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 that contain an ACEI with a dihydropyridine CCB or a nondihydropyridine CCB. Cost should be considered because this is a

concern for B.A. Multiple ACEI with thiazide diuretic combinations are available generically, but there is only one generic ACEI

with CCB combination.

Step-Down Therapy

CASE 14-5

QUESTION 1: T.J. is a 58-year-old man with a 10-year

history of hypertension. He has been treated with lisinopril/hydrochlorothiazide 20/25 mg daily and amlodipine 10

mg daily for more than 2 years, and his BP has been well

controlled during this time. His BP at an office visit today

317Essential Hypertension Chapter 14

is 128/74 and 130/72 mm Hg. He has no compelling indications and has no hypertension-associated complications,

but he is a smoker. T.J. also has dyslipidemia, which is well

controlled with simvastatin 40 mg daily. His Framingham

risk score is 15%, and he denies dizziness or difficulties with

his medications. Should T.J.’s antihypertensive therapy be

changed to reduce his medication doses or possibly discontinue some of his medications?

Some patients with hypertension can have their BP medications slowly withdrawn, resulting in normal BP values for weeks

or months after discontinuation of their medications. This is

called step-down therapy. However, it is not a feasible option for

most patients with hypertension. Primary prevention patients

with no additional major CV risk factors who have very wellcontrolled BP for at least 1 year might be eligible for a trial of

step-down therapy. This option should not be considered for

patients with other major CV risk factors, a Framingham risk

score of 10% or more, compelling indications, or hypertensionassociated complications. Step-down therapy consists of attempting to gradually decrease the dosage, the number of antihypertensive drugs, or both without compromising BP control. Abrupt

or large dosage reductions should be avoided because of the risk

of rapid return of uncontrolled BP and even rebound surges in BP

(as is seen with rapid withdrawal of a β-blocker or an α2-agonist).

Step-down therapy is most often plausible for patients who

have lost significant amounts of weight or have drastically

changed their lifestyle. Any attempt at step-down therapy must

be accompanied by scheduled follow-up evaluations because

BP values can rise over the course of months to years after

drug discontinuation, especially if lifestyle modifications are not

maintained. With adherence to lifestyle modifications (weight

loss, reduction in sodium and alcohol), nearly 70% of patients

remained free of antihypertensives for up to 1 year after being

withdrawn from thiazide-based therapy in the Hypertension

Control Program.142

Step-down therapy in T.J. is not an option. Although he does

not have compelling indications or hypertension-associated complications, he has multiple major CV risk factors and an elevated

Framingham risk score that is greater than or equal to 10%.

Angiotensin-Converting

Enzyme Inhibitor

CASE 14-6

QUESTION 1: A.R. is a 49-year-old black woman with type

2 diabetes. She started lisinopril 10 mg daily 2 weeks ago

when her BP values were consistently in the stage 1 hypertension range (150/90 mm Hg). Since then, she has had

weekly BP measurements, and her values have averaged

142/85 mm Hg despite strict adherence to her lifestyle modifications. Her BP today is 144/84 mm Hg (140/88 mm Hg

when repeated), and her heart rate is 78 beats/minute. She

is not a smoker, and her BMI is 29 kg/m2. All her laboratory test results, including kidney function, are within normal limits, except that her spot urine albumin-to-creatinine

ratio is 80 mg/g (2 weeks ago it was 90 mg/g). Is 2 weeks of

lisinopril therapy long enough to assess her antihypertensive response?

Several ACEIs are available (Table 14-12). Most ACEIs are

dosed once daily in hypertension (Table 14-12). In general, most

ACEIs, if used in equivalent doses, are considered interchangeable.

