Conversely, rhythm disturbances in patients taking digitalis are not always related to
toxicity. In one study of 100 consecutive patients with suspected digitalis-induced
arrhythmias, only 24 were confirmed as being toxic as defined by resolution of
cardiac irritability after drug withdrawal. In the other 76 patients, the dysrhythmia
persisted long after drug removal.
Most arrhythmias can occur as a result of digoxin toxicity. Decreased conduction
velocity through the AV node presents as a prolonged PR interval (first-degree AV
block) and is seen in many patients with therapeutic concentrations of digoxin.
However, higher concentrations of digoxin can impair conduction and result in
junctional rhythms. Increased automaticity of the atria can cause multifocal atrial
tachycardia with block, paroxysmal atrial tachycardia with block, or AF.
Ventricular arrhythmias are among the most common rhythm disturbances caused
by digoxin toxicity and include unifocal and multifocal premature ventricular
contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, and ventricular
In the DIG trial, 11.9% of patients in the digoxin treatment group
were found to have suspected digoxin toxicity compared with 7.9% in the placebo
group. Comprehensive reviews are available on the topic of digitalis-induced
Hyperkalemia can develop as a consequence of massive digoxin ingestion by
/K+ ATPase system, causing inhibition of the uptake of
potassium by the myocardium, skeletal muscle, and liver cells.
potassium from inside to outside the cell can result in significant hyperkalemia,
especially in patients with underlying renal insufficiency. These same patients also
accumulate digoxin in the body because of decreased clearance of the drug.
Drugs Lowering Serum Digoxin Concentration
195 Probable induction of intestinal P-glycoprotein causing
↓Serum concentration after oral, but not IV digoxin. No
change in digoxin renal clearance or half-life.
229 Possible induction of P-glycoprotein (33% reduction in
digoxin trough concentrations).
Sulfasalazine doses >2 g/day Malabsorption of digoxin (decrease AUC of digoxin by
Drugs Raising Serum Digoxin Concentration
213,221 ↑Serum digoxin levels inhibit intestinal P-glycoprotein
2,223 20% increase in serum digoxin concentration with 80-
mg dose, minimal effect with 20-mg dose. Speculated
to inhibit intestinal P-glycoprotein, but not proven.
213,221,226 Inhibition of P-glycoprotein. Best documented with
317 Diltiazem increases digoxin
concentrations by 50% in some patients.
227,316 Inhibition of P-glycoprotein, decreased digoxin renal
clearance. Digoxin clearance may be reduced by 60%,
and plasma concentrations may increase by twofold.
213,221 Inhibition of P-glycoprotein, decreased digoxin renal
Erythromycin ↑Bioavailability in persons who normally metabolize
digoxin in intestinal tract. May also inhibit Pglycoprotein in gut. Digoxin concentrations may
increase by 100% in some cases.
318 ↑Serum digoxin levels by unknown mechanism. In one
study, the AUC for digoxin was increased by 50% and
renal elimination was decreased by 20%.
213,319 Inhibition of P-glycoprotein. Increases digoxin
(usually doses above 500 mg/day may increase digoxin
Inhibition of P-glycoprotein, decreased digoxin renal
clearance, and increased bioavailability. Increases
25%–100% digoxin concentrations.
include a discussion of many of these interactions that do not include a specific reference
AUC, area under curve; IV, intravenous.
Vague gastrointestinal symptoms characteristic of digoxin toxicity are difficult to
evaluate because anorexia and nausea are also part of clinical picture seen in patients
CNS symptoms of digoxin are common, possibly associated with potassium
depletion in neural tissue. Chronic digoxin intoxication can manifest as extreme
fatigue, listlessness or psychic disturbances in the form of nightmares, agitation, and
233 Visual disturbances have been described as hazy vision and
difficulties in both reading and red–green color perception. Other complaints
included glitterings, dark or moving spots, photophobia, and yellow–green vision.
Disturbances in color vision returned to normal 2 or 3 weeks after discontinuation of
Digitalis-induced visual disturbances have been reported at serum concentrations
below those considered to be toxic (all <1.5 ng/mL; range, 0.2–1.5 ng/mL).
the reactions were described as photopsia (seeing lights not present in the
environment), and one person had decreased visual acuity. The symptoms resolved in
all but one subject when digoxin was discontinued.
