Despite remarkable initial benefits, vigorous diuretic therapy carries the risk of
volume depletion, electrolyte abnormalities, and diminished CO. Abrupt worsening
of renal function (increased BUN or SCr) or hypotension indicates the need to
temporarily withhold diuretics.
Furosemide is a commonly used loop diuretic because of clinical experience and low
cost. Bumetanide and torsemide are preferred in some settings because of more
62,63,100,101 Ethacrynic acid, which is also a loop diuretic, is not
preferred because of its ototoxic potential. However, unlike other loop diuretics,
ethacrynic acid does not contain a sulfonamide moiety, and it is mainly reserved for
patients with severe sulfonamide allergies to other loop diuretics.
According to one group of investigators, patients with HF treated with torsemide
fare better than those receiving furosemide.
101 During a 1-year open-label trial,
patients receiving torsemide were less likely to be admitted to the hospital for HF
(17% torsemide vs. 32% furosemide). Admissions for all CV causes were also
lower among patients taking torsemide (44%) than patients taking furosemide (59%).
Fatigue scores improved to a greater extent in patients treated with torsemide, but no
difference was found in the dyspnea score. Torsemide is more expensive than
furosemide, and this may be an issue for some patients.
Erratic responses to furosemide are prevalent in persons with severe HF or
diminished renal function. Some patients respond promptly and vigorously to small
oral doses of furosemide, whereas others require large IV doses to achieve only
minimal diuresis. Part of these differences can be explained by the drug’s
62,102 Loop diuretics are highly protein bound and have to be
actively secreted into the proximal tubular lumen to elicit a response. Tubular
secretion of loop diuretics can be compromised in the presence of increased levels
of endogenous organic acids due to renal insufficiency and drugs (NSAIDs) that are
competing for the same transporters. Also, oral absorption of furosemide is erratic
and incomplete, averaging 50% to 60% in healthy subjects and 45% in those with
renal failure. When taken with a meal, absorption is delayed, but the total amount
absorbed does not differ. There are claims that the absorption and, therefore,
effectiveness of furosemide are further diminished in patients with HF attributable to
edema of the bowel and decreased splanchnic blood flow. This has been partially
refuted by one investigator, who noted an average furosemide bioavailability of 61%
in patients with HF, the same as in normal patients.
101 Total absorption in patients
with HF varies widely (34%–80%); however, both the rate of absorption and the
time to peak urinary excretion are delayed for furosemide and bumetanide.
The rate and extent of absorption are not only different among individuals, but
intraindividual variability also exists. Ingestion of the same brand of furosemide by
the same individual on multiple occasions can show up to a threefold difference in
bioavailability. These differences are evident with the innovator’s brand (Lasix) or
Typically, a patient’s treatment is initiated with 20 to 40 mg of oral or IV furosemide
given as a single dose and monitored for responsiveness (Table 14-3). If the desired
diuresis is not obtained, the dose can be increased in 40- to 80-mg increments to a
total daily dose of 160 to 240 mg, usually divided into two or three doses. For
torsemide, a usual starting dose is 10 to 20 mg/day, but a ceiling effect is noted in
patients with HF at a dosage of 100 to 200 mg/day.
bumetanide are 0.5 to 1.0 mg once or twice daily, titrated to a maximum of 10 mg
daily. Because A.J. is not in acute distress, it could be argued that oral therapy would
suffice. The decision, however, is to give a single 40-mg IV dose of furosemide for
diuresis and sustain weight loss.
Another alternative in hospitalized patients is to administer loop diuretics via
continuous infusion. Multiple studies have demonstrated the benefits of continuous
infusions compared with intermittent infusions.
107–109 However, the results of these
studies have been questioned because of a lack of methodological rigor, and the
studies have been underpowered to address the primary end points. Recently, the
(Diuretic Optimization Strategies Evaluation) showed no difference in
efficacy or safety between intermittent IV bolus or continuous infusion. There are
potential benefits of continuous infusion when compared with intermittent bolus
dosing. Bolus diuretic dosing can cause a higher rate of diuretic resistance owing to
the postdiuretic phenomenon. Continuous IV infusion results in a constant delivery to
the tubule, potentially reducing this phenomenon. Additionally, continuous infusions
are also associated with a lower incidence of ototoxicity owing to lower peak
concentrations. Patients who are candidates for continuous IV infusion should receive
a loading dose before infusion to reach steady-state concentrations faster. However,
if the patient has received one or more IV boluses within the previous few hours, then
an infusion can be started without a loading dose. In case of inadequate response, the
loading dose should be repeated and the infusion rate increased. The infusion rate
depends on the patient’s renal function and response.
