trials included in the meta-analyses that suggest β-blocker–based therapy may not
reduce CV events as well as these other agents, used atenolol dosed once daily.44
Atenolol has a half-life of 6 to 7 hours and is nearly always dosed once daily, while
immediate-release forms of carvedilol and metoprolol have half-lives of 6 to 10 and 3
to 7 hours, respectively, and are dosed at least twice daily.44 It is also, hydrophilic,
which may not penetrate the brain and cell membrane as easily as lipophilic agents,
and has been shown to be inferior to lipophilic agents (metoprolol, propranolol, and
oxprenolol).43 Therefore, it is possible that these findings might only apply to
atenolol, particularly dosed once daily instead of twice daily. Based on available
evidence, metoprolol succinate or carvedilol are the preferred β-blockers if a β-
blocker is to be used.
Compelling indications represent specific comorbid conditions where
evidence from clinical trials supports using specific antihypertensive classes to treat
both the compelling indication and hypertension. Antihypertensive medication
recommendations typically consist of combination drug therapy. Data from clinical
trials have demonstrated a reduction in CV morbidity and/or mortality that justify use
for patients with hypertension and with such a compelling indication.
Evidence from clinical trials shows that ACEi therapy significantly modifies
disease progression by reducing morbidity and mortality. Although HFrEF was the
primary disease in these studies, ACEi therapy will also control BP in these patients
with concomitant hypertension. An ARB is an acceptable alternative for patients who
cannot tolerate an ACEi. An ACEi or ARB should be started using a low dose in
HFrEF, especially in patients with an acute exacerbation of HF. Acute HF
exacerbation induces a compensatory highrenin condition, so starting an ACEi or
ARB under these conditions can cause a pronounced first-dose effect and possible
orthostatic hypotension. Diuretics are a component of standard pharmacotherapy,
primarily to provide symptomatic relief of edema by inducing diuresis. Loop diuretics
are often needed, especially for patients with more advanced HF and/or CKD.
However, some patients with well-controlled HF and without significant CKD may be
managed with a thiazide.
β-Blocker therapy modifies disease in HFrEF and is a component of standard
treatment for these patients. For patients on an initial regimen of a diuretic with an
ACEi or ARB, add-on β-blocker therapy has been shown to reduce CV morbidity and
mortality.46 It is of paramount importance that β-blockers be dosed appropriately due
to the risk of inducing an acute exacerbation of HF. They must be started in very low
doses (much lower than that used to treat hypertension), and titrated slowly to high
doses based on tolerability. Bisoprolol, carvedilol, and metoprolol succinate are the
only β-blockers that are proved to be beneficial in HFrEF. After implementation of a
standard three-drug regimen (diuretic, ACEi or ARB, and evidence-based β-blocker),
other agents may be added to further reduce CV morbidity and mortality, and reduce
BP if needed. The addition of a mineralocorticoid receptor antagonist (e.g.
spironolactone) can reduce CV morbidity and mortality in HFrEF.46 For patients self-
described as African Americans, addition of a fixed-dose combination of isosorbide
dinitrate and hydralazine to the standard three-drug regimen (diuretic, ACEi or ARB,
and evidence-based β-blocker) is a recommended option to improve CV outcomes.
β-Blocker therapy has been a standard of care for treating patients with stable
(and unstable) ischemic heart disease and hypertension for decades. β-Blockers are
first-line therapy in stable ischemic heart disease and can reduce BP and improve
angina symptoms by decreasing myocardial oxygen consumption and demand.1 They
also decrease cardiac adrenergic stimulation and have been shown in clinical trials to
reduce the risk of a subsequent MI and sudden cardiac death. β-Blocker therapy seems
to be most effective in reducing the risk of CV events in patients with recent MI and/
or ischemic symptoms. While data are available that indicates that the long-term risk
of CV events and mortality may not be reduced with β-blocker therapy in patients
with very stable coronary artery disease (ie, do not have ischemic symptoms or have a
distant history of MI),47 β-blockers should be used for treatment of hypertension in
patients with stable ischemic heart disease.1 An ACEi (or an ARB as an alternative)
has been shown to improve cardiac remodeling and cardiac function and to reduce CV
events in stable ischemic heart disease as an add-on to a β-blocker. A long-acting
nondihydropyridine CCB is an alternative to a β-blocker (diltiazem and verapamil) in
stable ischemic heart disease.48 The International Verapamil–Trandolapril Study
(INVEST) demonstrated no difference in CV risk reduction when β-blocker– based
therapy was compared with nondihydropyridine CCB-based treatment in this
population.49 Nonetheless, the preponderance of data is with β-blockers, and they
remain the therapy of choice.
