which may partially explain some of the differences in response.

Nevertheless, many of these patients still respond to ACEIs as

monotherapy. Combination therapy, especially with a thiazide

diuretic, usually mitigates this race- and age-related difference in

BP response.

When an antihypertensive agent is being selected as initial

monotherapy in a black patient, an ACEI should generally not

be chosen unless the patient has a compelling indication for

an ACEI. A thiazide diuretic or CCB is otherwise preferred. If

combination therapy is chosen initially, it should be an ACEI

with either a thiazide or a CCB. Of note, black patients have

a twofold to fourfold increased risk of angioedema and cough

with ACEIs compared with white patients.82 This does not preclude ACEI use in black patients unless there is a prior history of

angioedema.

A.R. should not be treated as a primary prevention patient.

She has type 2 diabetes, which is a compelling indication for

an ACEI. She also has microalbuminuria, which further justifies

ACEI use as a first-line therapy. A.R. is also above her goal BP of

less than 130/80 mm Hg. Although an ACEI is ideal treatment,

a monotherapy approach is not expected to get her to goal.

She has had some BP reduction from lisinopril, and the dose

could be increased to the maximum, but she will likely require

the addition of a second agent, preferably a thiazide diuretic

(Fig. 14-3).

COMPELLING INDICATIONS

For all compelling indications, ACEI therapy is recommended as

a drug therapy that has been proven to reduce risk of CV events.

Evidence has clearly demonstrated reduction in hypertensionassociated complications in patients with these medical conditions.

DIABETES

ACEI therapy is first-line for management of hypertension in

diabetes based on evidence showing reduced hypertensionassociated complications, including CV events and kidney

disease.89,91 Multiple clinical trials of ACEIs in patients with diabetes have consistently demonstrated reductions in CV events

and kidney disease progression.69,89,144 These data further reinforce the role of ACEI in patients with diabetes and hypertension,

and also the benefits of combination therapy in this population.

An added benefit of ACEIs in diabetes is that, unlike some

other agents, they are metabolically neutral. Moreover, they may

improve insulin resistance, which can result in a lower risk of

progressing to type 2 diabetes for patients with hypertension

who have impaired fasting glucose.34

CHRONIC KIDNEY DISEASE

The ACEIs protect the kidney from the unrelenting deterioration that occurs with CKD, hypertension, and diabetes. Therefore, these agents are recommended as first-line therapy in CKD.

The increased intraglomerular pressure and mesangial cell proliferation that occurs in CKD leads to proteinuria and a progressive decline in kidney function. Reductions in renal blood

flow cause the kidneys to increase renin release, thus activating

the RAAS. This action constricts the efferent renal arteriole to

preserve glomerular pressure, but may propagate renal impairment. ACEIs preferentially dilate the efferent arteriole, which

relieves intraglomerular pressure. Data suggest that ACEIs may

have unique renal preservation properties, making CKD a compelling indication for ACEI therapy. Some of the risk reduction

is also related to systemic BP lowering.

Patients with diabetes are at high risk for nephropathy, especially those with type 1 diabetes. Evidence indicates that ACEI

therapy reduces progression to severe CKD and kidney failure in

patients with type 1 diabetes and proteinuria.92 In type 2 diabetes,

ACEI therapy has been proven to decrease initial development of

microalbuminuria, and to reduce worsening of proteinuria, but

evidence showing progression to severe CKD or failure is not

available.38,94 Nonetheless, both type 1 and type 2 diabetes are

considered compelling indications for the use of ACEI therapy.

CHRONIC AND ACUTE CORONARY ARTERY DISEASE

ACEI therapy is a first-line treatment in patients with chronic

CAD (post-MI, chronic stable angina) and acute CAD (non–STsegment elevation MI, ST-segment elevation MI).101,103,104 This

should be in addition to β-blocker therapy. The benefit of ACEI

therapy in patients with CAD is a reduced risk of CV events that

is independent of both left ventricular function and BP. Patients

with CAD who have controlled BP still appear to have reductions

in CV events with the addition of ACEI therapy.145 Because ACEI

therapy will not provide anti-ischemic effects, the role of ACEI

therapy in CAD is as an add-on to a β-blocker to reduce CV risk,

not to treat underlying ischemic symptoms.

