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.
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).
comparing an ARB with either placebo or an ACEI in patients with HF.
favorably improved exercise tolerance and EF compared with placebo. However,
they were not superior to ACEIs in reducing all-cause mortality or hospitalizations
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.
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.
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
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
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.
Clinical Trials of Angiotensin Receptor Blockers in Heart Failure
used in addition to βblockers.
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
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
Adverse Events that Lead to Permanent Drug Discontinuation
Trial Outcomes Candesartan (%) Placebo (%) p Value
Increased creatinine 6.1 2.7 <0.0001
Increased creatinine 7.8 4.1 0.0001
Increased creatinine 4.8 2.4 <0.001
Increased creatinine 6.2 3.0 <0.0001
The combined results of all three CHARM components (CHARM-Added,
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
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
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.
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.
ANGIOTENSIN-CONVERTING ENZYME INHIBITOR–INDUCED COUGH
CASE 14-1, QUESTION 15: A.J. presents to the outpatient HF clinic with an annoying productive cough
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
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
161 There may also be a higher incidence in women and black populations.
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
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.
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 (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.
women may have a higher prevalence. Of concern is the observation that ACEI–
induced angioedema is often misdiagnosed.
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.
however, have implicated candesartan, losartan, and valsartan as possible causative
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
Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor
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.
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.
aldosterone antagonist should be
avoided if creatinine clearance is
<30 mL/minute and baseline serum
An initial dose of spironolactone 12.5
recommended, after which the dose
may be increased to spironolactone
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
RAAS blockade by ACE inhibitors
Note: risk increases at higher doses
(enalapril or lisinopril ≥10 mg/day)
production or receptor binding
reduces the delivery of sodium and
water to the distal nephron, which,
Doses of drugs should be decreased
NSAIDs Inhibit renal prostaglandin synthesis
hyporeninemic hypoaldosteronism.
Decreased availability of sodium for
exchange with potassium at distal
Decreased excretion of potassium. Close monitoring of serum potassium
hyperkalemia should be decreased
Patients who have increased dietary
supplements in combination with
insufficiency, decreased potassium
Potassium supplements should be
Patients should be educated on foods
rich in potassium and to avoid salt
HF patients with diabetes taking
Hyporeninemic hypoaldosteronism
leading to decreased levels of
Insulin deficiency can stimulate the
Hyperglycemia should be monitored
and appropriate drug therapy should
be determined to treat diabetes.
Advanced age, low muscle mass, or
Impaired release of renin resulting
SCr may not accurately reflect
Risk of hyperkalemia increases
heart failure; NSAIDs, nonsteroidal antiinflammatory drugs; PGE2
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.
nonsteroidal antiinflammatory drugs; PGE, prostaglandin E.
laboratory measurements include the following results:
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.
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.
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.
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
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