Hypertension

2081CHAPTER 277

APPROACH TO THE PATIENT

Hypertension

HISTORY AND PHYSICAL

The initial assessment of a hypertensive patient should include a

complete history and physical examination to confirm a diagnosis

of hypertension, screen for other cardiovascular disease risk factors,

screen for secondary causes of hypertension, identify cardiovascular consequences of hypertension and other comorbidities, assess

blood pressure–related lifestyles, and determine the potential for

intervention. Most patients with hypertension have no specific

symptoms referable to their blood pressure elevation. Table 277-5

lists salient features of the history and physical examination of the

hypertensive patient.

Reliable measurements of blood pressure depend on attention

to the details of the technique and conditions of the measurement.

Proper training of observers, positioning of the patient, and selection of cuff size are essential. At the first visit, blood pressure should

be measured in both arms, and the arm with higher readings should

be used for subsequent measurements. An average of two to three

measurements obtained on two to three separate occasions will

provide a more accurate estimation of blood pressure than a single

casual measurement. Rarely, in older patients, pseudohypertension

may be related to the inability to measure blood pressure accurately

in severely sclerotic arteries. This condition is suggested if the radial

pulse remains palpable despite occlusion of the brachial artery

by the cuff (Osler maneuver). The actual blood pressure can be

determined by direct intra-arterial measurement. Owing to recent

regulations preventing the use of mercury because of concerns

about its potential toxicity, most office measurements are made

with aneroid sphygmomanometers or with oscillometric devices.

These instruments should be calibrated periodically, and their

accuracy confirmed.

LABORATORY TESTING

Table 277-6 lists recommended laboratory tests in the initial evaluation of hypertensive patients. Repeat measurements of renal

Mineralocorticoid Glucocorticoid Androgen

Cholesterol

Pregnenolone 17 OH Pregnenolone

Deoxycortisol

(17α hydroxylase)

DHEA

Progesterone

Corticosterone

Aldosterone

Deoxycorticosterone

17 OH Progesterone

Cortisone

Cortisol

Androstenedione Testosterone

(21 hydroxylase)

(11β hydroxylase)

(11β hydroxysteroid dehydrogenase)

FIGURE 277-3 Adrenal enzymatic defects. DHEA, dehydroepiandrosterone.

TABLE 277-5 Relevant History and Physical

History

Duration of hypertension

Previous therapies: responses and side effects

Family history of hypertension and cardiovascular disease

Dietary and psychosocial history

Alcohol consumption

Other risk factors: weight change, dyslipidemia, smoking, diabetes, physical

inactivity

Evidence of secondary hypertension: history of renal disease; change in

appearance; muscle weakness; spells of sweating, palpitations, tremor; erratic

sleep, snoring, daytime somnolence; symptoms of hypo- or hyperthyroidism; use

of agents that may increase blood pressure

Evidence of target organ damage: history of TIA, stroke, transient blindness;

angina, myocardial infarction, congestive heart failure; sexual function

Other comorbidities

Physical

Body habitus

Blood pressure in both arms

Supine and standing blood pressures

Funduscopic examination of retina

Quality of femoral and pedal pulses

Vascular and abdominal bruits

Cardiac rate and rhythm

Signs of congestive heart failure

Characteristics of secondary hypertension

Abbreviation: TIA, transient ischemic attack.

function, serum electrolytes, fasting glucose, and lipids may be

obtained after the introduction of a new antihypertensive agent

and then annually or more frequently if clinically indicated. More

extensive laboratory testing is appropriate for patients with apparent drug-resistant hypertension or when the clinical evaluation

suggests a secondary form of hypertension.

2082 PART 6 Disorders of the Cardiovascular System

TREATMENT

Hypertension

Lowering systolic blood pressure by 10–12 mmHg and diastolic

blood pressure by 5–6 mmHg confers relative risk reductions of

35–40% for stroke and 12–16% for CHD within 5 years of the initiation of treatment. The risk of heart failure is reduced by >50%;

although the benefit of blood pressure lowering on progression

of renal failure is less apparent, hypertension control is the single

most effective intervention for slowing the rate of progression of

hypertension-related kidney disease. There are more potentially

preventable cardiovascular disease events attributed to elevated

blood pressure in individuals at higher than at lower risk of cardiovascular disease and in older rather than younger adults.

LIFESTYLE INTERVENTIONS

Implementation of lifestyles that favorably affect blood pressure has

implications for both the prevention and the treatment of hypertension. Health-promoting lifestyle modifications are recommended

for individuals with “elevated” blood pressure and as an adjunct

to drug therapy in hypertensive individuals (Table 277-7). These

interventions should address overall cardiovascular disease risk.

