TRIPASS XR تري باس

 

143

Mortality, evaluated separately, was 4.2%, 3.3%, and 2.9%, for low (2.5 mg BID),

moderate (5 mg BID), and higher (10 mg BID) dosages respectively, and not

significantly different. The guidelines recommend prescribing doses that have

reduced the risk of CV events in clinical trials and if trial doses cannot be achieved,

then lower doses should be used.

For lisinopril, the recommended starting dosage is 2.5 to 5 mg/day. For older

patients or those with other risk factors (systolic BP <100 mm Hg, those taking large

doses of diuretics, or those with preexisting hyponatremia, hyperkalemia, or renal

insufficiency), the starting dose of 2.5 mg/day would be more appropriate. This dose,

or an equivalent with one of the other drugs, should be considered if the patient is

being started directly on a long-acting drug without prior titration on captopril. For a

patient such as A.J. who has already been treated with captopril for 2 days with no

evidence of intolerance, a 10-mg dose is appropriate.

The long-term target dosage of lisinopril for A.J. is 40 mg daily. No clear formula

exists for deciding how quickly to titrate to this dose. It depends on the degree of

reduction in his HF symptoms and side effects, and motivation to take the medication.

Whenever dosage adjustments are made, it may take as few as 24 hours for the

patient to perceive symptom reduction, but generally full hemodynamic affects are not

reached for 1 to 2 months. Hypotension and other side effects are more immediate.

A.J. should have his dose reassessed in 1 to 2 weeks to determine whether he can

tolerate a dosage increase to 20 mg daily. A SCr and potassium should be ordered at

this time to assess the safety of titrating the ACEI. Thereafter, a doubling of the dose

could occur every 2 to 4 weeks. Thus, it could take 2 months to titrate upward to 40

mg daily. If A.J.’s symptoms do not improve, but he has no side effects, titration can

occur more quickly either by shortening the assessment periods (e.g., every week) or

by using larger dose increments.

ANGIOTENSIN RECEPTOR BLOCKERS

CASE 14-1, QUESTION 14: When should an ARB be used in A.J.?

Several clinical trials in HF have shown the therapeutic benefit of ARBs in

modifying HF symptoms (Table 14-9).

144–151 A meta-analysis combined data on allcause mortality and HF-related hospitalizations from a total of 17 clinical trials

comparing an ARB with either placebo or an ACEI in patients with HF.

143 ARBs

favorably improved exercise tolerance and EF compared with placebo. However,

they were not superior to ACEIs in reducing all-cause mortality or hospitalizations

for HF.

The first major clinical trial comparing an ARB with an ACEI in patients with HF

was the Evaluation of Losartan in the Elderly (ELITE) study.

150 Losartan was

compared to captopril. For the primary end point, a sustained increase in renal

function decline, the two drugs performed identically with 10.5% of subjects in each

group having a greater than 0.3 mg/dL rise in SCr. An unexpected finding was an

insignificant trend toward more deaths from all causes in the captopril group (8.7%)

compared with losartan (4.8%).

The follow-up ELITE II Trial was specifically designed to test the hypothesis that

losartan was superior to captopril in terms of reduction in mortality and morbidity in

patients 60 years of age or older.

148 No significant difference was seen in all-cause

mortality, sudden death, or all-cause mortality plus hospitalization. Although ARB

treatment was not superior to ACEI therapy, it was better tolerated. Specifically,

significantly fewer patients experienced cough with the ARB.

The Valsartan Heart Failure Trial (Val-HeFT) was a double-blind, placebocontrolled study to measure the morbidity and mortality HFrEF patients given

valsartan.

152 Patients were randomly assigned to receive valsartan or placebo twice

daily. There was no significant difference in all-cause mortality between the

valsartan group (19.7%) and the control group (19.4%). Nearly 93% of patients in

both groups were receiving an ACEI. Dizziness, hypotension, and renal impairment

all occurred more frequently in those treated with valsartan.

