181

Based on all these factors, there is no question that A.J. should be started on a βblocker. Treatment with a β-blocker should be initiated at low doses, followed by

gradual increments in dose every 2 weeks as tolerated by the patient. Transient

bradycardia, hypotension, and fatigue are common during the first 24 to 48 hours

when β-blockers are first started or during subsequent increases in dosage. Thus,

patients should be monitored daily for changes in vital signs (pulse and BP) and

symptoms during this up-titration period. Bradycardia, heart block, and hypotension

can be asymptomatic and require no intervention other than instructing the patient not

to arise too quickly from a lying position to avoid postural changes. If either of these

complications is accompanied by dizziness, lightheadedness, or blurred vision, it

may be necessary to reduce the dose of β-blocker, the ACEI, or both or to slow the

up-titration. In patients in whom benefits are especially apparent, but bradycardia or

heart block is a concern, insertion of a pacemaker should be considered.

Because initiation of β-blocker therapy can also cause fluid retention, β-blockers

should only be started or uptitrated when the patient is euvolemic. Patients should be

instructed to weigh themselves daily and to adjust concomitantly administered

diuretics as appropriate. Diuretic doses should be decreased temporarily if patients

become hypotensive or their BUN begins to rise. Planned increments in the dose of a

β-blocker should be delayed until any side effects observed with lower doses are

tolerable or absent.

METOPROLOL AND BISOPROLOL

CASE 14-1, QUESTION 18: Metoprolol succinate (12.5 mg) is prescribed for A.J. Is this a good choice of

agent and starting dose? What other similar drugs have been used to treat HF?

Several clinical trials substantiate the clinical benefits of metoprolol, a relatively

selective β1

-receptor blocker, in HF.

182–185 By blocking β1

receptors in the

myocardium, HR, contractility, and CO are reduced at rest and during exercise,

without a compensatory increase in peripheral vascular resistance. The relative

sparing of β2

-receptors in the peripheral vasculature and lungs reduces

vasoconstrictive and bronchospastic complications.

The Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERITHF) showed a 35% reduction in all-cause mortality with sustained-release

metoprolol succinate.

185

In this trial, 3,991 patients, most of whom had NYHA class

II or III HF, were randomly assigned to receive metoprolol succinate controlledrelease/extended-release (CR/XL) or placebo. The starting dose of metoprolol was

12.5 to 25 mg/day, which was gradually increased every 2 weeks to the target dose

of 200 mg/day. Conventional therapy with diuretics, ACEIs, and digoxin was

continued. At the end of the trial, 64% of subjects assigned to the active drug had

reached the target dose. Although the number of subjects was too small to detect a

statistical difference, patients with severe (class IV) HF seemed to benefit as well.

Up to 15% of subjects had clinical worsening of HF, even at low metoprolol doses.

Positive results have also been seen with another relatively β1

-selective drug,

bisoprolol fumarate.

186,187

In the first Cardiac Insufficiency Bisoprolol Study (CIBIS

I), 641 subjects with moderate to severe HF were randomly assigned to placebo or

bisoprolol (starting dose, 1.25 mg/day; maximal dose, 5 mg/day) added to

conventional therapy for an average of 23 months.

186 A statistically

p. 287

p. 288

significant reduction in HF-associated hospitalization with the active drug and an

insignificant trend toward reduced mortality were noted. In the larger Second

Cardiac Insufficiency Bisoprolol Study (CIBIS II), reduction in both hospitalization

and mortality in the bisoprolol-treated group was significant.

187 A total of 2,647

patients were included in the second trial, and doses were increased to as high as 10

mg/day. The study was stopped prematurely because of a 34% reduction in total

mortality with bisoprolol. As in the MERIT-HF study, the number of patients with

severe (class IV) HF was inadequate to determine the value of β-blocker therapy in

this population.

Two dosage forms of metoprolol are marketed: metoprolol succinate extendedrelease and metoprolol tartrate immediate-release. Only metoprolol succinate is

approved for HF in the United States. It is indicated for patients with mild to

moderate (NYHA class II or III) HFrEF. The starting dose of 12.5 mg of metoprolol

succinate prescribed for A.J. is consistent with the clinical trials and manufacturer’s

labeling. If the initial dose is tolerated, the dose can be doubled to 25 mg daily for an

additional 2 to 4 weeks. The final target dose is 200 mg daily either as 100 mg BID

or 200 mg once daily.

When choosing among the various formulations of metoprolol, pharmacokinetic

and bioavailability differences should be considered.

182,183 Metoprolol succinate is

available as 25-, 50-, 100-, and 200-mg tablets. Each tablet is slowly released at a

constant rate for 20 hours, and provides β-blockade for 24 hours. The extendedrelease formulation retains its release characteristics even if the scored tablet is

divided in half, but it should not be crushed or chewed. Having the ability to split

tablets is useful in the titration of metoprolol succinate when the goal is to reach

target doses and sometimes patients require slower titrations.