Although the impact of lifestyle interventions on blood pressure

is more pronounced in persons with hypertension, in short-term

trials, weight loss and reduction of dietary NaCl have been shown to

prevent the development of hypertension. In hypertensive individuals, even if these interventions do not produce a sufficient reduction

in blood pressure to avoid drug therapy, the number of medications

or doses required for blood pressure control may be reduced.

Prevention and treatment of obesity are important for reducing

blood pressure and cardiovascular disease risk. In short-term trials,

even modest weight loss can lead to a reduction of blood pressure

and an increase in insulin sensitivity. In longitudinal studies, a

direct correlation exists between change in weight and change

in blood pressure over time. Average blood pressure reductions

of 6.3/3.1 mmHg have been observed with a reduction in mean

body weight of 9.2 kg. Regular physical activity facilitates weight

loss, decreases blood pressure, and reduces the overall risk of

TABLE 277-6 Basic Laboratory Tests for Initial Evaluation

SYSTEM TEST

Renal Microscopic urinalysis, albumin

excretion, serum BUN and creatinine

(compute eGFR)

Endocrine Serum sodium, potassium, calcium,

TSH

Metabolic Fasting blood glucose, total

cholesterol, HDL and LDL (often

computed) cholesterol, triglycerides

Other CBC, electrocardiogram

Abbreviations: BUN, blood urea nitrogen; CBC, complete blood count; eGFR,

estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density

lipoprotein; TSH, thyroid-stimulating hormone.

TABLE 277-7 Lifestyle Modifications to Manage Hypertension

Weight reduction Attain and maintain BMI <25 kg/m2

Dietary salt reduction <6 g NaCl/d

Adapt DASH-type

dietary plan

Diet rich in fruits, vegetables, and low-fat dairy

products with reduced content of saturated and

total fat. Diet is also rich in potassium, calcium, and

magnesium.

Moderation of alcohol

consumption

For those who drink alcohol, consume ≤2 drinks/d in

men and ≤1 drink/d in women

Physical activity Regular aerobic activity, e.g., brisk walking for 30 min/d

Abbreviations: BMI, body mass index; DASH, Dietary Approaches to Stop

Hypertension (trial).

cardiovascular disease. Blood pressure may be lowered by 30 min of

moderately intense physical activity, such as brisk walking, 6–7 days

a week, or by more intense, less frequent workouts.

There is individual variability in the sensitivity of blood pressure to NaCl, and this variability may have a genetic basis. Several

genetic loci have been associated with NaCl sensitivity. Based on

results of meta-analyses, lowering of blood pressure by limiting

daily NaCl intake to 4.4–7.4 g (75–125 meq) results in blood

pressure reductions of 3.7–4.9/0.9–2.9 mmHg in hypertensive individuals and lesser reductions in normotensive individuals. Salt

sensitivity is especially common in blacks, older adults, and those

with higher levels of blood pressure. Independent of its effect on

blood pressure, excessive consumption of NaCl is associated with

an increased risk of stroke and cardiovascular disease. Potassium

and calcium supplementation have inconsistent, modest antihypertensive effects, and, independent of blood pressure, potassium

supplementation may be associated with reduced stroke mortality.

Additionally, consuming three or more alcoholic drinks per day (a

standard drink contains ~14 g ethanol) is associated with higher

blood pressures, and a reduction of alcohol consumption is associated with a reduction of blood pressure. The Dietary Approaches

to Stop Hypertension (DASH) trial convincingly demonstrated that

over an 8-week period a diet high in fruits, vegetables, and low-fat

dairy products lowers blood pressure in individuals with highnormal blood pressures or mild hypertension. Reduction of daily

NaCl intake to <6 g (100 meq) augmented the effect of this diet on

blood pressure. Fruits and vegetables are enriched sources of potassium, magnesium, and fiber, and dairy products are an important

source of calcium.

PHARMACOLOGIC THERAPY

According to 2017 guidelines developed by the American College

of Cardiology (ACC)/American Heart Association (AHA), atherosclerotic cardiovascular disease (ASCVD) risk estimation guides

the threshold for initiation of blood pressure–lowering medications

(Table 277-8). A risk calculator may be used to estimate risk of

ASCVD, e.g., ACC/AHA Pooled Cohort Equations (http://tools.acc.

org/ASCVD-Risk-Estimator).

There is considerable variation in individual responses to different classes of antihypertensive agents, and the magnitude of

response to any single agent may be limited by activation of

counter-regulatory mechanisms. To achieve goal blood pressure,

most patients will require at least two antihypertensive agents.