Further post hoc analysis found that within the 35% of subjects taking the

combination of an ACEI and a β-blocker at baseline, the addition of valsartan as a

third drug was associated with a trend toward increased morbidity and a statistically

significant increase in the combined end point of mortality and morbidity. The

overall study results suggested that a combination of valsartan and an ACEI reduces

morbidity, but not mortality. More worrisome was the implication that the three-drug

combination of valsartan, an ACEI, and a β-blocker adversely affects morbidity and

mortality.

155

The Valsartan in Acute Myocardial Infarction Trial (VALIANT) of stable patients

after MI with LV dysfunction was designed to test the hypothesis that valsartan alone

and in combination with captopril (ACEI) would improve survival. In VALIANT,

70% of the patients were also receiving β-blockers. All-cause mortality, the primary

end point, was identical in all groups. In addition, an increased rate of side effects

was seen in the combination ACEI/ARB group. Interestingly, among the subgroup of

patients taking β-blockers, no evidence was found of harmful interaction with triple

therapy.

153 As a result of the VALIANT trial, the FDA approved the use of valsartan

in patients at high risk after a heart attack, and in those with HF.

p. 282

p. 283

Table 14-9

Clinical Trials of Angiotensin Receptor Blockers in Heart Failure

Trial Patient Population ARB

Treatment

Duration Outcome

ELITE

149 NYHA II–IV (n =

722)

EF ≤40%

Losartan (50 mg

every day) or

captopril (50 mg

TID)

48 weeks No significant

difference observed

for the primary end

point (persistent

renal dysfunction) or

the secondary end

point (composite of

death/HF

admissions).

Losartan was

associated with a

lower mortality than

captopril.

RESOLVD

151 NYHA II–IV (n =

768)

EF ≤40%

Candesartan (4, 8 or

16 mg), or

candesartan (4 mg

or 8 mg) + 20 mg

enalapril, or 20 mg

enalapril

43 weeks Combination has

greater benefits on

LV remodeling. No

difference in

mortality.

No difference in

NYHA class, QoL,

6-minute walking

distance.

ELITEII

150 NYHA II–IV (n =

3,152)

EF ≤40%

Losartan (50 mg

every day) or

captopril (50 mg

TID)

48 weeks Losartan was not

superior to captopril

in improving survival,

but was significantly

better tolerated. A

subgroup analysis of

ELITE II found a

greater risk of death

when losartan was

used in addition to βblockers.

Val-Heft

152 NYHA II–IV (n =

5,010)

EF <40%

Valsartan 160 mg

BID or placebo BID

23 months There was no

difference in

mortality between

the two groups. In

patients previously

receiving both ACEI

and a β-blocker (n =

1,610), the risk of

death was increased

with the addition of

valsartan.

CHARM154

Alternative

NYHA II–IV (n =

2,028)

EF ≤40%

Candesartan (32 mg)

vs. placebo

34 months 23% reduction in

CV mortality or HF

hospitalization

favoring the

candesartan group.

More side effects in

the candesartan

group (hypotension,

hyperkalemia, ↑

SCr) vs. placebo.

CHARM155

Added

NYHA II–IV (n =

2,548)

EF ≤40%

Candesartan (32 mg)

+ ACEI vs. placebo

41 months 15% risk reduction

in CV mortality or

HF admissions

compared with

placebo. However,

there were more

side effects in the

candesartan group

(hypotension,

hyperkalemia, ↑

SCr) vs. placebo.

CHARM157

Overall

NYHA II–IV (n =

7,599)

Candesartan (32 mg)

vs. placebo

38 months There was no

overall difference in

primary outcome of

all-cause death.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BID, 2 times a day; CV,

cardiovascular; EF, ejection fraction; HF, heart failure; LV, left ventricular; NYHA, New York Heart Association;

QoL, quality of life; SCr, serum creatinine; TID, three times a day.

The best evidence addressing the efficacy and safety of ARB in HF comes from a

series of three investigations known collectively as the Candesartan in Heart Failure

Assessment of Reduction in Morbidity and Mortality (CHARM) trial. The individual

components of the CHARM Program are (a) CHARM-Alternative, (b) CHARMAdded, and (c) CHARM-Preserved.