TABLE 14-12

Angiotensin-Converting Enzyme Inhibitors in Hypertension

Usual Starting Usual Dosage Dosing

Drug Dose (mg/d)a Range (mg/d) Frequency

Benazepril 10 20–40 Daily to BID

Captopril 25 50–100 BID to TID

Enalapril 5 10–40 Daily to BID

Fosinopril 10 20–40 Daily

Lisinopril 10 20–40 Daily

Moexipril 7.5 7.5–30 Daily to BID

Perindopril 4 4–16 Daily

Quinapril 10 20–80 Daily to BID

Ramipril 2.5 2.5–20 Daily to BID

Trandolapril 1 2–4 Daily

a Starting dose may be decreased 50% if patient is volume depleted, in acute

heart failure exacerbation, or very elderly (≥75 year).

BID, twice daily; TID, three times daily.

The time to reach steady-state BP conditions is similar to what

is seen with other antihypertensive agents. It may take several

weeks before the full antihypertensive effects of ACEIs are seen.

Therefore, evaluating BP response 2 to 4 weeks after starting

or changing the dose of an ACEI is appropriate. A.R. has been

taking lisinopril for 2 weeks, and her present BP should be used

to determine whether she has attained goal. Both her BP range

during the past few weeks and today’s average BP are above her

goal of less than 130/80 mm Hg (because she has diabetes).

CASE 14-6, QUESTION 2: Why should A.R. have serum

potassium and serum creatinine monitored while on lisinopril therapy?

Serum potassium can increase with ACEI therapy as a

result of aldosterone reduction. Potassium increases with ACEI

monotherapy are small (typically 0.1 to 0.2 mEq/L) and usually

do not cause hyperkalemia. This risk is increased when ACEIs are

used in patients with significant CKD (GFR<60 mL/minute/1.73

m2), or when they are used in combination with other drugs that

can also raise potassium.

ACEI therapy can also cause a small increase in serum creatinine owing to decreased vasoconstriction of the efferent arteriole

in the kidney. This results in a minor decrease in GFR that may

be evidenced by a small increase in serum creatinine. A common mistake is to discontinue an ACEI in response to this rise

in serum creatinine. Increases in serum creatinine of up to 30%

from the baseline creatinine value are safe and anticipated. In

these patients, the ACEI should be continued because a strong

association exists between acute increases in serum creatinine of

up to 30% that stabilize within the first 2 months of ACEI therapy and long-term preservation of renal function.143 Patients

with an increase in serum creatinine of greater than 30% should

have their ACEI therapy temporarily discontinued, as this may

indicate other medical problems. Some of these problems can be

underlying renal disease (such as bilateral renal artery stenosis) or

other situations that may be compromising renal blood flow (e.g.,

volume depletion, concomitant nonsteroidal anti-inflammatory

drug therapy, heart failure). Serum potassium and serum creatinine, in addition to BP, should to be monitored in A.R. within 2

to 4 weeks after starting ACEI therapy or increasing the dose.

CASE 14-6, QUESTION 3: A.R.’s lisinopril dose is increased

to 20 mg daily. Will this doubling of her dose place her at

risk for significant hypotension?

318 Section 2 Cardiac and Vascular Disorders

The very elderly, patients with volume depletion, or patients

with heart failure exacerbation may experience a significant firstdose response to an ACEI. This can manifest as orthostatic

hypotension, dizziness, or syncope. The increased pretreatment

activity of the RAAS, coupled with blockade of this system,

explains this effect. These patients should initiate ACEI therapy

at half the normal dose (Table 14-12), followed by slow titration

to standard doses.

Concurrent diuretic therapy may predispose some patients to

first-dose hypotension. When ACEIs were first approved, dosing

guidelines recommended starting at half the standard dose of the

ACEI, decreasing the dose of the diuretic, or stopping the diuretic

before initiating the ACEI. This was owing to fear that BP would

sharply and acutely drop. These dosing recommendations are

not necessary unless the patient is hemodynamically unstable

(volume depleted, hyponatremic, or poorly compensated heart

failure) or very elderly. A.R. does not have any of these characteristics and can safely increase her dose of lisinopril.

CASE 14-6, QUESTION 4: Is an ACEI an effective therapy in

a black patient such as A.R.?

ACEI monotherapy is generally more effective at lowering

BP in white patients than in black or elderly patients. Elderly and

black patients are more likely to have low renin hypertension,

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