More often than not, combinations of agents, with complementary

antihypertensive mechanisms, are required to achieve goal blood

pressure reductions. Selection of antihypertensive agents and combinations of agents should be individualized, taking into account

TABLE 277-8 ACC/AHA Guidelines for Hypertension Management

Indications for Use of Blood Pressure–Lowering Medications

Secondary prevention of recurrent CVD events in patients with clinical CVD

(defined as CHD, CHF, stroke) and SBP ≥130 mmHg or DBP ≥80 mmHg

Primary prevention in patients with an estimated 10-year ASCVD risk ≥10% and

SBP ≥130 mmHg or DBP ≥80 mmHg

Primary prevention of CVD and low CVD risk in patients with SBP ≥140 mmHg or

DBP ≥90 mmHg

Blood Pressure Goal for Patients with Hypertension

For adults with confirmed hypertension and known CVD or 10-year ASCVD event

risk ≥10% , a BP target <130/80 mmHg

Possible Exceptions to Therapeutic Target of <130/80 mmHg

Patients >80 years of age

Patients previously untreated for hypertension who experience an ischemic

stroke or TIA and have blood pressure <140/90 mmHg

Acute therapy of most hypertensive urgencies and emergencies

Abbreviations: ACC, American College of Cardiology; AHA, American Heart

Association; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure;

CHD, coronary heart disease; CHF, congestive heart failure; CVD, cardiovascular

disease; DBP, diastolic blood pressure; SBP, systolic blood pressure.

Hypertension

2083CHAPTER 277

age, severity of hypertension, other cardiovascular disease risk

factors, comorbid conditions, and practical considerations related

to cost, side effects, and frequency of dosing. The primary classes of

drugs used to treat hypertension are listed in Table 277-9.

Diuretics Low-dose thiazide diuretics may be used alone or in

combination with other antihypertensive drugs. Thiazides inhibit

the Na+/Cl–

 pump in the distal convoluted tubule and hence

increase sodium excretion. In the long term, they also may act as

TABLE 277-9 Examples of Oral Drugs Used in Treatment of Hypertension

DRUG CLASS EXAMPLES

USUAL TOTAL DAILY DOSEa

(DOSING FREQUENCY/DAY) OTHER INDICATIONS CONTRAINDICATIONS/CAUTIONS

Diuretics

Thiazides Hydrochlorothiazide 6.25–50 mg (1–2) Diabetes, dyslipidemia, hyperuricemia,

gout, hypokalemia

Chlorthalidone 25–50 mg (1)

Loop diuretics Furosemide 40–80 mg (2–3) CHF due to systolic dysfunction,

CHF with preserved ejection

fraction, renal failure

Diabetes, dyslipidemia, hyperuricemia,

gout, hypokalemia

Ethacrynic acid 50–100 mg (2–3)

Aldosterone antagonists Spironolactone 25–100 mg (1–2) CHF, primary aldosteronism,

resistant hypertension

Renal failure, hyperkalemia

Eplerenone 50–100 mg (1–2)

K+

 retaining Amiloride 5–10 mg (1–2) Liddle’s syndrome Renal failure, hyperkalemia

Triamterene 50–100 mg (1–2)

Beta blockers Asthma, COPD, second- or third-degree

heart block, sick-sinus syndrome

Cardioselective Atenolol 25–100 mg (1) Angina, CHF, post-MI, sinus

tachycardia, ventricular

tachyarrhythmias, thoracic

aortic disease

Metoprolol 25–100 mg (1–2)

Nonselective Propranolol 40–160 mg (2)

Propranolol LA 60–180 (1)

Combined alpha/beta Labetalol 200–800 mg (2)

Carvedilol 12.5–50 mg (2)

Alpha antagonists

Selective Prazosin 2–20 mg (2–3) Prostatism

Doxazosin 1–16 mg (1)

Terazosin 1–10 mg (1–2)

Nonselective Phenoxybenzamine 20–120 mg (2–3) Pheochromocytoma

Sympatholytics

Central Clonidine 0.1–0.6 mg (2)

Clonidine patch 0.1–0.3 mg (1/week)

Methyldopa 250–1000 mg (2)

Reserpine 0.05–0.25 mg (1)

Guanfacine 0.5–2 mg (1)

ACE inhibitors Captopril 25–200 mg (2) Post-MI, coronary syndromes,

CHF, nephropathy

Acute renal failure, bilateral renal artery

stenosis, pregnancy, hyperkalemia

Lisinopril 10–40 mg (1)

Ramipril 2.5–20 mg (1–2)

Angiotensin II antagonists Losartan 25–100 mg (1–2) CHF, nephropathy, ACE inhibitor

cough

Renal failure, bilateral renal artery

stenosis, pregnancy, hyperkalemia

Valsartan 80–320 mg (1)

Candesartan 2–32 mg (1–2)

Renin inhibitors Aliskiren 150–300 mg (1) Diabetic nephropathy Pregnancy

Calcium antagonists

Dihydropyridines Nifedipine

(long-acting)

30–60 mg (1)

Nondihydropyridines Verapamil

(long-acting)

120–360 mg (1–2) Post-MI, supraventricular

tachycardias, angina

Second- or third-degree heart block

Diltiazem

(long-acting)

180–420 mg (1)

Direct vasodilators Hydralazine 25–100 mg (2) Severe coronary artery disease

Minoxidil 2.5–80 mg (1–2)

a

At the initiation of therapy, lower doses may be preferable for elderly patients and for select combinations of antihypertensive agents.