154–156 All three investigations were randomized,

double-blind, placebo-controlled trials that enrolled adult patients (>18 years of age)

with at least a 4-week history of symptomatic (NYHA class II–IV) HF. Subjects

randomly assigned to candesartan were started on 4 mg and titrated to 32 mg once

daily, as tolerated. Some standard therapy (diuretics, β-blockers, digoxin,

spironolactone, and ACEI) was continued. For all three trials, the primary end point

was the combined incidence of CV death, HF hospitalizations, or both. The

differences in admission criteria and outcomes among the individual trials are

discussed below.

CHARM-Alternative enrolled 2,028 subjects who met all of the inclusion criteria

defined above plus two additional criteria: an EF of 40% or less and intolerance of

ACEIs (cough, 72%; hypotension, 13%; renal dysfunction, 12%). Thus, subjects in

this group received either an ARB alone or placebo without an ACEI. A 23%

reduction was found in the primary outcome of CV death, hospital admission for HF,

or both in the candesartan group compared with placebo. The overall incidence of

drug discontinuations because of adverse events was not statistically different

between candesartan and placebo, but there were significantly more reports of

symptomatic hypotension, increased creatinine levels, and hyperkalemia in those

treated with candesartan (Table 14-10).

The CHARM-Added trial attempted to determine whether the combination of an

ACEI plus an ARB offered any clinical advantages compared with an ACEI alone in

patients with symptomatic HF with an EF of 40% or less. At baseline, 55% of the

patients were treated with β-blockers and 17% with spironolactone. The addition of

candesartan to an ACEI and other usual HF treatments led to a 15% relative risk (p =

0.011) reduction in the primary outcome of CV death, hospital admission for HF in

the combination group compared to the ACEI-alone group. It is interesting to

compare the result of the CHARM-Added trial with those of the Val-HeFT study. In

Val-HeFT, 93% of the subjects receiving the ARB valsartan were concurrently

receiving an ACEI. The combined end point of morbidity and mortality was

significantly reduced with combination therapy in Val-HeFT, but mortality alone was

not reduced. A trend toward more deaths in the small subgroup receiving the triple

combination of a β-blocker with an ACEI and ARB was observed, whereas βblocker use had no adverse effect in CHARM-Added.

p. 283

p. 284

Table 14-10

Adverse Events that Lead to Permanent Drug Discontinuation

Trial Outcomes Candesartan (%) Placebo (%) p Value

CHARMAlternative

152

Any adverse event

or laboratory

abnormality

21.5 19.3 0.23

Hypotension 3.7 0.9 <0.0001

Increased creatinine 6.1 2.7 <0.0001

Hyperkalemia 1.9 0.3 0.0005

CHARM-Added

153 Any adverse event

or laboratory

abnormality

0.0003

Hypotension 4.5 3.5 0.079

Increased creatinine 7.8 4.1 0.0001

Hyperkalemia 3.4 0.7 <0.0001

CHARMPreserved

154

Any adverse event

or laboratory

abnormality

17.8 13.5 0.001

Hypotension 2.4 1.1 0.006

Increased creatinine 4.8 2.4 <0.001

Hyperkalemia 1.5 0.6 0.019

CHARM-Overall

155 Any adverse event

or laboratory

abnormality

21 16.7 <0.001

Hypotension 3.5 1.7 <0.0001

Increased creatinine 6.2 3.0 <0.0001

Hyperkalemia 2.2 0.6 <0.0001

The combined results of all three CHARM components (CHARM-Added,

CHARM-Alternative, and CHARM-Preserved; see discussion of CHARMPreserved in Case 14-7, Question 1) were reported in the CHARM-Overall trial.

157

This composite analysis evaluates the benefits of candesartan in symptomatic patients

with HF, regardless of LV systolic function. A different primary end point was

chosen for the CHARM-Overall analysis: all-cause death. Although the combined

results failed to detect a clinically significant reduction in all-cause death between

candesartan and placebo (9% reduction; p = 0.32), significant reductions were seen

in CV death (12%), hospital admission for HF (21%), and combined CV death or

hospital admission for HF (16%), which was the primary end point for the individual

trials.