Some prospective studies have shown a good correlation between serum digoxin
serum concentration and toxicity,
233,235,236 whereas other investigators found a poor
237,238 Once levels exceed 6 ng/mL, the risk of mortality greatly
239 Patients with hypokalemia can demonstrate digitalis toxicity at low
For many patients without life-threatening arrhythmias or major electrolyte
imbalances, simple withdrawal of digoxin is the only treatment required. Potassium
replacement should be considered in any patient with digoxin-induced ectopic beats
who is hypokalemic. Digoxin-specific antibodies that bind digoxin molecules,
rendering them unavailable for binding at receptors, are available.
digoxin Fab products is restricted to potentially life-threatening intoxications (severe
arrhythmias or hyperkalemia) that are either refractory to more conservative therapy
or associated with extremely high serum digoxin concentrations.
Non–Angiotensin-Converting Enzyme Inhibitor
QUESTION 1: T.R. is a 57-year-old African American man (LVEF of 35%) who presents to the HF clinic
of the isosorbide? Is combination therapy rational?
T.R. is treated with an ACEI, a β-blocker, and spironolactone. Despite this
therapy, he is still having HF symptoms. He was started
on hydralazine and isosorbide dinitrate, which is a possible next step in treating a
Hydralazine’s predominate action is as an arteriolar dilator. Decreasing afterload
improves LV function. SVR is decreased, and this leads to an increase in CO.
Hydralazine is a direct-acting smooth muscle relaxant with significant arteriolar
dilating effects in the kidneys and limbs. It has no effect on the venous system or on
The reflex tachycardia and hypotension that accompany hydralazine in treating
HTN are minimal or absent when treating HF. In patients with end-stage
cardiomyopathy, significant hypotension can occur if the heart cannot respond
appropriately by increasing CO. Because hydralazine is devoid of venous dilating
properties, central venous pressure and pulmonary capillary wedge pressure
The effect of a single dose of hydralazine occurs in about 30 minutes and lasts up
to 6 hours. The average maintenance dose is 50 to 100 mg every 6 to 8 hours. T.R. is
receiving an initial dose at this time and may warrant a higher dose in the future.
Hydralazine used as monotherapy is not associated with long-term improvement in
248 Combination therapy of hydralazine with either nitrates or ACEIs
Although tachyphylaxis generally is not a significant problem with prolonged
courses of hydralazine, some patients require increased diuretic doses to counteract
hydralazine-induced fluid retention. This latter response reflects activation of the
renin–angiotensin system after vasodilation of the renal vasculature. Other side
effects with hydralazine include transient nausea, headache, flushing, tachycardia,
and a lupus syndrome associated with prolonged, high doses (see Chapter 9,
Nitrates have effects complementary to those of hydralazine.
dilate venous capacitance vessels. Venous dilation reduces preload, resulting in
reductions in PCWP and right atrial pressure. They are especially effective in
reducing the symptoms of pulmonary congestion. The lack of significant arterial
dilation accounts for the observations that SVR is minimally reduced and CO remains
Because sublingual NTG has a short duration of action, more attention has been
focused on isosorbide dinitrate. Sublingual isosorbide dinitrate is well absorbed and
does not undergo first-pass metabolism. Its onset is rapid (5 minutes), but its effects
are relatively short (1–3 hours). The usual starting dosage is 5 mg every 4 to 6 hours,
but dosages may be titrated to 20 mg or more. Larger doses are associated with
longer beneficial effects (approximately 3 hours), but also a high frequency of
Oral isosorbide has a slower onset (15–30 minutes), but the duration of activity is
longer (4–6 hours) than sublingual tablets. The smallest effective dose is 10 mg, with
titration to dosages as high as 80 mg every 4 to 6 hours. The best dose for both
sublingual and oral nitrates is that which provides the desired beneficial effect with
the least side effects. Isosorbide mononitrate is frequently used as it is generally
HYDRALAZINE–NITRATE COMBINATION
Combined afterload and preload reduction is clearly of benefit in improving
symptoms and enhancing long-term survival. Compared with ACEIs, the hydralazine–
isosorbide combination provides more improvement in exercise tolerance, but the
side effect profile and survival statistics are better with ACEIs.
of the two drugs together is not accompanied by reflex tachycardia or hypotension.