CASE 14-1, QUESTION 8: Examine A.J.’s laboratory values (see Question 1). Does A.J. have any
abnormal values? What is the significance of these abnormalities?
A.J. has an elevated BUN (40 mg/dL) but a normal SCr (0.8 mg/dL). Worsening
renal function is characterized by an elevation of BUN and creatinine. A
disproportionately elevated BUN relative to creatinine is indicative of prerenal
azotemia, secondary to poor renal perfusion from HF or overdiuresis. SCr will also
rise in some patients with prerenal azotemia, but will quickly return to normal with
A.J.’s laboratory values reflect prerenal azotemia. The most probable cause of his
azotemia is decreased RBF secondary to decompensated HF. Diuretics should not be
withheld and, in fact, judicious diuresis should improve his HF and help lower his
BUN. Caution must be exercised because excessive diuresis and volume depletion
can cause renal ischemia, leading to true renal damage. If this happens, the SCr also
A low serum sodium of 132 mEq/L is noted. Low serum sodium, however, is not
necessarily a sign of overdiuresis. A person may
be significantly overdiuresed with a body deficit of sodium, but if that sodium is lost
isotonically, the serum sodium concentration will be normal. Conversely, a person
such as A.J. can be hypervolemic, indicating excessive body sodium, but the serum
sodium concentration may be normal or even low.
Hyponatremia (low serum sodium concentration) reflects the dilutional effect of
extra free water in the plasma. The most common causes of dilutional hyponatremia
are excess ADH production or excessive free water intake. Individuals on severely
sodium-restricted diets can experience hyponatremia. Likewise, patients given too
much diuretic and who are then given salt-free fluids or who have compensatory
ADH release can become hyponatremic. Patients with HF or hepatic cirrhosis are
more likely to develop diuretic-induced dilutional hyponatremia because of
preexisting defects in free water excretion. The exact cause of hyponatremia in A.J.
is unknown, but his marginally low serum sodium does not contraindicate continued
diuretic therapy. In general, levels of serum sodium concentration less than 120 to
125 mEq/L are associated with adverse events in HF patients; chronic serum sodium
concentrations of 130 mEq/L or less are associated with higher morbidity and
111 Asymptomatic hyponatremia can be treated with water restriction. In the
setting of volume depletion, IV administration of normal saline may be effective.
Vasopressin receptor antagonists can be used in patients with HF and hypervolemic
A.J. has a serum potassium of 3.2 mEq/L. Hypokalemia is associated with an
increased incidence of arrhythmias. Some studies showed increased ectopic activity
with serum levels between 3.0 and 3.5 mEq/L.
It is estimated that the risk of
arrhythmias increases by 27% with each 0.5 mEq/L reduction in the plasma
potassium concentration less than 3.0 mEq/L.
In chronic HF, potassium abnormalities are commonly seen. The risk of SCD in
patients with HF may be lessened by using low doses of diuretics in combination
with potassium-sparing agents, with the goal of maintaining serum potassium levels
A.J. will be receiving increased doses of diuretics for the next several days and,
therefore, may need additional potassium supplementation to prevent life-threatening
hypokalemia. In addition, if he needs digoxin therapy in the future, low serum
potassium levels can predispose him to digitalis toxicity. Potassium replacement is
warranted for A.J. at this time. Long-term potassium supplementation may not be
necessary with concomitant administration of ACEIs. If hypokalemia persists, A.J.
can be started on an aldosterone antagonist.
A.J.’s serum magnesium level is 1.5 mEq/L. Severe hypomagnesemia can lead to
somnolence, muscle spasms, a decreased seizure threshold, and cardiac arrhythmias,
effects similar to those seen with hypokalemia. Some investigators have claimed that
many of the arrhythmias previously ascribed to diuretic-induced hypokalemia were
actually caused by diuretic-induced hypomagnesemia.
117 Concurrent hypokalemia and
hypomagnesemia can be especially dangerous. A.J. should be given 1 g of magnesium
sulfate IV and observed for changes in his magnesium level. If needed, he could be
given chronic oral supplements of magnesium.