The collective results of the CHARM program reinforce the conclusion that ARBs

can reduce morbidity and mortality in symptomatic patients with HFrEF, and they can

be safely used in patients who are intolerant of ACEI therapy. Combination therapy

(ACEI plus ARB) with concomitant use of β-blockers appears to be beneficial and

safe, as long as patients are closely monitored for adverse effects. Current guidelines

recommend addition of an aldosterone antagonist over ARB in patients receiving an

ACEI and β-blockers.

Because ELITE II failed to demonstrate any survival benefits of losartan 50

mg/day, over captopril 150 mg/day in HFrEF patients, the “Effects of high-dose

versus low-dose losartan on clinical outcomes in patients with heart failure”

(HEAAL) study was designed to compare the effect of two doses of losartan (50 mg

daily versus 150 mg daily) on the combined end point of all-cause mortality and

hospitalizations in HFrEF. A median follow-up of 4.7 years showed losartan 150 mg

daily reduced the rate of death or HF admission when compared with losartan 50 mg

daily. The high-dose group experienced more renal dysfunction, hypotension, and

hyperkalemia, although these results did not lead to significantly more treatment

discontinuations. Old age, concomitant aldosterone antagonist dose, and baseline

levels of potassium and SCr were common predictors of adverse events and resulted

in increased mortality among patients who experienced these adverse events.

Therefore, dose titrations should be done with close monitoring especially in

individuals at high risk of developing adverse events.

158

In summary, ARB HF trials demonstrate survival benefits in HFrEF in ACEI–

intolerant patients or as an add-on therapy to ACEIs and β-blockers. However,

current guidelines do not recommend the routine use of triple therapy, and A.J. should

not be started on an ARB in addition to his lisinopril. If A.J. develops a cough on

lisinopril, he can be switched to an ARB such as candesartan.

Side Effects

ANGIOTENSIN-CONVERTING ENZYME INHIBITOR–INDUCED COUGH

CASE 14-1, QUESTION 15: A.J. presents to the outpatient HF clinic with an annoying productive cough

after 6 weeks of lisinopril therapy. His chest examination reveals no evidence of wheezing, with only a few

crackles, his neck veins are only minimally elevated over normal, his ankle edema is 1+, and his weight is stable.

All laboratory values are normal. Could the cough be a symptom of his HF or is it ACEI–induced? What are

the recommendations for managing an ACEI–induced cough?

Cough can be a sign of HF in patients with pulmonary congestion. In extreme

cases, patients have “cardiac asthma” with severe air hunger, wheezing, and dyspnea.

However, A.J.’s HF is much improved as evidenced by the objective data. The

absence of wheezing and no prior history of asthma or smoking make an obstructive

airways disease (asthma or chronic obstructive pulmonary disease) unlikely. It is

possible that he does have bronchitis, but he does not report having a cold or other

respiratory illness

p. 284

p. 285

preceding the cough. Without other causes, an ACEI–induced cough is most likely.

This side effect occurs with all ACEIs.

159 Cough is a well-established

complication of ACEIs and presents as dry and nonproductive; sometimes described

as a “tickle in the back of the throat.” This complication can arise within hours of the

first dose, or it can present after weeks to months of treatment. Although resolution of

the cough usually occurs within 1 to 4 weeks, in some patients it can persist up to 3

months after discontinuation of therapy.

Bradykinin accumulation within the upper airway and decreased metabolism of

pro-inflammatory mediators such as substance P or prostaglandins are proposed

mechanisms of ACEI–induced cough. These chemicals then act as irritant substances

in the airways to increase bronchial reactivity and induce coughing.

Various case reports have found an incidence of cough in 5% to 35% of all

patients. The incidence is dose-independent.

160 One investigator found a 5% to 10%

incidence in white patients of European descent that rose to nearly 50% in Chinese

patients.