PRIOR STROKE

The perindopril protection against recurrent stroke study

(PROGRESS) was a double-blind, placebo-controlled evaluation

of an ACEI in combination with a thiazide diuretic for 4 years

in 6,105 patients with a history of stroke or transient ischemic

attack.63 The incidence of stroke and total major vascular events

were significantly reduced with the combination regimen, and

reductions were seen regardless of baseline BP or reduction in

BP. These data justify the compelling indication to use an ACEI

(in combination with a thiazide diuretic) to reduce recurrence of

stroke in patients who have had a stroke.

LEFT VENTRICULAR DYSFUNCTION

ACEIs reduce morbidity and mortality in patients with left ventricular dysfunction as a component of standard therapy (diuretic

with an ACEI followed by the addition of a β-blocker).108 In

general, the CV benefits of ACEI therapy in left ventricular dysfunction are considered a class effect, and ACEIs are used interchangeably at equivalent dosages in these patients (see Chapter

19, Heart Failure).15

319Essential Hypertension Chapter 14

CASE 14-6, QUESTION 5: A.R. has microalbuminuria, and

lisinopril may help preserve kidney function. However, is

there a risk that lisinopril can cause acute renal dysfunction?

The ACEIs are effective in patients with hypertensionassociated renal disease. They are contraindicated, however, in

several situations, including bilateral renal artery stenosis, pregnancy, and volume depletion (Table 14-10). In the case of bilateral renal artery stenosis or volume depletion, high angiotensin

concentrations maintain renal blood flow, and acute renal dysfunction can occur when an ACEI is started. Because it is often

not known whether a patient has bilateral renal artery stenosis,

problems with ACEI can be minimized by starting with recommended doses and careful monitoring of serum creatinine within

2 to 4 weeks of starting therapy. Modest elevations in serum

creatinine that are less than 30% (for baseline creatinine values

<3.0 mg/dL) do not warrant adjustment in therapy.143 If greater

increases occur, ACEI therapy should be stopped, and further

medical evaluation should occur. Patients with elevated serum

creatinine at baseline (up to 3.0 mg/dL) may particularly benefit

from the vasodilatory effects of ACEIs in the kidney, but require

careful drug initiation and close monitoring. A.R.’s serum creatinine was normal after 4 weeks of lisinopril therapy. She is not

experiencing any kidney-related adverse effects from lisinopril.

CASE 14-6, QUESTION 6: What are the risks of using ACEIs

in women of childbearing age?

Because ACEIs are teratogenic in the second and third

trimester,146 their use in pregnancy is contraindicated. Moreover,

their use in women of childbearing potential is discouraged. If

used in this population, patient education should be explicitly

clear regarding risks to the fetus, which include potentially fatal

hypotension, anuria, renal failure, and developmental deformities. A highly effective form of contraception should be strongly

recommended.

Angiotensin Receptor Blockers

CASE 14-6, QUESTION 7: A.R.’s lisinopril is increased to 20

mg daily, then to 40 mg daily during a period of 8 weeks. Her

current BP is 136/78 mm Hg (134/76 mm Hg when repeated)

at an office visit today. Her serum potassium and creatinine

are unchanged from previous values. However, she reports

a persistent dry cough for the past few months. She has no

additional signs suggesting upper respiratory infection or

left ventricular dysfunction. How should A.R.’s therapy be

modified?