Data supporting the use of combination hydralazine and nitrate vasodilator therapy
come from two Veterans Administration Cooperative Studies (V-HeFT I and VHeFT II).
70,140,247 These two studies confirmed symptomatic relief and improved
exercise tolerance with combination therapy, and improved survival. (See Case 14-
3, Question 2, for the discussion of the therapy in African American patients.)
In summary, nitrates alone are indicated for those patients with signs and
symptoms of pulmonary and venous congestion. Use of an arterial dilator is
beneficial in a patient with high SVR and low CO. Most patients, such as T.R.,
exhibit symptoms of decreased CO and elevated venous pressure, making
combination therapy an attractive option. Although the hydralazine–isosorbide
combination actually reduces symptoms slightly better than ACEIs, the data on
survival are better with the ACEIs, probably owing to better adherence. A
combination of an ACEI plus hydralazine, a nitrate, or both is common in patients
Role of Race in the Pharmacotherapy of Heart Failure
CASE 14-3, QUESTION 2: Because T.R. is African American, would he be expected to respond differently
to ACEIs or hydralazine–isosorbide dinitrate than a patient who is not African American?
In general, African American patients experience HF at an earlier age and are
more likely to have HTN as a cause. The death rate of HF is higher for African
American than for non–African American patients.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND
Racial differences in response to drug therapy have been proposed, although this
showed no difference in annual mortality between African American and non–
African American patients receiving placebo. African American patients in the
hydralazine–nitrate group had a significantly lower mortality rate than those in the
placebo group. This implies that African American patients, but not non–African
American patients, derive benefit from the treatment with hydralazine–isosorbide.
These same investigators then reanalyzed the V-HeFT II trial results for possible
racial differences between response to enalapril and the hydralazine–nitrate
140,250 The outcome is difficult to interpret because of the absence of a
placebo group. The all-cause annual mortality rate for African American patients
was identical in the two drug groups (12.8% with enalapril and 12.9% with
hydralazine–isosorbide). In non–African American patients, the corresponding
mortality rates were 11% with enalapril and 14.9% with hydralazine–isosorbide.
These data could be interpreted as either superior response to hydralazine–
isosorbide in African Americans or inferior response to ACEIs in African
Americans. The latter interpretation is consistent with the hypothesis that ACEIs
might have a lesser BP-lowering effect in African American patients with HTN. A
similar reanalysis of the SOLVD Prevention and Treatment trials,
enalapril with placebo in patients with recent MI, concluded that enalapril is
associated with a significant reduction in the risk for HF hospitalization among white
patients (44% reduction) with LV dysfunction, but not among African American
patients. Confounding variables contributing to all of these analyses include
disproportionately low numbers of African American subjects in the trials, and
possibly more underlying risk factors in African American subjects.
To address the effect of race on response to ACEIs, a meta-analysis of seven
major ACEI studies with 14,752 patients, was conducted.
The authors concluded that the relative risk for mortality when taking an ACEI
compared with placebo was identical (0.89) for both African American and white
patients. The authors urged that ACEIs not be withheld from African American
patients. Although rare, there is a higher rate of angioedema with ACEIs in black
patients compared to white patients.
The African American Heart Failure Trial (AHeFT) was a randomized
comparison trial of hydralazine–isosorbide dinitrate versus placebo in African
American patients with NYHA class III or IV HF who were receiving standard HF
therapy (diuretics, β-blockers, ACEIs or ARB, digoxin, and aldosterone
71 The primary end point was a composite of all-cause death, first
hospitalization for HF, and quality of life scores at 6 months. Reduction in the
primary end point events was statistically significant in favor of the active drug
combination. All-cause mortality declined 43% with hydralazine–isosorbide
dinitrate versus placebo (p = 0.012). The study also reported a 39% reduction in first
hospitalization for HF with hydralazine–isosorbide dinitrate versus placebo (p <
0.001). The addition of hydralazine and isosorbide dinitrate is effective in African
American patients with NYHA class III or IV HF already receiving ACEIs and βblockers.
1 The results of AHeFT were also the primary factor leading the FDA to
approve the combination product of hydralazine and isosorbide dinitrate (BiDil) for
adjunctive treatment in self-identified African American patients. Using BiDil might
improve compliance by using a combination tablet. Cost is lower using generic
hydralazine and isosorbide as separate drugs.