161 There may also be a higher incidence in women and black populations.

158

Because this is a pharmacologic effect rather than an allergic reaction, dose

reduction or switching from one ACEI to another is generally not helpful. The only

way to definitively diagnose the drug-induced cough is to discontinue therapy. Even

then, false-positive results can occur if the patient had a mild case of bronchitis that

spontaneously resolved at about the same time that the ACEI was discontinued. If the

cough persists after drug discontinuation, other causes should be investigated such as

coexisting gastroesophageal reflux disease or allergic rhinitis.

For patients with persistent cough, ARB or hydralazine–isosorbide are safe

alternatives. Therefore, A.J. can continue taking lisinopril for another couple of

weeks to determine whether the cough will resolve on its own. His symptoms of HF

have abated since the initiation of ACEI therapy, and the cough may be no more than

an annoyance. He is not at risk of experiencing asthma or other airway problems. If

his cough persists, an ARB is probably the best alternative.

OTHER ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AND

ANGIOTENSIN RECEPTOR BLOCKER SIDE EFFECTS

Hyperkalemia

CASE 14-1, QUESTION 16: What other side effects of both ACEIs and ARBs need to be monitored? Does

changing from an ACEI to an ARB reduce the risk of any of these side effects?

The ACEIs, and ARBs, have the potential to raise serum potassium concentrations

via indirect aldosterone inhibition and other neurohormonal actions.

162,163 For most

patients, the magnitude of increase in serum potassium concentration fromACEIs and

ARBs alone is relatively small, but the risk of developing hyperkalemia is greater if

the patient has compromised renal function or advanced HF. Combination therapy of

an ACE or ARB with potassium supplements, or potassium-sparing diuretics, further

accentuates the risk of hyperkalemia.

Several case reports and case series have reported hyperkalemia and

hospitalizations secondary to spironolactone in patients with HF. This became more

evident as prescribing patterns for spironolactone dramatically increased after

publication of the RALES study.

164 Not only was there a significant increase in the

number of prescriptions for spironolactone for patients with HF, but doses higher

than those recommended by the clinical trials were often used, especially in patients

with evidence of preexisting renal dysfunction. In addition, evidence indicated

inadequate monitoring of serum potassium, renal function, and concomitant drug

therapy. Although concurrent use of a potassium-wasting diuretic (thiazide or loop

diuretic) may counteract potassium retention from spironolactone or other drugs

(ACEIs, ARB), it is nearly impossible to predict who will exhibit hypokalemia,

hyperkalemia, or remain normokalemic.

165,166 Each patient must be assessed

individually for personal response to various drug combinations. Close monitoring of

serum potassium is required; potassium levels and renal function should be checked

in 3 days and at 1 week after initiation of therapy known to affect potassium and at

least monthly for the first 3 months (Table 14-11).

Angioedema

Angioedema (angioneurotic edema) is a severe, potentially life-threatening

complication of ACEI treatment.

167–169 Characterized by facial and neck swelling,

with obstruction to air flow by laryngeal and bronchial edema, this reaction

resembles anaphylaxis. The mechanism of ACEI induction of angioedema is

unknown, but is thought to be hypersensitivity to accumulated vasodilating kinins.

Some, but not all, persons with drug-induced angioedema have a history of

familial angioedema associated with a genetic defect in their complement system.

ACEIs are contraindicated in this population. In one series of case reports, 22% of

the reported angioedema reactions occurred within 1 month of starting therapy, with

the remaining 77% arising from several months to years later.

168 Black patients and

women may have a higher prevalence. Of concern is the observation that ACEI–

induced angioedema is often misdiagnosed.

169

It is prudent to avoid all ACEIs in any

patient with a history of angioedema from any cause.

Because the mechanism of ACEI–induced angioedema is thought to be caused by

kinin accumulation, changing to an ARB might be an option.

170 Several case reports,

however, have implicated candesartan, losartan, and valsartan as possible causative

agents of angioedema.

167,171–174

In some cases, the subjects had previously

experienced angioedema with an ACEI (indicating possible cross-reactivity),

whereas others were ACEI–naïve. A small but potential risk for ARB-induced

angioedema in patients who are ACEI–intolerant comes from the CHARMAlternative trial.