A well-known side effect of ACEIs is a nonproductive, dry

cough, which can occur in up to 15% of patients, with some estimates of cough prevalence being higher.147 Patients may describe

this as a tickling sensation in the back of the throat that commonly

occurs late in the evening. This is distinctly different from the

cough associated with left ventricular dysfunction, which might

be associated with crackles and rales (on auscultation) indicating

possible pulmonary edema. ACEI-related cough resolves with

discontinuation. Many agents have been used to treat an ACEI

cough with poor results. The best treatment option for a patient

with an intolerable ACEI cough is to switch agents. For A.R.,

switching to an ARB would likely eliminate the cough and is an

acceptable first-line treatment option for her considering her diabetes and microalbuminuria.89,91 A.R. will also require the addition of a second agent, either a CCB or thiazide diuretic, because

she has not achieved her goal BP of less than 130/80 mm Hg.

TABLE 14-13

Angiotensin Receptor Blockers in Hypertension

Drug

Starting

Dose

(mg/d)a

Usual

Dosage

Range

(mg/d)

Dosing

Frequency

Azilsartan medoxomil 80 80 Daily

Candesartan cilexetil 16 8–32 Daily to BID

Eprosartan mesylate 600 600–800 Daily to BID

Irbesartan 150 75–300 Daily

Losartan potassium 50 25–100 Daily to BID

Olmesartan medoxomil 20 20–40 Daily

Telmisartan 40 20–80 Daily

Valsartan 80–160 80–320 Daily

a Starting dose may be decreased 50% if patient is volume depleted, very elderly,

or taking a diuretic.

BID, twice daily.

ARBs are first-line options for primary prevention patients and

have data demonstrating reductions in CV events.32,59 There

are eight ARBs (Table 14-13), and many are available as twodrug fixed-dose combination products (Online Table 14-1), as

well as two different three-drug fixed-dose combination products (Online Table 14-2).

PHARMACOLOGIC DIFFERENCES BETWEEN AN

ANGIOTENSIN-CONVERTING ENZYME INHIBITOR

AND AN ANGIOTENSIN RECEPTOR BLOCKER

CASE 14-6, QUESTION 8: How is an ARB different from an

ACEI?

Unlike ACEIs, ARBs specifically bind to angiotensin II receptors in vascular smooth muscle, adrenal glands, and other tissues. Access of angiotensin II to its receptors is blocked, and

angiotensin I–mediated vasoconstriction and aldosterone release

is prevented, resulting in BP reduction. ARBs do not affect

bradykinin; therefore dry cough does not occur.

Considerable investigation has focused on describing the pharmacologic differences between the angiotensin II type 1 and

type 2 receptors. Stimulation of the type 1 receptor causes vasoconstriction, salt and water retention, and vascular remodeling.

Other deleterious effects from type 1 receptor stimulation include

myocyte and smooth muscle hypertrophy, fibroblast hyperplasia, cytotoxic effects in the myocardium, altered gene expression,

and possible increased concentrations of plasminogen activator

inhibitor. Stimulation of the type 2 receptor results in antiproliferative actions, cell differentiation, and tissue repair.

Theoretically, an ideal antihypertensive agent would block

only type 1 and not type 2 receptors as is the case with

ARBs. Therefore, it is possible that an ARB would be superior

to an ACEI in reducing hypertension-associated complications

because ACEIs ultimately decrease stimulation of both type 1

and type 2 receptors by decreasing production of angiotensin

II. This argument is purely speculative and is not supported by

clinical trial data. ONTARGET was a prospective, double-blind,

randomized controlled trial that directly compared ARB-based

therapy, ACEI-based therapy, and the combination of an ACEI

with ARB.121 After a median of 56 months, the incidence of CV

events was no different among all three treatment groups. Therefore, ARB therapy is as effective as, but no more superior than,

ACEI therapy in the overall management of hypertension.

320 Section 2 Cardiac and Vascular Disorders

COMPELLING INDICATIONS

CASE 14-6, QUESTION 9: Under what circumstances would

an ARB be a more appropriate initial antihypertensive agent

than an ACEI?