A dihydropyridine CCB (eg, amlodipine, felodipine) is recommended as an
add-on therapy in stable ischemic heart disease patients who have ongoing ischemic
symptoms (aka, angina or chest pain).48 CCBs (especially nondihydropyridine CCBs)
and β-blockers provide anti-ischemic effects; they lower BP and reduce myocardial
oxygen demand in patients with hypertension and stable (and unstable) ischemic heart
disease. However, cardiac stimulation may occur with dihydropyridine CCBs
(particularly immediate release formulations) or β-blockers with intrinsic
sympathomimetic activity (ISA), making these agents less desirable. Moreover, β-
blockers with ISA should be avoided due to these deleterious effects. Once ischemic
symptoms are controlled with β-blocker and/or CCB therapy, other antihypertensive
drugs can be added to provide additional CV risk reduction. Clinical trials have
demonstrated that the addition of an ACEi further reduces CV events in patients with
stable ischemic heart disease.48 ARB therapy may provide similar benefits but have
not been as extensively studied as ACEi therapy. Therefore, in stable ischemic heart
disease, an ARB is generally considered an alternative to an ACEi. Thiazides can be
added after that to provide additional BP lowering and to reduce CV risk further.
However, thiazides do not provide anti-ischemic effects.
The primary cause of mortality in patients with diabetes is CV disease, and
hypertension management is an important risk reduction strategy.1 All four first-line
antihypertensive agents (ACEi, ARB, CCB, thiazides) have been shown to reduce CV
events in patients with diabetes. The evidence-based review performed for the 2017
ACC/AHA guideline found no difference in all-cause mortality, CV mortality, HF, or
stroke between ACEi-, ARB-, CCB-, and thiazide-based regimens in patients with
diabetes.19 Traditionally, an ACEi or ARB was considered as a preferred
antihypertensive agent for patients with diabetes.2 The reasons for this were that
pharmacologically both of these agents should provide nephroprotection due to
vasodilation in the efferent arteriole of the kidney. Moreover, ACEi therapy has strong
data demonstrating CV risk reduction in patients with established forms of heart
disease. Evidence from clinical studies have demonstrated reductions in both CV risk
(mostly with an ACEi) and reduction in risk of progressive kidney dysfunction
(mostly with ARBs) in patients with diabetes.15,50 However, data indicate that an
ACEi or ARB does not confer significantly better CV risk reduction compared to
CCBs, thiazides, or β-blockers in patients with diabetes.51 In addition, the risk of
kidney disease progression is low in absence of albuminuria (urine albumin-to-
creatinine ratio ≥30 mg/g [3.4 mg/mmol creatinine]),15 and many of the studies
evaluating the ability of an ACEi or ARB to slow progression of kidney dysfunction
were placebo controlled.51 Therefore, an ACEi or ARB is recommended similarly to
a CCB or thiazide in patients with diabetes and hypertension that do not have
persistent albuminuria.
After first-line antihypertensives (ACEi, ARB, CCB, thiazide), a β-blocker is a
useful add-on therapy for BP control for patients with diabetes, or to treat another
compelling indication (eg, stable ischemic heart disease). A β-blocker (especially
nonselective agents) can possibly mask the signs and symptoms of hypoglycemia in
patients with tightly controlled diabetes because most of the symptoms of
hypoglycemia (eg, tremor, tachycardia, and palpitations) are mediated through the
sympathetic nervous system. Sweating, a cholinergically mediated symptom of
hypoglycemia, still occurs during a hypoglycemic episode despite β-blocker therapy.
Patients may also have a delay in hypoglycemia recovery time because compensatory
recovery mechanisms need the catecholamine inputs that are antagonized by β-
blocker therapy. Finally, unopposed α-receptor stimulation during the acute
hypoglycemic recovery phase (due to endogenous epinephrine release intended to
reverse hypoglycemia) may result in acutely elevated BP due to vasoconstriction.