A possible racial difference in response to β-blocker drugs has also been
hypothesized based on effects observed in HTN.
249,251,252 A post hoc analysis of the
U.S. Carvedilol Heart Failure trials
190–194 concluded that the benefit of carvedilol
was similar in both black and nonblack patients.
Contradictory evidence comes from BEST.
In this trial (discussed in Case 14-1
Question 20), 2,708 patients with NYHA class III or IV HF were randomly assigned
to either bucindolol or placebo. Bucindolol is a nonselective β-blocker with partial
agonist activity that imparts weak vasodilation. A unique characteristic of this study
was a preplanned subgroup analysis for racial differences. Although there was a
trend toward reductions in CV mortality and hospitalization with bucindolol, the trial
was terminated after 2 years. A subgroup analysis showed a mortality benefit in
that black patients will derive similar benefit from β-blockers as do white patients
when given carvedilol, metoprolol, or bisoprolol.
Critical Care Management of Heart Failure
furosemide 40 mg daily, lisinopril 10 mg daily, carvedilol 12.5 mg BID, digoxin 0.125 mg daily, and
venous distension, bilateral rales, hepatomegaly, and 3+ peripheral edema. Chest radiograph showed
cardiomegaly and pulmonary congestion. His BP was 154/100 mm Hg and pulse was 105 bpm.
Laboratory test results include:
hospital with ADHF. What factors are used to stratify risk for in-hospital mortality and morbidity?
ADHF is associated with high morbidity and mortality. It is the leading reason for
hospitalizations among the elderly. Post discharge mortality among patients with HF
is 11% at 30 days and 37% at 1 year.
253 The most common precipitants of HF
hospitalization are noncompliance (dietary or medication), acute myocardial
ischemia, uncontrolled comorbidities (HTN, diabetes mellitus, chronic kidney
disease, arrhythmias), and prescribing of negative inotropic agents, NSAIDs, or other
inappropriate agents. Regardless of the precipitating event, the common
pathophysiologic state that perpetuates the progression of HF is complex. A cascade
of hemodynamic and neurohormonal derangements provoke activation of adrenergic
systems and RAAS, leading to volume overload and hypoperfusion—classic
symptoms of ADHF. According to the ADHF National Registry, nearly half of the
patients who present with ADHF have preserved EF (>50%).
In-hospital mortality remains as high as 20% for patients who present with
elevated BUN and creatinine, and low systolic BP (SCr >2.75 mg/dL, BUN >43
). Patients presenting with hyponatremia (serum
sodium less than 135 mEq/L) have the worst outcomes and are more likely to receive
inotropic agents. After discharge, patients who continue to be hyponatremic have an
8% risk of rehospitalization per 3 mEq/L decrease in serum sodium. Uric acid
greater than 7 mg/dL in men and greater than 6 mg/dL in women is associated with a
high admission rate for HF. Admission and discharge levels of BNP are also helpful
in predicting rehospitalizations. According to studies, a 30% to 40% reduction in
BNP levels during hospitalization may improve outcomes. Other biomarkers such as
cardiac troponin levels, C-reactive protein, and apolipoprotein A-I levels are all
9 All these factors can be used to stratify risk for inhospital mortality.
Another approach to risk stratification and therapeutic decision-making is based
on hemodynamic profiles. Most patients with acute HF can be classified into one of
four hemodynamic profiles using relatively simple assessment techniques (Fig. 14-
255–258 Patients are assessed for the presence or absence of elevated venous filling
pressures (“wet” vs. “dry”) and adequacy of vital organ perfusion (“warm” vs.
“cold”). Elevated filling pressure can be assessed at the bedside by observing
jugular venous distension, presence of a third heart sound (S3
and ascites. Presence or absence of rales on auscultation is not considered a reliable
258 Hypotension, weak peripheral pulse, a narrow pulse pressure, cool
extremities, decreased mental alertness, and rising BUN and SCr are indicators of
decreased organ perfusion. Continuous BP, ECG, urine output, and pulse oximetry
measurements are standard noninvasive monitoring for all patients in an intensive
care unit. Invasive hemodynamic monitoring is used in critically ill patients when
more precise measurements of filling pressures, SVR, and CO or cardiac index are
desired. The goals are to achieve a right atrial pressure of less
than 8 mm Hg, pulmonary artery pressure of less than 25/10 mm Hg, pulmonary
artery wedge pressure of 12 to 16 mm Hg, SVR 900 to 1,400 dyne second/m5
cardiac index greater than 2.5 L/minute/m2
. (See Chapter 17, Shock, for more
detailed discussion of hemodynamic monitoring.)