Increases of 1 to 2 mg/dL in uric acid levels are common during thiazide
administration. Rarely, 4- to 5-mg/dL elevations have been reported. A.J.’s uric acid
level is 8 mg/dL, which is slightly elevated. It has been proposed that serum uric acid
levels may be a valuable prognostic marker in HF patients. One study indicates a
graded relationship between serum uric acid and HF survival.
oxidase is upregulated, which can lead to endothelial dysfunction. Therefore,
treatment with allopurinol may improve endothelial function and promote reverse
remodeling. The relationship between serum uric acid and CV disease is still
controversial, and the guidelines do not recommend the use of xanthine oxidase
inhibitors to prevent CV disease. In patients who experience symptomatic
hyperuricemia, the addition of allopurinol or other urate lowering agent should be
considered (Chapter 45, Gout and Hyperuricemia).
A.J.’s BNP is elevated (1,365 pg/mL). Various studies evaluating the diagnostic
accuracy of BNP and NT-proBNP have used different lower limits to define normal
values. The most commonly used plasma concentration to define the upper limit of
normal for BNP is 100 pg/mL, with concentrations greater than 400 pg/mL being
considered a strong indicator of HF. The age-related NT-proBNP diagnostic upper
limit of normal is 125 pg/mL for patients younger than 75 years, and 450 pg/mL for
patients older than 75 years of age. If the patient has a level below the upper limit of
normal for the respective assay used, then the symptoms are most likely attributable
to causes other than HF. In patients with renal impairment, the clearance of these
peptides is reduced; therefore, the upper limit of normal is 200 pg/mL for BNP and
the corresponding value for NT-proBNP is 1,200 pg/mL.
concentrations of these biomarkers are influenced by age, sex, obesity, and other
cardiac and noncardiac comorbidities. Asymptomatic patients with HF can also
present with elevated BNP or NT-proBNP levels. This confounds the accurate
interpretation of these markers and makes it challenging to integrate their usefulness
into routine clinical practice. Elevated BNP and NT-proBNP have an established
utility in ruling out HF in patients who present to the emergency department with
25 According to the ACC/AHA guidelines, measurement of BNP or NT-proBNP
is useful for establishing prognosis or disease severity in chronic HF; however, the
role of these biomarkers in reducing morbidity or mortality in HF is not well
established. Several NP–guided therapy trials have been published.
120–122 The BNPor NT-proBNP-guided HF therapy can be useful to achieve GDMT in selected
clinically stable patients, but it is unclear if such an approach improves outcome. The
Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDEIT) study,
123 designed to assess the effects of NP-guided therapy in high risk patients
with left ventricular systolic dysfunction did not improve clinical outcomes between
biomarker guided treatment strategy vs usual care. It is still not clear when to use
biomarkers to adjust HF medications. BNP levels may be elevated in patients
receiving ARNI, as BNP is a substrate for neprilysin. Therefore, the 2017 update
states that the utility of natriuretic peptide biomarker levels should be cautiously
interpreted in patients on ARNI.
6 A.J.’s elevated BNP level, along with his clinical
presentation, is indicative of HF exacerbation.
CASE 14-1, QUESTION 9: The physician gave A.J. one 1-g dose of magnesium sulfate and three 20-mEq
At this time A.J. does not need further magnesium replacement, but his serum
magnesium level should be measured again after he has received furosemide for a
few days. If the level drops again, maintenance therapy with oral magnesium oxide
A fall in serum potassium concentration can be seen within hours of the first dose
of a diuretic, and the maximal fall usually is reached by the end of the first week of
treatment. Potassium supplementation is not required in all patients receiving
diuretics. They should be monitored frequently in the first few months of diuretic
therapy to determine their potassium requirements. Similarly, when diuretics are
stopped, it can take several weeks for
serum potassium to return to baseline. Therefore, it is possible that A.J.’s
admitting potassium level of 3.2 mEq/L reflects the nadir of his response to HCTZ.