Despite these potential problems, β-blockers can be safely used for patients with
diabetes. Based on the weight of all evidence, any first-line agent can be used for
controlling hypertension for patients with diabetes in the absence of albuminuria.
Regardless of what agent is initially chosen, most patient will require combination
therapy, which typically will include an ACEi or ARB with a CCB or thiazide.
Ischemic stroke (not hemorrhagic stroke) and transient ischemic attack (TIA)
are considered hypertension-associated complications. More than two-thirds of
patients who have had an ischemic stroke or TIA have hypertension.1 Achieving goal
BP values in patients who have experienced an ischemic stroke is considered a
primary modality to reduce the risk of a second stroke or TIA. A thiazide, either in
combination with an ACEi or as monotherapy, is an evidence-based antihypertensive
regimen for patients with a history of stroke or transient ischemic attack.1,54,55
ARB-based therapy has also been studied in this population.56,57 Antihypertensive
drug therapy should only be implemented after patients have stabilized following an
acute cerebrovascular event, typically a few days after the event.1 Moreover, the
threshold for starting antihypertensive drug therapy in patients with a history of stroke
is when BP is above 140/90 mm Hg.
It is sometimes necessary to use other agents such as a direct renin inhibitor,
an α-blocker, a central α2 -agonist, an adrenergic inhibitor, or an arterial vasodilator in
some patients. Although these agents are effective in lowering BP, they either do not
have convincing evidence showing reduced morbidity and mortality in hypertension
or have a high incidence of adverse effects that significantly hinders tolerability.
Alternative agents are generally reserved for patients with resistant hypertension or as
an add-on therapy with multiple other first-line antihypertensive agents.
Hypertension often presents as isolated systolic hypertension in older
patients.1 Epidemiologic data indicate that CV morbidity and mortality are more
directly correlated to SBP than to DBP for patients aged 50 and older. This population
is also at high risk for hypertension-associated complications.1 Although several
placebo-controlled trials have specifically demonstrated risk reduction in this
population, many older people with hypertension are either not treated or treated but
not to goal BP. The SHEP was a landmark double-blind, placebo-controlled trial that
evaluated chlorthalidone-based treatment for isolated systolic hypertension.9 A 36%
reduction in total stroke, a 27% reduction in coronary artery disease, and 55%
reduction in HF were demonstrated versus placebo. The Systolic Hypertension in
Europe (Syst-Eur) trial was another placebo-controlled trial that evaluated treatment
with a long-acting dihydropyridine CCB.10 Treatment resulted in a 42% reduction in
stroke, 26% reduction in coronary artery disease, and 29% reduction in HF. These
data demonstrate reductions in CV morbidity and mortality in older patients with
isolated systolic hypertension, especially with thiazides and long-acting
dihydropyridine CCBs.
Thiazide or β-blocker therapy has been compared with either an ACEi or CCB
in older patients with either systolic hypertension, diastolic hypertension, or both in
the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) study.59 In this trial,
no significant differences in the primary CV event endpoint were seen between
conventional drugs and either an ACEi or CCB. These data support that overall
treatment may be more important than specific antihypertensive agents in this
population. Older patients are more sensitive to volume depletion and sympathetic
inhibition than younger patients. This may lead to orthostatic hypotension. In older
patients, this can increase the risk of falls due to the associated dizziness. Centrally
acting agents and α1 -blockers should generally be avoided or used with caution in
older patients because they are frequently associated with dizziness and orthostatic
hypotension. First-line antihypertensives provide significant benefits and can safely
be used in older patients, especially those age 80 years and older, but smaller-
thanusual initial doses must be used for initial therapy.
Orthostatic hypotension is a significant drop in BP when standing and can be
associated with dizziness and/or fainting. It is defined as a SBP decrease of >20 mm
Hg or DBP decrease of >10 mm Hg when changing from supine to standing.1 The
risk of orthostatic hypotension is increased in older patients (especially those with
isolated systolic hypotension, or those age 80 years or older) and those with long-
standing diabetes, severe volume depletion, baroreflex dysfunction, autonomic
insufficiency (eg, diabetes), and concomitant use of medications that cause
venodilation (α-blockers, mixed α-/β-blockers, nitrates, and phosphodiesterase
inhibitors). For patients with these risk factors, antihypertensive agents, especially a
thiazide, an ACEi, or an ARB should be started in low doses.
e. Evaluation of Therapeutic Outcomes
Routine, ongoing monitoring to assess the desired effects of antihypertensive
therapy (efficacy, including BP goal attainment), undesired adverse effects (side
effects and toxicity), and disease progression is needed in all patients treated with
antihypertensive drug therapy.