CASE 14-4, QUESTION 2: From his clinical presentation, what is L.M.’s hemodynamic profile? What are
L.M.’s DOE, rales, peripheral edema, PND, and jugular venous pressure are
consistent with ADHF and volume overload. L.M. does not have signs of
hypoperfusion. His hemodynamic profile is “warm and wet” (subset II, Fig. 14-8).
According to the guidelines, a rapid diagnosis of ADHF is necessary to initiate
appropriate treatment. In patients who have established HF, precipitating factors
should be identified and addressed. At the time of discharge, medications that
decrease morbidity and mortality in HF should be optimized. BNP levels should be
considered when the diagnosis is uncertain can be helpful in differentiating between
cardiac and noncardiac causes of dyspnea.
Because volume overload is central to the pathophysiology of most episodes of
ADHF, the primary goal is to relieve congestion. However, diuretics should be
cautiously used in subset IV to avoid decreases in PCW less than 15 mm Hg as this
can compromise preload and further reduce CO. Despite diuretics being the main
therapy in reducing volume overload, their routine use in ADHF is associated with
worsening renal function and mortality. Mortality rates are higher in patients
receiving chronic diuretic therapy compared with those not receiving diuretics.
These findings are based on retrospective data. Nevertheless, they suggest an
association between mortality and diuretic use in patients with ADHF. (See Case 14-
1, Question 7, for diuretic dosing.)
Ultrafiltration is an alternative approach for treating hypervolemia. It involves the
use of a small device to rapidly remove fluid (up to 500 mL/hour). Typically,
ultrafiltration for HF is reserved for patients with renal failure or those unresponsive
in ADHF patients have shown that peripheral venovenous
ultrafiltration results in greater weight loss and fluid removal, and reduced hospital
length of stay and hospital readmissions compared with medical therapy. Significant
reductions in neurohormonal activation and no significant changes in SCr or
electrolytes were reported with ultrafiltration.
261 The Ultrafiltration versus
Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart
randomly assigned 200 patients to either ultrafiltration or
aggressive IV diuretic therapy. The study showed ultrafiltration significantly
improved weight loss at 48 hours (5.0 vs. 3.1 kg; p < 0.001), decreased the need for
vasoactive drugs (3% vs. 13%; p = 0.02), and reduced 90-day hospital readmission
(18% vs. 32%; p = 0.02) compared with diuretics alone. Ultrafiltration has a class
IIb recommendation for patients with refractory HF not responsive to medical
therapy. Patients with fluid overload and some degree of renal insufficiency and
those refractory to diuretic therapy are candidates for ultrafiltration.
CASE 14-4, QUESTION 3: L.M. received a 40-mg IV furosemide dose with no improvement in symptoms.
Then he received an 80-mg IV dose with only marginal improvement. The decision is made to start
nitroprusside. What is the role of IV vasodilator therapy in someone with ADHF?
after acute myocardial infarction. Am J Cardiol. 1977;39:137.)
recommend the addition of vasodilators in conjunction with
diuretics to reduce congestion in patients with fluid overload. In the presence of
asymptomatic hypotension, IV NTG, nitroprusside, or nesiritide may be considered
cautiously in combination with diuretics. In the presence of low SVR, arterial
vasodilators (e.g., nitroprusside, high-dose NTG, nesiritide) can further compromise
perfusion and should be avoided, especially in patients who have preexisting
Nitroprusside dilates both arterial and venous vessels, decreasing afterload and
preload. Nitroprusside is valuable in severely congested patients with HTN or
severe mitral valve regurgitation complicating LV dysfunction. Its major
disadvantages include risk of hypotension, reflex tachycardia, “coronary steal” in
CAD patients, and accumulation of toxic metabolites. Thiocyanate and cyanide
toxicity are most likely seen in renal insufficiency and in patients who receive more
than 4 mcg/kg/minute of nitroprusside for greater than 48 hours. When stopping
nitroprusside therapy, a slow taper is recommended because a rebound increase in
HF has been observed 10 to 30 minutes after drug withdrawal (see Chapter 16,
Nitroprusside must be given by continuous IV infusion, with arterial line
placement and intensive care unit admission in most institutions. It is unstable if
exposed to heat and light after reconstitution.