His initial response to potassium supplementation shows that his hypokalemia will
be easily controlled. It might be argued that he should be observed for a few days and
not given further supplements; however, because his diuresis is to be increased and if
digoxin may later be considered, potassium supplementation is warranted. Long-term
potassium supplementation may not be necessary with concomitant administration of
ACEIs and aldosterone antagonists. Because A.J. is started on furosemide, HCTZ
should be discontinued. If hypokalemia persists, the aldosterone antagonist dose can
It is difficult to predict the dose of potassium chloride that will be required to
maintain proper potassium balance. Many patients do well with 20 mEq/day, but it is
124–126 Those patients with disease states associated with high
circulating aldosterone levels require doses of potassium in excess of 60 mEq/day. In
patients who need long-term potassium supplementation, efforts should be made to
increase doses of ACEIs to target doses or maximal tolerated doses, and appropriate
addition of an aldosterone antagonist should be considered. However, a few selected
patients may still need to take potassium supplementation, despite the addition of an
CASE 14-1, QUESTION 10: After a single 40-mg IV dose of furosemide, A.J. is begun on 40 mg of
A.J. needs to be monitored for both an improvement in his HF and for side effects
(Tables 14-4 and 14-6). Subjectively, the clinician should monitor for decreased
pulmonary distress and an increased exercise tolerance, demonstrating control of HF.
Objective monitoring parameters for disease control include weight loss (ideal, 0.5–
1 kg/day until ideal dry weight is achieved), a decrease in edema, flattening of neck
veins, and disappearance of the S3 gallop and rales. Because A.J. has HTN, his BP
also requires monitoring with a goal to reduce it to <130/80 mm Hg.
Patients are instructed to record their weight each day and are allowed to adjust
their diuretic dose based on changes observed. If they are at their ideal “dry weight,”
they may reduce their dose of diuretic by 50% or even hold one or more doses. If
weight increases more than 1 or 2 pounds in a day or 5 pounds per week, edema
increases, or SOB returns, the dose of diuretic is temporarily increased.
Dizziness and weakness are subjective indices of volume depletion, hypotension,
or potassium loss. Muscle cramps and abdominal pain could indicate rapid changes
in electrolyte balance. Objectively, a lowering of BP, especially on standing, and a
rising BUN (prerenal azotemia) signify overdiuresis. Serum sodium, potassium, and
uric acid should be monitored routinely. Questioning the patient with regard to the
onset of diuresis (relative to drug ingestion) and the duration of the diuretic effect
helps develop the most convenient and effective schedule for the patient.
REFRACTORY PATIENTS: COMBINATION THERAPY
CASE 14-1, QUESTION 11: If A.J.’s furosemide dose was increased to 80 mg twice a day without much
response, what should be the next step?
All loop and thiazide diuretics must reach the tubular lumen to be effective.
Because these drugs are highly bound to serum proteins and endogenous organic
acids, they cannot enter the tubular lumen by glomerular filtration. For diuresis to
begin, they must be transported into the proximal tubule by active secretion from the
blood into the tubule. If this active transport is blocked, diuretics will not reach their
site of action. This can lead to a diminished diuretic response in patients with either
renal insufficiency or decreased RBF associated with decompensated HF. Patients
with renal insufficiency or poor RBF often require large doses of diuretics to achieve
a desired response. Endogenous organic acids can accumulate during renal
insufficiency, avidly binding the drug and preventing its access to the site of
62,63 Both the total amount of drug delivered to the tubule and the rate of
delivery of the drug to the tubule determine the magnitude of diuretic response
62,63 This explains why 80 mg of furosemide yields more diuresis than a 40-
mg dose and why an IV injection provides a more rapid and vigorous diuresis than an
oral dose. Once a threshold concentration (ceiling dose) is achieved within the
tubule, higher concentrations produce no greater intensity of effect, but the duration of
Many patients exhibit a blunted diuretic response with continued therapy for
unknown reasons. Generally, alternative treatment plans are pursued when the dose
given approaches the ceiling doses for each drug listed in Table 14-3. Continuous
infusions of furosemide (5–15 mg/hour), bumetanide (0.5–1 mg/hour), or torsemide
(3 mg/hour) can be more efficacious than intermittent bolus doses in patients with
severe HF or renal insufficiency.
62,63,127–129 Even higher doses have been
recommended: 0.25 to 1 mg/kg/hour for furosemide, 0.1 mg/kg/hour for bumetanide,
and 5 to 20 mg/hour for torsemide.
130 An aggressive protocol of a 100-mg IV bolus of
furosemide followed by a continuous IV infusion at a rate of 20 to 40 mg/hour, which
is doubled every 12 to 24 hours in unresponsive patients, to a maximal infusion rate
of 160 mg/hour to attain a diuresis rate of 100 mL/hour or greater has been
In some instances, switching from one loop diuretic to another can overcome the
131 For example, torsemide or bumetanide might work when furosemide fails
because of more reliable absorption.
If this maneuver fails, a combination of
diuretics can be tried. The most effective regimens combine drugs that work at two
different parts of the tubule.