Both clinic-based and self-measurement home BP monitoring are important
components for monitoring and managing hypertension. Patients should be
encouraged to obtain a validated home BP monitor, record the results, and send or
bring them to follow-up clinic visits. BP response should be evaluated in the clinic 4
weeks after initiating or making changes in therapy and results compared to home BP
readings. Once goal BP is attained, assuming no signs or symptoms of acute end-
organ damage are present, clinic BP monitoring can be done every 3 to 6 months.
More frequent evaluations are required for patients with a history of poor control,
nonadherence, progressive end-organ damage, or symptoms of adverse drug effects.
Automated ABP monitoring can be useful clinically to establish effective 24-
hour control. This type of monitoring may become the standard of care in the future
because evolving data have demonstrated significant benefits of using these types of
measurements to diagnose hypertension, confirm white coat or masked uncontrolled
hypertension, and could be a stronger predictor of CVD.1 For patients self-measuring
their BP at home, it is important that they measure during the early morning hours,
taking at least two measurements 1 minutes apart before taking antihypertensive days
of the week using appropriate technique.1 BP measurements should be recorded daily,
or ideally, a monitor with a built-in memory should be used. Patients should be
instructed to bring their actual measurements and/or BP monitor with built-in memory
to follow-up clinic appointments, and any changes to drug therapy should be based on
an average BP reading from two or more occasions.
Patients should be monitored routinely for adverse drug effects. The most
common side effects associated with each class of antihypertensive agents were
discussed in the previous “Individual Antihypertensive Agents” section, and
laboratory parameters for first-line agents. Laboratory monitoring should typically
occur 4 weeks after starting a new agent or dose increase, and then every 6 to 12
months in stable patients. Additional disease-specific monitoring might be needed (eg,
diabetes, dyslipidemia, gout) depending on which agents are used.
Moreover, patients who are treated with a mineralocorticoid receptor
antagonist (MRA), such as eplerenone or spironolactone, require diligent monitoring
to ensure safety and efficacy. These medications are often prescribed for conditions
like resistant hypertension, heart failure, and primary aldosteronism due to their
ability to block the effects of aldosterone, thereby promoting sodium excretion and
potassium retention. However, due to their mechanism of action, these medications
can significantly affect electrolyte balance, particularly potassium levels, and renal
function.
To prevent potential complications, it is essential that healthcare providers
closely monitor patients' potassium concentrations and kidney function. Specifically,
these assessments should be conducted within 3 days of initiating therapy to quickly
identify any early signs of hyperkalemia, a condition characterized by elevated
potassium levels in the blood, which can be life-threatening if not managed promptly.
Following this initial check, it is crucial to reassess these parameters again at 1 week
to ensure that the patient’s body is responding well to the medication without
developing adverse effects.
Hyperkalemia can lead to serious cardiac arrhythmias, muscle weakness, and
paralysis, making early detection and intervention critical. If elevated potassium
levels or renal dysfunction are detected during these early assessments, the healthcare
provider may need to adjust the medication regimen. This could involve reducing the
dosage of the MRA or, in some cases, discontinuing the medication altogether and
substituting it with an alternative antihypertensive agent that has a lower risk of
causing hyperkalemia.
Beyond the initial monitoring period, ongoing regular monitoring is essential
for patients on MRAs. This includes periodic checks of serum electrolytes and renal
function every 1 to 3 months, depending on the stability of the patient’s condition and
the presence of any risk factors for hyperkalemia or renal impairment. Patients with
underlying renal disease, diabetes, or those taking other medications that affect
potassium levels, such as ACE inhibitors or angiotensin II receptor blockers (ARBs),
are at a particularly increased risk and may require more frequent monitoring.
In addition to laboratory monitoring, patient education is a critical component
of safe and effective treatment with MRAs. Patients should be informed about the
potential signs and symptoms of hyperkalemia, such as muscle cramps, weakness,
fatigue, palpitations, and shortness of breath. They should also be advised to avoid
high-potassium foods, such as bananas, oranges, tomatoes, and certain salt substitutes,
and to stay hydrated to support kidney function. Encouraging patients to promptly
report any unusual symptoms or changes in their health can facilitate early detection
and management of adverse drug reactions.