NTG primarily dilates the venous capacitance vessels with a slight effect on the
arterial bed. Patients with acute MI and pulmonary edema are often considered ideal
candidates for IV NTG. The resulting reduction in preload reduces PCWP. Because
nitrates have minimal effect on afterload, CO will likely remain unchanged or
increase slightly. In some patients, NTG could decrease CO if preload is reduced to
less than 15 mm Hg. NTG is generally initiated at 10 mcg/minute and increased by
increments of 10 to 20 mcg, until the patient’s symptoms are improved or PCWP is
less than 16 mm Hg. The most common side effect is headache, which can be treated
with analgesics and often resolves after continuous therapy. Tachyphylaxis to NTG
occurs within 24 hours after initiation of therapy. Approximately 20% of HF patients
exhibit resistance to high doses of NTG.
1 Nitroprusside is a good choice for patients
such as L.M. because he has elevated BP and no history of CAD.
Nesiritide is recombinantly produced BNP.
31,32 BNP binds to guanylate cyclase
receptors on vascular smooth muscle leading to expression of cyclic guanosine
monophosphate and vasodilation. Other actions include inhibition of ACE,
sympathetic outflow, and ET-1. Peripheral and coronary dilation coupled with
improved RBF and increased glomerular filtration all contribute to the beneficial
effects of nesiritide. Metabolic clearance of nesiritide is by a combination of binding
to cell surfaces with cellular internalization and lysosomal proteolysis as well as
proteolytic cleavage by endopeptidase. It undergoes minimal renal clearance. The
elimination half-life is 8 to 22 minutes, necessitating a constant IV infusion.
In clinical trials of hospitalized patients with severe HF, nesiritide produced
hemodynamic effects and reduction in dyspnea scores comparable to NTG when used
in combination with IV diuretics and either dopamine or dobutamine.
31,32 Dosedependent hypotension is the most common side effect with nesiritide, reported in
11% to 32% of patients. The incidence of PVC and nonsustained ventricular
tachycardia is less with nesiritide than with dopamine, dobutamine, or milrinone.
Nesiritide’s side effects include headache, abdominal pain, nausea, anxiety,
The use of nesiritide is generally restricted to those patients with acute HF
exacerbations who are hypervolemic and have a PCWP greater than 18 mm Hg
despite high doses of diuretics and IV NTG. In contrast to NTG, nesiritide has
natriuretic properties that are additive to loop diuretics. It should be avoided in
patients with a systolic BP less than 90 mg Hg or in cases of cardiogenic shock.
Dobutamine or milrinone should be added or substituted in hypotensive patients or
those with a cardiac index of less than 2.2 L/minute/m2
The IV infusion of nesiritide is prepared by diluting the contents of a 1.5-mg vial
to 6 mcg/mL in 250 mL of 5% dextrose or 0.9% NaCl. An initial loading dose of 2
mcg/kg is sometimes given intravenously over 60 seconds, followed by a continuous
IV infusion at a rate of 0.01 mcg/kg/minute. The desired response is a reduction of
PCWP of 5 to 10 mm Hg at 15 minutes. The dose can be increased in 0.005
mcg/kg/minute increments at 3-hour intervals to a maximum of 0.03 mcg/kg/minute.
Dosage should be titrated to a PCWP less than 18 mm Hg and a systolic BP greater
Although nesiritide is indicated in the treatment of ADHF, concerns were raised
about its safety. A meta-analysis of randomized, controlled trials of nesiritide in
ADHF suggests that nesiritide may be associated with worsening renal function and
263,264 The conclusions of the meta-analysis have been criticized,
however. For example, the Vasodilation in the Management of Acute Congestive
Heart Failure (VMAC) study was included in the meta-analysis but was not designed
to evaluate renal end points, and therefore its inclusion may not be appropriate.
Differences in baseline characteristics of the treatment groups may have contributed
to an increased risk of 30-day mortality seen in those patients treated with nesiritide.