Metoprolol has several metabolic routes of elimination that can affect dosing and

drug interactions. The major routes of elimination are via α-hydroxylation, Odemethylation, and N-dealkylation.

182,183 A smaller portion is metabolized by

cytochrome P-450 2D6 (CYP2D6), and drugs that inhibit metabolism of that

isoenzyme may affect the drug’s plasma levels. Approximately 10% of patients are

poor metabolizers, resulting in higher drug plasma concentrations in these patients.

A.J. should be advised that the beneficial clinical response to metoprolol is

usually delayed and may require 2 to 3 months to become apparent. Even if symptoms

do not abate, long-term treatment should be maintained to reduce the risk of major

clinical events. Abrupt withdrawal of treatment with a β-blocker can lead to clinical

deterioration and should be avoided.

188

Bisoprolol is FDA approved for treatment of HFrEF. Dosage size limitations,

however, limit the clinical use of this drug. For example, the starting dose of

bisoprolol is 1.25 mg/day, whereas the smallest commercially available dose in the

United States is a 5-mg scored tablet. Attempting to break the tablet into quarters is

not practical.

CARVEDILOL

Carvedilol is a β-blocker with some α blocking acivity.

189

It is also theorized to

possess antioxidant effects, which can protect against loss of cardiac myocytes and

scavenge oxygen free radicals that are thought to potentiate myocardial necrosis. The

correlation of these findings with clinical outcome is unknown.

Two pivotal studies support the use of carvedilol. The first was the U.S.

Carvedilol Heart Failure Study.

190–194 Subjects were almost equally divided between

NYHA class II and III HF and all had an EF of 35% or less despite diuretics,

digoxin, and an ACEI. Subjects were stratified based on the severity of their HF and

then randomly assigned to receive either placebo or carvedilol. The maximal dose

given was 50 mg twice daily. During an average of 6.5 months, the mortality rate in

the placebo group was 7.8% compared with 3.2% in the active treatment group, a

statistically significant 65% risk reduction. The patients treated with carvedilol also

had fewer HF-related hospitalizations. The most common side effect with carvedilol

was dizziness.

In the Australia/New Zealand Carvedilol Study, 415 patients with chronic, stable

HF were randomly assigned to receive placebo or carvedilol.

195 Those with severe

symptoms were excluded. Maintenance doses in subjects randomly assigned to

receive carvedilol ranged from 6.25 to 25 mg twice daily with an average follow-up

of 19 months. After 12 months, EF had increased by 5.3%, and heart size was

reduced in the carvedilol group. No differences between groups were found in

treadmill exercise time, change in NYHA classification, or HF symptom scores,

however. Most (58% in both groups) had neither improvement nor worsening of

symptoms. The frequency of episodes of worsening HF was similar in the two

groups. Total deaths in the carvedilol group were less than the placebo group, but

most of the difference in mortality was attributed to non-CV deaths. There were 68%

fewer hospital admissions for HF in the carvedilol group than for the placebo group.

Overall, these findings could be interpreted as evidence for safety with either no

overall benefit or a modest improvement with carvedilol.

The starting dose of carvedilol is 3.125 mg twice daily, with a doubling of the

dose every 2 weeks or as tolerated up to a maximum of 25 mg twice daily in patients

weighing less than 85 kg and 50 mg twice daily in larger patients. Hypotension,

bradycardia, fluid retention, and worsening HF symptoms can occur in the first few

weeks of therapy, necessitating additional diuretics, a reduction in dose, or

discontinuation of carvedilol. Taking carvedilol with food slows the rate of

absorption and reduces the incidence of orthostatic hypotension, which occurs in up

to 10% of patients taking the drug. As with any β-blocker, carvedilol is not

recommended for use in patients with asthma or poorly controlled diabetes.

Because carvedilol is metabolized by the CYP2D6 enzyme system, several

potential drug interactions should be considered.

189,196 The best-documented ones are

inhibition of metabolism by cimetidine and decreased carvedilol serum

concentrations when taken with rifampin. Known inhibitors of CYP2D6 (quinidine,

fluoxetine, paroxetine, and propafenone) might increase the risk of toxicity

(especially hypotension). Carvedilol has been reported to increase serum digoxin

levels by 15% by an unknown mechanism. Other sources of intrasubject variability in

carvedilol response may be caused by differences in the extent or rate or absorption,

stereospecific metabolism of the two isomers of the drug (carvedilol is a racemic

mixture of S[–] and R[+] isomers), and impaired metabolism in the 10% of the

population who lack CYP2D6 activity.

196

CHOICE OF β-BLOCKER: METOPROLOL VERSUS CARVEDILOL

CASE 14-1, QUESTION 19: Would carvedilol be a better alternative than metoprolol for A.J.? What would

be an appropriate dose and dosing schedule?

No consensus exists regarding the relative superiority of one β-blocker versus

another. The additional α1

-blockade and antioxidant properties of carvedilol provide

a theoretical basis for selecting carvedilol instead of metoprolol succinate or

bisoprolol.