For healthcare providers, it is essential to maintain a high index of suspicion
for hyperkalemia and other potential adverse effects when prescribing MRAs. This
involves a comprehensive review of the patient's medical history, current medications,
and overall health status to identify any potential contraindications or risk factors. It is
also important to have a clear plan for managing hyperkalemia should it occur, which
may include the use of potassium binders, diuretics, or other interventions to lower
serum potassium levels.
Furthermore, the occurrence of an adverse drug event related to MRA therapy
should prompt a thorough evaluation of the patient's treatment regimen. In some
cases, reducing the dosage of the MRA may be sufficient to mitigate the adverse
effect while still providing therapeutic benefits. In other cases, it may be necessary to
switch to an alternative class of antihypertensive agents. Options include thiazide
diuretics, which can lower blood pressure without significantly affecting potassium
levels, or calcium channel blockers, which are effective in managing hypertension and
have a different side effect profile.
In summary, the management of patients treated with mineralocorticoid
receptor antagonists requires careful and ongoing monitoring of potassium
concentrations and kidney function to detect and address potential hyperkalemia and
other adverse effects. Initial assessments within 3 days and again at 1 week after
starting therapy, followed by regular ongoing monitoring, are essential to ensure
patient safety. Adjustments to the medication regimen should be made as necessary
based on these assessments, and patient education on recognizing and preventing
hyperkalemia is a vital part of comprehensive care. Through diligent monitoring and
proactive management, healthcare providers can help ensure the safe and effective use
of MRAs in the treatment of hypertension and other conditions.
Patients should be monitored for signs and symptoms of hypertension-
associated complications. A careful history for ischemic chest pain (or pressure),
palpitations, dizziness, dyspnea, orthopnea, headache, sudden change in vision, one-
sided weakness, slurred speech, and loss of balance should be taken to determine the
presence of CV and cerebrovascular disease. Other monitoring parameters that may
be used include funduscopic changes on eye exam, LVH on electrocardiogram,
albuminuria, and changes in kidney function by calculating estimated GFR. These
parameters should be monitored periodically because any sign of deterioration
requires additional assessment and follow-up.
Poor medication use behaviors and lack of persistence with antihypertensive
pharmacotherapy is a major problem and associated with significant increases in costs
due to development of complications. Since hypertension is a relatively asymptomatic
disease, poor adherence is frequent, particularly in newly treated patients. Up to 25%
of patients do not fill their initial prescription for antihypertensive medication and
during the first year of treatment an average patient possesses their BP medication
only half of the time.1 Long-term risk of CV events can be significantly reduced
when patients are adherent to their antihypertensive drug therapy. Therefore, it is
imperative to assess patient adherence and medication taking behavior on a regular
basis.
Improving adherence to antihypertensive treatment and hypertension control
requires a multifactorial approach.1 These include interventions aimed at the patient,
provider, and healthsystem level. Examples can include (a) focusing on clinical
outcomes (eg, following national guidelines, use of once-daily antihypertensives and
combination rather than free individual components, encouraging self-monitoring of
BP), (b) empowering informed activated patients (eg, behavioral and motivational
strategies, use of pill boxes, systems to prompt patients to refill prescriptions), (c)
implementing a team approach (eg, collaborative interprofessional models of care),
(d) use of telehealth strategies (eg, transmission of data from self-monitored BP to
assist in BP management), and (e) advocating for health policy reform (eg, use of
performance measures, reduce patient copayments for healthcare services and
medications, provide financial incents to providers for improved performance).
After identifying less than optimal adherence in a patient with hypertension,
appropriate patient education, counseling, and intervention should occur. Once-daily
regimens are recommended in most patients to improve adherence. Some patients
may incorrectly believe that aggressive treatment may negatively impact the quality
of life and thus result in nonadherence. However, several studies have found that most
patients feel better once their BP is controlled, and patients should be made aware of
this. Patients on antihypertensive therapy should be questioned periodically about
changes in their general health perception, physical functioning, and overall
satisfaction with treatment. Lifestyle modifications should always be recommended to
augment antihypertensive drug therapy and provide other potential health benefits.
Persistence with lifestyle modifications should also be continually encouraged.