Abbreviations: ACE, angiotensin-converting enzyme; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction.

2084 PART 6 Disorders of the Cardiovascular System

vasodilators. Thiazides are safe, efficacious, inexpensive, and reduce

clinical events. They provide additive blood pressure–lowering

effects when combined with beta blockers, ACEIs, or ARBs. In

contrast, addition of a diuretic to a calcium channel blocker is less

effective. Usual doses of hydrochlorothiazide range from 6.25 to

50 mg/d. Owing to an increased incidence of metabolic side effects

(hypokalemia, insulin resistance, increased cholesterol), higher

doses generally are not recommended. Chlorthalidone is a diuretic

structurally similar to hydrochlorothiazide, and like hydrochlorothiazide, it blocks sodium-chloride cotransport in the early distal

tubule. However, chlorthalidone has a longer half-life (40–60 h vs

9–15 h) and an antihypertensive potency ~1.5–2.0 times that of

hydrochlorothiazide. Potassium loss is also greater with chlorthalidone. Two potassium-sparing diuretics, amiloride and triamterene,

act by inhibiting ENaC in the distal nephron. These agents are weak

antihypertensive agents but may be used in combination with a

thiazide to protect against hypokalemia. The main pharmacologic

target for loop diuretics is the Na+-K+-2Cl–

 cotransporter in the

thick ascending limb of the loop of Henle. Loop diuretics generally

are reserved for hypertensive patients with reduced glomerular filtration rates (reflected in serum creatinine >220 μmol/L [>2.5 mg/

dL]), CHF, or sodium retention and edema for some other reason,

such as treatment with a potent vasodilator, e.g., minoxidil.

Blockers of the Renin-Angiotensin System ACEIs decrease the

production of angiotensin II, increase bradykinin levels, and reduce

sympathetic nervous system activity. ARBs provide selective blockade of AT1

Rs, and the effect of angiotensin II on unblocked AT2

Rs

may augment their hypotensive effect. Both classes of agents are

effective antihypertensive agents that may be used as monotherapy or in combination with diuretics, calcium antagonists, and

alpha-blocking agents. ACEIs and ARBs improve insulin action and

ameliorate the adverse effects of diuretics on glucose metabolism.

Although the overall impact on the incidence of diabetes is modest,

compared with amlodipine (a calcium antagonist), valsartan (an

ARB) has been shown to reduce the risk of developing diabetes in

high-risk hypertensive patients. ACEI/ARB combinations are less

effective in lowering blood pressure than is the case when either

class of these agents is used in combination with other classes of

agents. In patients with vascular disease or a high risk of diabetes,

combination ACEI/ARB therapy has been associated with more

adverse events (e.g., cardiovascular death, myocardial infarction,

stroke, and hospitalization for heart failure) without increases in

benefit.

Side effects of ACEIs and ARBs include functional renal insufficiency due to efferent renal arteriolar dilation in a kidney with a

stenotic lesion of the renal artery. Additional predisposing conditions to renal insufficiency induced by these agents include dehydration, CHF, and use of nonsteroidal anti-inflammatory drugs.

Dry cough occurs in ~15% of patients, and angioedema occurs in

<1% of patients taking ACEIs. Angioedema occurs most commonly

in individuals of Asian origin and more commonly in African

Americans than in whites. Hyperkalemia due to hypoaldosteronism

is an occasional side effect of both ACEIs and ARBs.

An alternative approach to blocking the renin-angiotensin system has recently been introduced into clinical practice for the

treatment of hypertension: direct renin inhibitors. Blockade of the

renin-angiotensin system is more complete with renin inhibitors

than with ACEIs or ARBs. Aliskiren is the first of a class of oral,

nonpeptide competitive inhibitors of the enzymatic activity of

renin. Monotherapy with aliskiren seems to be as effective as an

ACEI or ARB for lowering blood pressure, but not more effective.

Further blood reductions may be achieved when aliskiren is used in

combination with a thiazide diuretic or a calcium antagonist. Currently, aliskiren is not considered a first-line antihypertensive agent.