The efficacy and safety of nesiritide have been evaluated in outpatients. The
Follow-up Serial Infusions of Nesiritide (FUSION I) trial
with NYHA class III and IV who had been hospitalized for ADHF at least twice
within the preceding year and once in the preceding month. Patients were randomly
assigned to receive usual care with or without open-label nesiritide. A subgroup of
patients was identified as high risk if they had at least four of the following: SCr
greater than 2.0 mg/dL during the preceding month, NYHA class IV for the preceding
2 months, age greater than 65 years, history of sustained ventricular tachycardia,
ischemic HF etiology, diabetes, or use of nesiritide or inotropic agents as outpatients
within the preceding 6 months. These patients at high risk experienced fewer HF
exacerbations and renal adverse effects with nesiritide infusions.
The benefit and safety in outpatients with severe HF was further explored in the
Follow-Up Serial Infusions of Nesiritide for the Management of Patients With Heart
HF. Subjects were randomly assigned to receive a 2-mcg/kg nesiritide bolus
followed by a 0.01-mcg/kg/minute infusion for 4 to 6 hours, or a matching placebo
regimen, once or twice weekly for 12 weeks. Both groups also received optimal
medical therapy and device therapy. Patients were required to have a creatinine
clearance less than 60 mL/minute. No outpatient IV inotropic or vasodilator therapy
was allowed. After 24 weeks, no difference was noted in the primary end point of
compared with placebo (27.5%). The incidence of worsening renal function was
significantly lower with nesiritide (32%) vs. placebo (39%).
The results of these studies alleviated some concerns regarding the safety of
nesiritide; however, a group of independent cardiologists designed an “Acute Study
of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure” (ASCENDHF)
trial to definitively answer the question of nesiritide safety and efficacy.
This was a double-blind placebo trial, which enrolled 7,141 patients with ADHF.
The participants were randomly assigned to receive an IV bolus (at the investigator’s
discretion) of nesiritide 2 mcg/kg or placebo followed by continuous IV infusion of
nesiritide 0.01 mcg/kg/minute or placebo for 7 days in addition to standard therapy.
The co-primary end points were the rate of HF hospitalizations or all-cause mortality
through day 30 and a significant improvement in self-assessed dyspnea at 6 or 24
hours. Compared with placebo, nesiritide did not reduce 30-day mortality or
rehospitalization. Nesiritide improved dyspnea at 6 and 24 hours compared with
placebo. Nesiritide did not worsen renal function. Proponents of nesiritide argue that
even though the ASCEND-HF trial failed to show a major benefit, it is the only
vasodilator that has been well studied. The controversy regarding the safety of
nesiritide can be put to rest.
L.M. responded well to nitroprusside and needed no other therapy. However, IV
NTG and IV nesiritide are alternatives to nitroprusside in patients with “wet and
warm” acute HF. NTG or nesiritide can either be a substitute for nitroprusside or be
combined with nitroprusside. At the time of discharge, furosemide therapy should be
continued, although the dose should be titrated to prevent DOE and peripheral edema.
The dose of lisinopril and carvedilol should also be titrated to target or tolerated
QUESTION 1: B.J. is a 60-year-old man who presents to the emergency department with worsening DOE.
HF (EF 25%). His medications include metoprolol succinate 100 mg daily, enalapril 5 mg twice daily,
include BP 100/75 mm Hg, HR 92 bpm, respiratory rate 18 breaths/minute, and O2
Laboratory values were BUN 20 mg/dL and SCr 1.4 mg/dL. Physical examination reveals pulmonary and
peripheral edema and JVP 10 cm. He is given 80 mg IV furosemide with minimal response. His dose was
unit where a pulmonary artery catheter (Swan–Ganz catheter) is placed, and the following hemodynamic
variables are: PCWP 21 mm Hg; CO 3.64 L/min (cardiac index 1.8 L/minute/m
. Is B.J. a candidate for inotropic therapy?
The hemodynamic profile of B.J. is category IV (cold and wet) because of
hypoperfusion and congestion. According to the ACC/AHA guidelines,
agents (dobutamine, dopamine, milrinone) are indicated in symptomatic patients with
reduced LVEF, low CO, or end-organ dysfunction (i.e., worsening renal function)
and in patients who are intolerant to vasodilators. They are recommended for patients
with cardiogenic shock or refractory symptoms, and may be used in patients requiring
perioperative support after surgery or for those awaiting transplantation. Dobutamine
is usually preferred in patients with low-output HF. Dobutamine improves CO,
decreases PCWP, and decreases total SVR with little effect on HR or systemic
arterial pressure when compared with dopamine.
further information on dopamine and dobutamine.)