DIABETES

Patients with diabetes should be treated with either an ACEI

or ARB. ARB-based treatment regimens, similar to ACEI-based

treatment regimens, have been shown in clinical trials to reduce

the progression of diabetic nephropathy among patients with

type 2 diabetes and microalbuminuria.89 ARB-based therapy is

the only antihypertensive regimen for which evidence shows

reduced kidney failure in patients with type 2 diabetes who have

diabetic nephropathy with albuminuria (not microalbuminuria)

and elevated serum creatinine.73 Therefore, for patients with

type 2 diabetes and advanced nephropathy, evidence supports

ARB therapy, although ACEI therapy has not been studied in

this population.

CHRONIC KIDNEY DISEASE

An ARB, similar to an ACEI, minimizes damage that occurs with

CKD. Both ACEIs and ARBs preferentially dilate the efferent

arteriole, which relieves intraglomerular pressure. Thus, CKD is

a compelling indication for ARB therapy. For nondiabetic kidney

disease, less evidence supports ARB use, and these agents should

be reserved as alternatives to an ACEI.

CHRONIC AND ACUTE CORONARY ARTERY DISEASE

Angiotensin receptor blocker therapy is a reasonable alternative

to ACEI therapy in patients with CAD although data are limited.

PRIOR STROKE

The role of ARB therapy in patients with a history of stroke is controversial. In the Morbidity and Mortality after Stroke Eprosartan

Compared with Nitrendipine for Secondary Prevention study,

ARB-based therapy reduced the incidence of recurrent stroke

more than dihydropyridine CCB-based therapy in a large number

of patients with cerebrovascular disease.80 However, in the Prevention Regimen for Effectively Avoiding Second Strokes study

20,332 patients who recently had an ischemic stroke were randomly assigned to ARB therapy or placebo.107 After a mean of

2.5 years, there was no difference in the incidence of the primary end point of recurrent stroke between the two groups.

Therefore, it is unclear how well ARB therapy would work as

an alternative to ACEI therapy in patients with a history of

stroke.

LEFT VENTRICULAR DYSFUNCTION

Pharmacologic blockade of the RAAS in left ventricular dysfunction is of paramount importance. An ARB is a reasonable alternative in patients with hypertension and left ventricular dysfunction who cannot tolerate an ACEI (e.g., those who experience

cough).109 As sequential add-on therapy for patients with left ventricular dysfunction who are already treated with the standard

regimen of a diuretic with an ACEI and β-blocker, ARB therapy

has been proved to reduce risk of CV events.122 However, the

benefits are limited primarily to decreasing risk of heart failure

hospitalizations. This is not similar to the reduction in mortality

seen when adding an aldosterone antagonist. Aldosterone antagonists would be preferred over ARBs when considering sequential add-on therapy. Additionally, if an ARB is used with an ACEI,

there is a significant increase in risk of side effects.121

CASE 14-6, QUESTION 10: If A.R. experienced angioedema

from lisinopril, would treatment with an ARB be appropriate?

A history of ACEI-induced angioedema does not preclude the

use of ARB therapy. The cross-reactivity between angioedema

with an ACEI and ARB is not exactly known. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and

Morbidity Alternative study prospectively included patients with

a history of ACEI intolerance who were randomly assigned, in

a double-blind manner, to placebo or candesartan. Of the 2,028

patients enrolled, 39 had a history of ACEI angioedema, and only

1 of these patients experienced repeat angioedema that required

discontinuation of the ARB.109 In the Telmisartan Randomised

Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease trial, 5,926 patients with a history of ACEI intolerance

were randomly assigned in this double-blind trial to an ARB or

placebo for a median duration of 56 months.148 A total of 75

patients had a history of ACEI angioedema, and none of those

patients who were randomly assigned to the ARB treatment

arm experienced repeat angioedema. Therefore, cross-reactivity

in angioedema between ACEIs and ARBs appears possible, but

unlikely and very small. ARBs are an alternative for patients who

experience ACEI angioedema but should be reserved for patients

with a compelling indication for an ACEI. Of note, the ACC/AHA

guidelines recommend an ARB in patients who have experienced

angioedema from an ACEI.108

Calcium-Channel Blockers