Aldosterone Antagonists Spironolactone is a nonselective

aldosterone antagonist that may be used alone or in combination

with a thiazide diuretic. It may be a particularly effective agent in

patients with low-renin primary hypertension, resistant hypertension, and primary aldosteronism. In patients with CHF, low-dose

spironolactone reduces mortality and hospitalizations for heart

failure when given in addition to conventional therapy with ACEIs,

digoxin, and loop diuretics. Because spironolactone binds to progesterone and androgen receptors, side effects may include gynecomastia, impotence, and menstrual abnormalities. These side effects

are circumvented by a newer agent, eplerenone, which is a selective

aldosterone antagonist.

Calcium Channel Blockers Calcium antagonists reduce vascular

resistance through L-channel blockade, which reduces intracellular calcium and blunts vasoconstriction. This is a heterogeneous

group of agents that includes drugs in the following three classes:

phenylalkylamines (verapamil), benzothiazepines (diltiazem), and

1,4-dihydropyridines (nifedipine-like). Used alone and in combination with other agents (ACEIs, beta blockers, α1

-adrenergic blockers), calcium antagonists effectively lower blood pressure; however,

it is unclear if adding a diuretic to a calcium blocker results in a further lowering of blood pressure. Side effects of flushing, headache,

and edema with dihydropyridine use are related to their potencies

as arteriolar dilators; edema is due to an increase in transcapillary

pressure gradients, not to net salt and water retention.

Beta Blockers β-Adrenergic receptor blockers lower blood pressure by decreasing cardiac output owing to a reduction of heart rate

and contractility. Other proposed mechanisms by which beta blockers lower blood pressure include a central nervous system effect and

inhibition of renin release. Beta blockers are particularly effective

in hypertensive patients with tachycardia, and their hypotensive

potency is enhanced by co-administration with a diuretic. In lower

doses, some beta blockers selectively inhibit cardiac β1

 receptors

and have less influence on β2

 receptors on bronchial and vascular

smooth muscle cells; however, there seems to be no difference in

the antihypertensive potencies of cardioselective and nonselective

beta blockers. Some beta blockers have intrinsic sympathomimetic

activity, although it is uncertain whether this constitutes an overall

advantage or disadvantage in cardiac therapy. Beta blockers without

intrinsic sympathomimetic activity decrease the rate of sudden

death, overall mortality, and recurrent myocardial infarction. In

patients with CHF, beta blockers reduce the risks of hospitalization

and mortality. Carvedilol and labetalol block both β receptors and

peripheral α-adrenergic receptors. The potential advantages of

combined β- and α-adrenergic blockade in treating hypertension

remain to be determined. Nebivolol represents another class of

cardioselective beta blockers that has additional vasodilator actions

related to enhancement of nitric oxide activity. Whether this confers greater clinical effectiveness remains to be determined.

α-Adrenergic Blockers Postsynaptic, selective α-adrenoreceptor

antagonists lower blood pressure by decreasing peripheral vascular

resistance. They are effective antihypertensive agents used either

as monotherapy or in combination with other agents. However,

in clinical trials of hypertensive patients, alpha blockade has not

been shown to reduce cardiovascular morbidity and mortality or to

provide as much protection against CHF as other classes of antihypertensive agents. These agents are also effective in treating lower

urinary tract symptoms in men with prostatic hypertrophy. Nonselective α-adrenoreceptor antagonists bind to postsynaptic and

presynaptic receptors and are used primarily for the management

of patients with pheochromocytoma.

Sympatholytic Agents Centrally acting α2

 sympathetic agonists

decrease peripheral resistance by inhibiting sympathetic outflow.

They may be particularly useful in patients with autonomic neuropathy who have wide variations in blood pressure due to baroreceptor denervation. Drawbacks include somnolence, dry mouth, and

rebound hypertension on withdrawal. Peripheral sympatholytics

decrease peripheral resistance and venous constriction by depleting nerve terminal norepinephrine. Although they are potentially

Hypertension

2085CHAPTER 277

effective antihypertensive agents, their usefulness is limited by

orthostatic hypotension, sexual dysfunction, and numerous drugdrug interactions. Rebound hypertension is another concern with

abrupt cessation of drugs with a short half-life.

Direct Vasodilators Direct vasodilators decrease peripheral

resistance and concomitantly activate mechanisms that defend

arterial pressure, notably the sympathetic nervous system, the reninangiotensin-aldosterone system, and sodium retention. Usually,

they are not considered first-line agents but are most effective when

added to a combination that includes a diuretic and a beta blocker.

Hydralazine is a direct vasodilator that has antioxidant and nitric

oxide–enhancing actions. Minoxidil is a particularly potent vasodilator and is used most frequently in patients with renal insufficiency

who are refractory to all other drugs. Hydralazine may induce a

lupus-like syndrome, and side effects of minoxidil include hypertrichosis and pericardial effusion. Intravenous nitroprusside can

be used to treat malignant hypertension and life-threatening left

ventricular heart failure associated with elevated arterial pressure.