154 Of 39 patients with a history of angioedema while taking an

ACEI, three experienced angioedema on candesartan, although only one of the three

actually discontinued taking candesartan. For now, it is prudent to assess risk–

benefit, and ARBs should be used cautiously in the management of patients who have

angioedema from ACEIs.

Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor

Blockers on Kidney Function

As seen in Figure 14-7, glomerular filtration is optimal when intraglomerular

pressure is normal. The balance between afferent flow into the glomerulus and

efferent flow exiting the glomerulus determines the intraglomerular pressure. A drop

in afferent flow or pressure occurring as a result of hypotension, volume loss,

hypoalbuminemia, decreased CO, or obstructive lesions such as renal artery stenosis

can significantly lower intraglomerular pressure and lead to impaired renal function.

Similarly, long-standing HTN can damage glomerular basement membrane

capillaries and cause renal insufficiency.

In the case of low-pressure or low-flow states, the RAAS is activated to maintain

intraglomerular pressure. A key factor in preserving glomerular pressure is efferent

vasoconstriction mediated by angiotensin II. Increased efferent pressure helps to

maintain intraglomerular pressure by impeding blood flow out of the glomerulus.

When patients with low-pressure states are given ACEIs or ARBs, the protective

mechanism of efferent vasoconstriction is inhibited and GFR decreases to a modest

degree, resulting in an increase in SCr.

p. 285

p. 286

Table 14-11

Various Causes of Hyperkalemia and Strategies to Minimize Risk

Cause Mechanism Strategies to Minimize Risk

Aldosterone blockers Decreased levels of aldosterone

and subsequent potassium retention.

GFR should be determined and

aldosterone antagonist should be

avoided if creatinine clearance is

<30 mL/minute and baseline serum

potassium is >5.0 mEq/L.

An initial dose of spironolactone 12.5

mg or eplerenone 25 mg is

recommended, after which the dose

may be increased to spironolactone

25 mg or eplerenone 50 mg if

appropriate.

Close monitoring of serum potassium

is required; potassium levels and

renal function should be checked in 3

days and at 1 week after initiation of

therapy and at least monthly for the

first 3 months.

RAAS blockade by ACE inhibitors

and ARBs

Note: risk increases at higher doses

(enalapril or lisinopril ≥10 mg/day)

Inhibition of angiotensin II

production or receptor binding

reduces the delivery of sodium and

water to the distal nephron, which,

in combination with

hypoaldosteronism, promotes

Doses of drugs should be decreased

as appropriate.

hyperkalemia.

NSAIDs Inhibit renal prostaglandin synthesis

(PGE2

and PGI2

), resulting in

hyporeninemic hypoaldosteronism.

Decreased availability of sodium for

exchange with potassium at distal

tubular sites.

NSAIDs and cyclooxygenase-2

inhibitors should be avoided.

Potassium-sparing diuretics,

cyclosporine, tacrolimus,

trimethoprim, and heparin

Decreased excretion of potassium. Close monitoring of serum potassium

is required.

Doses of drugs known to cause

hyperkalemia should be decreased

as appropriate.

Patients who have increased dietary

potassium intake, use salt

substitutes (a rich source of

potassium), or take potassium

supplements in combination with

aldosterone antagonists

In the presence of renal

insufficiency, decreased potassium

excretion occurs.

Potassium supplements should be

discontinued or reduced.

Patients should be educated on foods

rich in potassium and to avoid salt

substitutes.

HF patients with diabetes taking

aldosterone antagonists

Hyporeninemic hypoaldosteronism

leading to decreased levels of

aldosterone and subsequent

potassium retention.

Insulin deficiency can stimulate the

shift of potassium to the

extracellular space.

Hyperglycemia should be monitored

and appropriate drug therapy should

be determined to treat diabetes.

Advanced age, low muscle mass, or

renal insufficiency (serum

creatinine >1.6 mg/dL)

Impaired release of renin resulting

in hypoaldosteronism.