130 For example, a loop diuretic is used with metolazone,
which blocks sodium reabsorption in the distal tubule. Various thiazide diuretics,
including chlorthalidone, chlorothiazide, and HCTZ, have been reported to
effectively enhance diuresis when combined with a loop diuretic. Triple-therapy
regimens of metolazone, a loop diuretic, and an aldosterone antagonist are used to
optimize diuresis and electrolyte control.
Most clinicians choose a combination of metolazone plus furosemide or
bumetanide. A wide range of metolazone dosages has been investigated.
a low dose of metolazone (2.5–5 mg) is first added to the furosemide therapy.
Metolazone can be given intermittently (2–3 times/week or as needed) to relieve
congestion. The longer duration of action for metolazone can cause a greater than
predicted diuresis and electrolyte loss when combined with a loop diuretic. Thus,
careful monitoring of weight, urine output, BP, BUN, potassium, magnesium and SCr
is required. Because no parenteral form of metolazone exists, chlorothiazide, at a
dose of 500 to 1,000 mg once or twice daily, is an alternative to the thiazide diuretic
that can be given intravenously. Although A.J.’s furosemide dose could be increased,
metolazone 2.5 mg daily was added. A.J. may also require additional doses of
potassium supplementation to avoid hypokalemia with the addition of metolazone.
Angiotensin-Converting Enzyme Inhibitors
specific ACEIs approved for use in HFrEF patients?
As a general rule, formulary decisions are first based on comparative
pharmacologic activity, efficacy, and drug safety. Other factors to consider are
labeled (FDA approved) indications, convenience of dosing schedule, and—all else
being equal—the cost to the institution and the patient. HTN is the primary indication
for all of the ACEIs. Not all ACEIs have an indication for HF.
ACEIs inhibit ACE (also called kinase II), reducing the activation of angiotensin
II, a major contributor to the undesired hemodynamic responses to HF. Decreased
circulating levels of NE, vasopressin, neurokinins, luteinizing hormone, prostacyclin,
and NO also have been noted after administration of ACEIs.
In addition, ACE is responsible for degradation of bradykinin, substance P, and
possibly other vasodilatory substances unrelated to angiotensin II. Thus, part of the
beneficial effects of ACEIs is caused by the accumulation of bradykinin (Fig. 14-6).
After attaching to bradykinin-2 (B2
) receptors, vasodilation is produced by
stimulating the production of arachidonic acid metabolites, peroxidases, NO, and
endothelium-derived hyperpolarizing factor in the vascular endothelium. In the
kidney, bradykinin causes natriuresis through direct tubular effects.
The net effect is that ACEIs regulate the balance between the vasoconstrictive and
salt-retentive properties of angiotensin II and the vasodilatory and natriuretic
properties of bradykinin. The effects of ACEIs are reduced pulmonary capillary
wedge pressure (preload) and lowered SVR and systolic wall stress (afterload). CO
increases without an increase in HR. ACEIs promote salt excretion by augmenting
RBF and reducing the production of aldosterone and ADH. The beneficial effects on
RBF, coupled with the drug’s indirect inhibition of aldosterone, lead to a mild
diuretic response, a distinct benefit compared to hydralazine.
Vasodilation and diuresis are not the only value of ACEIs in HF. Angiotensin II
enhances vascular remodeling, whereas bradykinin impedes this process.
impede ventricular remodeling by blocking the effects of angiotensin II on cardiac
myocytes. Evidence as to whether preserving bradykinin levels affects remodeling is
inconclusive, although it might attenuate the progressive deposition of collagen
during the chronic phase of post-MI cardiac remodeling.
Monitoring Parameters with Diuretics
↓CHF symptoms (see Table 14-4)
Weight loss or gain; goal is 1- to 2-lb weight loss/day until “ideal weight” achieved
Serum potassium and magnesium (avoid hypokalemia and hypomagnesemia)
aWeight loss may be greater during the first few days when significant edema is present.
aWeight loss may be greater during the first few days when significant edema is present.
bA ↓ in systolic BP of 10 to 15 mm Hg or a ↓ in diastolic BP of 5 to 10 mm Hg.
BUN. However, if the patient has severe HF, the saline could cause pulmonary edema.
BP, blood pressure; BUN, blood urea nitrogen; HF, heart failure.