COMPARISONS OF ANTIHYPERTENSIVES

Meta-analyses of pooled clinical trials suggest essentially equivalent

blood pressure–lowering effects of the following six major classes

of antihypertensive agents when used as monotherapy: thiazide

diuretics, beta blockers, ACEIs, ARBs, calcium antagonists, and

α1

 blockers. On average, standard doses of most antihypertensive

agents reduce blood pressure by 8–10/4–7 mmHg; however, there

may be subgroup differences in responsiveness. Younger patients

may be more responsive to beta blockers and ACEIs, whereas

patients aged >50 years may be more responsive to diuretics and

calcium antagonists. There is a limited relationship between plasma

renin and blood pressure response. Patients with high-renin hypertension may be more responsive to ACEIs and ARBs than to other

classes of agents, whereas patients with low-renin hypertension are

more responsive to diuretics and calcium antagonists. Hypertensive African Americans tend to have low renin and may require

higher doses of ACEIs and ARBs than whites for optimal blood

pressure control, although this difference is abolished when these

agents are combined with a diuretic. Beta blockers also appear to

be less effective than thiazide diuretics in African Americans than

in non–African Americans. Early pharmacogenetic studies, utilizing a candidate gene approach, genome-wide scans, or integrated

metabolomic and genetic profiles, have shown associations of gene

polymorphisms with blood pressure responsiveness to specific antihypertensive drugs. However, the reported effects have generally

been too small to affect clinical decisions, and associated polymorphisms remain to be confirmed.

A meta-analysis of >30 randomized trials of blood pressure–

lowering therapy indicates that for a given reduction in blood pressure,

with several notable exceptions, the major drug classes produce

similar overall net effects on total cardiovascular events. For example, the Antihypertensive and Lipid-Lowering Treatment to Prevent

Heart Attack Trial (ALLHAT) demonstrated that the occurrence

of fatal CHD and nonfatal myocardial infarction was virtually

identical in hypertensive patients treated with an ACEI (lisinopril),

a diuretic (chlorthalidone), or a calcium antagonist (amlodipine).

However, one arm of ALLHAT involving therapy with a peripherally acting α antagonist (doxazosin) was terminated prematurely

because the incidence of heart failure, stroke, and combined cardiovascular disease events was higher in doxazosin-treated than in

chlorthalidone-treated patients. Increasing evidence suggests that

beta blockers are inferior to other classes of agents for prevention of

cardiovascular events, stroke, renal failure, and all-cause mortality.

Some beta blockers have less effect on central aortic pressure than

other classes of antihypertensive agents. However, beta blockers

remain appropriate therapy for hypertensive patients with concomitant heart disease and related comorbidities. Calcium channel

blockers may be inferior and diuretics superior to other classes of

agents for the prevention of heart failure.

In specific patient groups, ACEIs may have particular advantages,

beyond that of blood pressure control, in reducing cardiovascular

and renal outcomes. ACEIs and ARBs decrease intraglomerular

pressure and proteinuria and may retard the rate of progression of

renal insufficiency, not totally accounted for by their hypotensive

effects, in both diabetic and nondiabetic renal diseases. In patients

with type 2 diabetes, treatment with an ACEI, an ARB, or aliskiren

decreases proteinuria and delays the progression of renal disease.

In experimental models of hypertension and diabetes, renal protection with aliskiren is comparable to that with ACEIs and ARBs.

However, in patients with type 2 diabetes, addition of aliskiren to

an ACEI provides no additional protection against cardiovascular

or renal disease and may be associated with more adverse outcomes.

Among African Americans with hypertension-related renal disease,

ACEIs appear to be more effective than beta blockers or dihydropyridine calcium channel blockers in slowing, although not preventing, the decline of glomerular filtration rate. The renoprotective

effect of these renin-angiotensin blockers, compared with other

antihypertensive drugs, is less obvious at lower blood pressures.

In most patients with hypertension and heart failure due to

systolic and/or diastolic dysfunction, diuretics, ACEIs or ARBs,

and beta blockers improve survival. Independent of blood pressure, in both hypertensive and normotensive individuals, ACEIs

attenuate the development of left ventricular hypertrophy, improve

symptomatology and risk of death from CHF, and reduce morbidity and mortality rates in post–myocardial infarction patients.

Similar benefits in cardiovascular morbidity and mortality rates

in patients with CHF have been observed with the use of ARBs.