SCr may not accurately reflect

GFR.

Risk of hyperkalemia increases

progressively as SCr rises.

GFR should be determined and

doses adjusted accordingly.

ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; GFR, glomerular filtration rate; HF,

heart failure; NSAIDs, nonsteroidal antiinflammatory drugs; PGE2

, prostaglandin E2

; PGI2

, prostaglandin I2

;

RAAS, renin–angiotensin–aldosterone system.

By decreasing afterload, CO may improve after ACEI or ARB therapy, thus

preserving or even enhancing RBF. If, however, starting ACEIs or ARB leads to a

rapid decrease in systemic BP that is not followed by an increase in CO, worsening

renal function may ensue. It is impossible to predict which event will occur.

Therefore, ACEI or ARB therapy needs to be started with low doses, and careful

monitoring of the BP and renal function should occur as dosages are increased. Renal

function and BP should be checked before and 1 to 2 weeks after initiation or dose

increase. Patients with risk factors such as preexisting renal insufficiency or

concomitant treatment with NSAIDs or high-dose diuretics may require more

frequent monitoring. Diuretics are not contraindicated, but the diuretic dosage may

need to be reduced to avoid overly aggressive diuresis and the accompanying volume

depletion and hypotension. The guidelines recommend caution when prescribing

ACEIs/ARBs in patients who have low systolic BPs (80 mm Hg), increased SCr (>3

mg/dL), bilateral renal artery stenosis, or serum potassium >5.0 mEq/L.

1

p. 286

p. 287

Figure 14-7 Factors affecting renal blood flow. Glomerular filtration is optimal when adequate hydrostatic

pressure is maintained in the glomerulus. Governing factors include the blood flow rate to the glomerulus and the

balance of afferent and efferent arteriole dilation and constriction. ACE, angiotensin-converting enzyme; NSAIDs,

nonsteroidal antiinflammatory drugs; PGE, prostaglandin E.

Use of β-Blockers in HFrEF

CASE 14-1, QUESTION 17: After 3 days of furosemide and an ACEI, A.J.’s PND has resolved, but he still

has difficulty walking without SOB and fatigue. His lower extremity edema has been significantly reduced. His

current BP is 145/90 mm Hg, his pulse is 82 bpm, and his weight has dropped to 73 kg after diuresis. Repeat

laboratory measurements include the following results:

Na, 139 mEq/L

K, 4.3 mEq/L

Cl, 98 mEq/L

CO2

, 27 mEq/L

BUN, 27 mg/dL

SCr, 0.6 mg/dL

The medical team has decided to discharge A.J. soon. You recommend that A.J. should be started on a βblocker before discharge. What is your rationale?

β-Blockers have been evaluated during randomized clinical trials in more than

20,000 patients with varying degrees of HFrEF. Five meta-analyses have arrived at

the same conclusions: the use of three β-blockers (bisoprolol, metoprolol succinate,

or carvedilol) is associated with a consistent 30% reduction in mortality and a 40%

reduction in hospitalizations in patients with HF.

175–179

The ACC/AHA guidelines recommend bisoprolol, metoprolol succinate, or

carvedilol for all patients with HFrEF unless there is a contraindication to their use

or the patient is unable to tolerate treatment with a β-blocker.

1,5,6 They should be a

part of the primary treatment plan with an ACEI or ARB. Patients should receive a βblocker to slow the rate of disease progression and reduce the risk of sudden death.

Patients do not need to be taking high doses of ACEIs before being considered for

treatment with a β-blocker. To the contrary, in patients taking a low dose of an ACEI,

the addition of a β-blocker produces a greater reduction in symptoms and in the risk

of death than an increase in the dose of an ACEI. β-Blockers should be initiated

before discharge in the vast majority of patients hospitalized for HF.

180 Only those

clinically unstable patients who are hospitalized in an intensive care unit, require IV

positive inotropic support, have severe fluid overload or depletion, have

symptomatic bradycardia or advanced heart block that is not treated with a

pacemaker, or have a history of poorly controlled reactive airways disease, are not

candidates for a β-blocker.