Individual ACEIs with FDA-labeled approvals for the treatment of HF or LV
dysfunction after MI are included in Table 14-7. There is no reason to favor one
ACEI over another except in the case of optimizing dosing schedules for patients and
trying to use once-daily dosing if possible to improve medication adherence rates.
Numerous placebo-controlled trials have documented the favorable effects of
ACEI therapy on hemodynamic variables, clinical status, and symptoms of HF,
and demonstrated a consistent 20% to 30% relative reduction in HF mortality. ACEI
therapy is generally better than other vasodilator regimens, including the
hydralazine–nitrate combination or ARBs after considering efficacy and tolerability.
Drug Available Dosage Form Initial Dose
c 2.5, 5, 10, 20 mg tablets 2.5–5 mg every day 20 mg BID
Fosinopril 10, 20, 40 mg tablets 5–10 mg every day 40 mg every day
Lisinopril 2.5, 5, 10, 20, 40 mg
2.5–5 mg every day 40 mg every day
c 5, 10, 20, 40 mg tablets 5–10 mg every day 20 mg BID
Perindopril 2, 4, 8 mg tablets 2 mg every day 16 mg every day
1.25–2.5 mg every day 10 mg BID
Trandolapril 1, 2, 4 mg tablets 1 mg every day 8 mg every day
ACE, angiotensin-converting enzyme; BID, 2 times a day; TID, three times a day.
b Captopril is short acting. Start with a 6.25- or 12.5-mg test dose, then 6.25 to 12.5 mg TID.
Table 14-8 provides a brief summary of the results of the key ACEI HFrEF
18,66,67,135–137 Of the five approved agents, the best evidence for improved
survival is available for enalapril in both chronically symptomatic patients (NYHA
classes II–IV) and asymptomatic patients with evidence of an impaired EF after an
The ACC/AHA guidelines recommend selecting an ACEI that has shown
reductions in both morbidity and mortality in clinical trials in HFrEF. The following
ACEIs are considered first-line options based on clinical trials: captopril, enalapril,
fosinopril, lisinopril, perindopril, quinapril, ramipril, or trandolapril.
Captopril and lisinopril are both active as the parent compound and do not have
active metabolites. All other ACEIs are prodrugs that require enzymatic conversion
to active metabolites. Captopril has a short duration of action, necessitating three
times daily administration in most patients. Although this characteristic may be
advantageous when initiating therapy by allowing closer assessment of early side
effects, for chronic maintenance, it is preferable to use a drug that can be given either
once or twice daily. All other ACEIs meet this criterion. Package insert labeling and
common standards of practice have led to twice-daily dosing, especially at higher
doses, for enalapril, quinapril, and ramipril.
Clinical Trials of ACE Inhibitors in HFrEF
Studies in LV Dysfunction after MI
3–16 days 24–60 months Decreased
MI (n = 6,090) Enalaprilat/enalapril
24 hours 41–180 days No change in
314 MI (n >50,000) Captopril vs.
315 MI (n = 19,394) Lisinopril vs.
3–7 days 24–50 months Decreased
166 MI (n = 1,556) Zofenopril vs.
Source: Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998;97:1411.
A.J.’s physician chooses to start lisinopril 10 mg daily based on evidence of
clinical efficacy, improved survival, and availability as a generic medication. If
there were concerns about hypotension, then captopril would be preferred during the
initial 1 to 2 days of initiation therapy to avoid dropping the patient’s BP too quickly.
Clinical evidence shows a relationship between the degree of improvement in HF
symptoms and the dose of drug given. Larger doses are more likely to improve the
patient’s quality of life and reduce the incidence of hospital stays, but the impact of
larger doses on mortality is less clear. At the same time, higher doses are associated
with a greater risk of side effects. Based on these principles, proposed recommended
starting and maximal doses for the ACEIs are listed in Table 14-7.
The guidelines recommend that ACEIs be initiated at low doses, and titrated to the
maximal tolerated target dose. Supporting this principle are the results of the
Assessment of Treatment with Lisinopril and Survival trial.
mg (low dosage) or 32.5 to 35 mg (high dosage) was given to over 3,000 patients.
were reduced by 24% (p = 0.003) and 12% (p = 0.002), respectively. The higher
dose was tolerated by 90% of patients assigned this dose.
Despite these recommendations for using the highest tolerated doses, evidence
also suggests that lower doses are beneficial. The UK Heart Failure Network Study
found that 10 mg of twice-daily enalapril was no more effective than 2.5 mg BID.
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