ACEIs provide better coronary protection than do calcium channel

blockers, whereas calcium channel blockers provide more stroke

protection than do either ACEIs or beta blockers. Results of a large,

double-blind, prospective clinical trial (Avoiding Cardiovascular

Events through Combination Therapy in Patients Living with Systolic Hypertension [ACCOMPLISH] Trial) indicated that combination treatment with an ACEI (benazepril) plus a calcium antagonist

(amlodipine) was superior to treatment with the ACEI plus a

diuretic (hydrochlorothiazide) in reducing the risk of cardiovascular events and death among high-risk patients with hypertension.

However, the combination of an ACEI and a diuretic has recently

been shown to produce major reductions in morbidity and mortality in the very elderly. After a stroke, combination therapy with

an ACEI and a diuretic, but not with an ARB, has been reported to

reduce the rate of recurrent stroke.

There has been a recent resurgence of interest in two nonpharmacologic antihypertensive therapies that interrupt sympathetic outflow: (1) device-based carotid baroreflex activation by

electrical stimulation of the carotid sinus; and (2) endovascular

radiofrequency ablation of the renal sympathetic nerves. Both

have been suggested as potential options for treatment of resistant

hypertension. Whereas renal denervation is a minimally invasive

procedure, carotid baroreceptor stimulation is a surgical procedure,

usually performed under general anesthesia, that involves implanting electrodes on both the right and left carotid arteries. Clinical

experience with baroreflex activation is limited. Enthusiasm for

renal denervation has been questioned by the results of Simplicity

HTN-3, a randomized, prospective clinical trial comparing bilateral renal denervation with a sham procedure in 535 patients with

resistant hypertension. At the end of 6 months, there was no benefit

of renal artery denervation on both office and ambulatory systolic

blood pressures, the trial’s primary endpoints. Subsequent clinical

trials have demonstrated substantial blood pressure variability in

responses to both of these interventions. It remains to be seen

whether these interventions will be adopted into clinical practice.

BLOOD PRESSURE GOALS OF ANTIHYPERTENSIVE

THERAPY

Based on clinical trial data, the maximum protection against

combined cardiovascular endpoints is achieved with pressures

2086 PART 6 Disorders of the Cardiovascular System

<135–140 mmHg for systolic blood pressure and <80–85 mmHg

for diastolic blood pressure; however, treatment has not reduced

cardiovascular disease risk to the level in nonhypertensive individuals. According to a recent meta-analysis, the magnitude of the proportional reduction of cardiovascular events is broadly consistent

regardless of baseline comorbidity, although the absolute benefit

of blood pressure reduction is greater among individuals with the

highest risk for cardiovascular events.

The degree of benefit derived from antihypertensive agents

is related to the magnitude of the blood pressure reduction. An

intensive blood pressure–lowering strategy is superior to a less

intensive strategy for prevention of stroke and myocardial infarction. For example, the SPRINT trial studied 9361 subjects aged

>50 years at increased risk for cardiovascular events. Intensive blood

pressure control (systolic blood pressure <120 mmHg) reduced the

risk of cardiovascular events and mortality by 25% compared with

less intensive control (systolic blood pressure 135–139 mmHg).

In patients with chronic renal insufficiency, a small, nonprogressive increase in the serum creatinine concentration may occur

with intensive blood pressure lowering. This generally reflects a

hemodynamic response, not structural renal injury, indicating that

intraglomerular pressure has been reduced. Blood pressure control

should not be allowed to deteriorate in order to prevent the modest

creatinine rise.

In diabetic patients, effective blood pressure control reduces

the risk of cardiovascular events and death as well as the risk for

microvascular disease (nephropathy, retinopathy). Various guidelines have been recommended for hypertension control in patients

with type 2 diabetes (e.g., <140/90, <140/85, or <130/80 mmHg).

One widely cited study, the Action to Control Cardiovascular Risk

in Diabetes (ACCORD) clinical trial, failed to find superiority of

intensive blood pressure lowering (<120 mmHg) over standard

blood pressure control (<140 mmHg) in reducing the risk of the

study’s primary outcome (a composite endpoint of myocardial

infarction, stroke, and cardiovascular death) in diabetic patients.

However, that trial did demonstrate a significant reduction of stroke

and left ventricular hypertrophy with more intensive therapy.