PHOSPHODIESTERASE INHIBITORS: MILRINONE
Although β-agonists, such as dobutamine, have been traditionally used in patients
with ADHF, the phosphodiesterase inhibitor milrinone is an alternative to the
catecholamines and vasodilators for the short-term parenteral treatment of severe
congestive failure. This agent selectively inhibits phosphodiesterase III, the cyclic
adenosine monophosphate (cAMP)-specific cardiac phosphodiesterase. Enzyme
inhibition results in increased cAMP levels in myocardial cells and enhances
contractility. The activity is not blocked by β-blockers. Phosphodiesterase inhibitors
are also vasodilators. It has been suggested that at low doses they act more as
unloading agents rather than as inotropic agents; others refute this viewpoint. Their
overall hemodynamic effect probably results from a combination of positive
inotropic action plus preload and afterload reduction.
Milrinone is structurally and pharmacologically similar to inamrinone, which is no
271–273 Besides inhibiting phosphodiesterase, it also may increase calcium
availability to myocardial muscle. It has both inotropic and vasodilating properties.
HR increase and myocardial consumption may be less with milrinone than with
274,275 The half-life of milrinone is 1.5 to 2.5 hours, with renal clearance
accounting for approximately 80% to 90% of total body elimination and is prolonged
in patients with renal dysfunction. Although a loading dose of 50 mcg/kg is in the
product labeling, it is rarely given due to resulting hypotension. Maintenance
infusions are typically between 0.2 and 0.75 mcg/kg/minute. The infusion is adjusted
according to hemodynamic and clinical responses and should be decreased in
patients with renal insufficiency. The primary concern with milrinone is ventricular
arrhythmias, reported in up to 12% of patients. Supraventricular arrhythmias,
hypotension, headache, and chest pain also have been reported. Thrombocytopenia is
The Outcomes of a Prospective Trial of Intravenous Milrinone for Chronic Heart
Failure (OPTIME-CHF) trial assessed the in-hospital management of 951 patients
with acute HF exacerbation (mean LVEF 23%) but not in cardiogenic shock.
addition to standard diuretic and ACEI therapy, subjects were randomly assigned to
receive either milrinone or placebo. The initial milrinone infusion rate was 0.5
mcg/kg/minute with no loading dose. The primary end point was total numbers of
days hospitalized for CV causes from the time of the start of study drug infusion to
day 60. No difference was found between milrinone and placebo with mortality at 60
days (10.3% with milrinone and 8.9% with placebo).
categorized subjects as ischemic vs. nonischemic.
275 Within the cohort of patients
with ischemia, milrinone-treated patients tended to have worse outcomes than those
treated with placebo. In contrast, nonischemic patients had a trend toward better
outcomes with milrinone than with placebo. From these data, it can be concluded that
the benefits of milrinone in patients with acute exacerbations of HF are minimal and
more likely to be seen in patients with a nonischemic etiology of HF. Worse
outcomes may be seen in patients with ischemic HF. However, short-term infusions
of milrinone were not associated with excess mortality.
Few trials have compared dobutamine to milrinone in ADHF. One small
retrospective analysis evaluated 329 patients admitted for ADHF (EF of less than
20%) who either received IV dobutamine or milrinone.
need for additional therapies, adverse effects, length of stay, and drug cost were
evaluated. Patients were similar in clinical presentation, but the milrinone group had
higher mean pulmonary arterial pressure. A greater percentage of patients received
versus milrinone (18.3%.). Only 19% of patients were taking β-blockers before
admission. Clinical outcomes were similar and there was no significant difference in
the in-hospital mortality rate, adverse effects, ventilator use, or length of stay. More
patients in the dobutamine group required nitroprusside to achieve optimal
hemodynamic response. The study concluded that both drugs have comparable
Other factors to consider when deciding which inotropic agent should be used in
ADHF are renal function, BP, and concomitant β-blocker use. Milrinone has a longer
half-life than dobutamine, and accumulates in cases of renal dysfunction. Milrinone is
also a vasodilator, which can limit its use in patients with hypotension. The
concomitant use of β-blockers may antagonize the action of dobutamine.
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