Guidelines establishing blood pressure targets for hypertension

control continue to evolve. According to 2017 guidelines developed

by the ACC/AHA, the recommended goal of blood pressure control

for the primary and secondary prevention of cardiovascular disease

is a blood pressure <130/80 mmHg, including patients with diabetes mellitus and chronic kidney diseases (Table 277-8). However,

in hypertensive patients without elevated ASCVD risk, the clinical

trial evidence is strongest for a target blood pressure of 140/90

mmHg. In contrast to other ACC/AHA recommendations that

are based on randomized clinical trials, this guideline is primarily

based on observational studies. Among older patients with isolated

systolic hypertension, further lowering of diastolic blood pressure

does not result in harm. Relatively little information is available

concerning the risk-versus-benefit ratio of intensive antihypertensive therapy in individuals >80 years of age, and in this population,

gradual blood pressure reduction to a less aggressive target level of

control may be appropriate (e.g., 130–150 mmHg). More intensive

control may be associated with a higher incidence of adverse events

(e.g., syncope, electrolyte abnormalities, deterioration of renal function). Additionally, the <130/80 mmHg target blood pressure may

not be acceptable or implementable in low- and middle-income

countries because of the lack of supporting resources. In the final

analysis, all patients need to be carefully monitored, and clinical

decision-making should be individualized.

To achieve recommended blood pressure goals, the majority of

individuals with hypertension will require treatment with more

than one drug. Three or more drugs frequently are needed in

patients with diabetes and renal insufficiency. For most agents,

reduction of blood pressure at half-standard doses is only ~20%

less than at standard doses. Appropriate combinations of agents at

these lower doses may have additive or almost additive effects on

blood pressure with a lower incidence of side effects. Hypertension

control rates are <20% worldwide and <50% in the United States.

These low control rates reflect patient nonadherence and lack of

implementation of recommended guidelines.

The term resistant hypertension refers to patients with blood

pressures persistently >140/90 mmHg despite taking three or more

antihypertensive agents, including a diuretic. Resistant or difficultto-control hypertension is more common in patients aged >60 years

than in younger patients. Resistant hypertension may be related

to nonadherence to therapy, identifiable causes of hypertension

(including obesity, primary aldosteronism, and excessive alcohol

intake), and the use of any of a number of nonprescription and prescription drugs (Table 277-3). Evaluation of patients with resistant

hypertension might include home blood pressure monitoring to

determine if office blood pressures are representative of the usual

blood pressure. A more extensive evaluation for a secondary form

of hypertension should be undertaken if no other explanation for

hypertension resistance becomes apparent. In the absence of a

specific identifiable cause, mineralocorticoid receptor antagonists,

especially spironolactone, have been demonstrated to be the most

effective add-on drugs for the treatment of resistant hypertension. Additionally, resistant hypertension is often associated with

increased sympathetic nervous activity, raising the possibility that

electrical stimulation of the carotid baroreceptor or renal denervation may have a role in the treatment of these patients. However,

that remains to be determined.

HYPERTENSIVE EMERGENCIES

Probably due to the widespread availability of antihypertensive

therapy, in the United States, there has been a decline in the numbers of patients presenting with hypertensive urgencies and emergencies. Severe asymptomatic hypertension (systolic blood pressure

≥180 mmHg or diastolic blood pressure ≥120 mmHg) is considered

a hypertensive “urgency,” but when accompanied by acute target

damage, it is considered a hypertensive “emergency.” Most patients

who present with severe hypertension are chronically hypertensive,

and there are inherent risks to overly aggressive initial antihypertensive therapy. In hypertensive individuals, the upper and lower

limits of autoregulation of cerebral blood flow are shifted to higher

levels of arterial pressure, and rapid lowering of blood pressure to

below the lower limit of autoregulation may precipitate cerebral

ischemia or infarction as a consequence of decreased cerebral blood

flow. Renal and coronary blood flows also may decrease with overly

aggressive acute therapy. Consequently, the rapidity with which

blood pressure should be lowered is dependent on the presence of

new or worsening target organ damage and the presence or absence

of cardiovascular disease complications. In patients with a hypertensive urgency, except for those with acute aortic dissections or

hemorrhagic strokes, blood pressure is generally gradually lowered

over 24 h to ~25% of the initial value. Tables 277-10 and 277-11 list

a number of hypertension-related emergencies and recommended

therapies.

The syndrome of malignant hypertension is an example of a

hypertensive emergency that is associated with an abrupt increase

of blood pressure in a patient with underlying hypertension or

related to the sudden onset of hypertension in a previously normotensive individual. The absolute level of blood pressure is not as

important as its rate of rise. Pathologically, the syndrome is associated with diffuse necrotizing vasculitis, arteriolar thrombi, and

fibrin deposition in arteriolar walls. Fibrinoid necrosis has been

observed in arterioles of kidney, brain, retina, and other organs.

Clinically, the syndrome is recognized by progressive retinopathy (arteriolar spasm, hemorrhages, exudates, and papilledema),

deteriorating renal function with proteinuria, microangiopathic

hemolytic anemia, and encephalopathy. Historic inquiry should

include questions about the use of monoamine oxidase inhibitors

and recreational drugs (e.g., cocaine, amphetamines). In patients

with encephalopathy, the initial goal of therapy is to reduce mean