The Carvedilol or Metoprolol European Trial (COMET) was a multicenter,

double-blind trial, where 3,029 patients with NYHA class II through IV HF and EF

less than 35% were randomly assigned to receive either carvedilol (target dose, 25

mg BID) or metoprolol tartrate (target dose, 50 mg BID). Diuretics and ACEIs were

continued in all subjects if tolerated. All-cause

p. 288

p. 289

mortality was 34% for carvedilol compared with 40% with metoprolol (p =

0.0017).

197 The composite end point of mortality or all-cause hospital admissions

was not significantly different. One major criticism of this study was the use of

metoprolol tartrate instead of metoprolol succinate. Comparable doses between the

two study groups have been questioned because the target dose of carvedilol was 25

mg twice daily compared with the target dose of metoprolol tartrate being 50 mg

twice daily. Also, the trial used resting HR to determine comparable β-blockade

among study groups rather than HR response to exercise. Exercise-induced HR

changes are considered a better indicator of β-blockade.

Side effects and patient tolerability are similar among β-blockers in most trials.

One investigator observed that carvedilol caused more hypotension and dizziness

than metoprolol or bisoprolol, possibly owing to α1

-blockade or more rapid

absorption.

198 Thus, metoprolol or bisoprolol may be preferred in patients with

hypotension or with complaints of dizziness. Conversely, carvedilol may be

preferred in patients with inadequately controlled HTN.

Whether carvedilol is a better choice for A.J. cannot be definitely answered. A

starting dosage of 3.125 mg twice daily of carvedilol could be used in place of

metoprolol succinate. Both drugs are generic, although the metoprolol sustainedrelease product is more expensive. A.J.’s provider decided to continue metoprolol

and reserve use of carvedilol if he has difficulty tolerating metoprolol.

β-Blockers in Severe Heart Failure

CASE 14-1, QUESTION 20: The original clinical trials of β-blockers excluded patients with severe (NYHA

class IV) HF at the time of randomization. For this reason, the FDA limited the original approval of carvedilol

for use in NYHA class II and III HF. Likewise, the ACC/AHA guidelines strongly support the use of βblockers in NYHA class II and III HF, but are less definitive about severe HF. If A.J. presented with NYHA

class IV HF, what evidence supports or refutes the use of β-blockers in A.J.?

The COPERNICUS

199 study demonstrated clear benefit of carvedilol in patients

with severe HF. COPERNICUS was a double-blind, placebo-controlled trial

assessing the clinical benefits and risks of carvedilol in patients with advanced HF

(NYHA class IIIB or IV).

199 Subjects were excluded who required intensive care,

had significant fluid retention, were hypotensive, had evidence of renal insufficiency,

or were receiving IV vasodilators or positive inotropic drugs. The starting dose of

carvedilol was 3.125 mg twice daily, and increased every 2 weeks to a target dose

of 25 mg twice daily. Of those in the carvedilol group, 65% achieved the target dose,

with the mean dose being 37 mg at the end of the first 4 months of the trial. The trial

was discontinued prematurely after an average patient follow-up of 10.4 months

because of a significant survival benefit from carvedilol.

The BEST Investigators failed to demonstrate that bucindolol, a nonselective βblocker with vasodilator properties, improved overall survival in patients with

NYHA class III and IV HF.

200 They randomly assigned 2,708 patients to receive

either bucindolol or placebo. Although the active drug yielded a significant decrease

in NE levels and improvement in LV function, the study was stopped prematurely

because of the low probability of showing any significant CV mortality benefit

compared with placebo. A possible explanation is that bucindolol has intrinsic

sympathomimetic activity that may counteract some of the benefits of β-blockade.

Moreover, subgroup analysis suggested that black patients might have fared worse

with bucindolol, raising concerns that β-blockers may not be effective therapy for

black patients with advanced HF (see Case 14-3, Question 2, for further discussion

of possible racial differences in drug response). Bucindolol has not been approved

by the FDA.

Controversy still remains about the safe and effective use of β-blockers in class IV

HF. There are data to support the safe and effective use of carvedilol. Clinically, the

use of β-blockers is generally continued unless the patient requires inotropic therapy

or if a dose increase of the β-blockers caused the ADHF episode. If the dose titration

resulted in ADHF, then most patients should receive their previous β-blocker dose,

but some may require acutely holding the β-blockers and reinitiating once stabilized.

Aldosterone Antagonists

CASE 14-2

QUESTION 1: B.D. is a 65-year-old Caucasian man with an LVEF of less than 25% who presents to the HF

clinic today for follow-up of his recent HF hospitalization. His BP is 120/85 mm Hg and his pulse is 70 bpm. His

current medications include lisinopril 10 mg daily, metoprolol succinate 150 mg daily, and furosemide 20 mg

daily. You have reviewed his chart and noted that these are the maximal tolerated doses of lisinopril and

metoprolol owing to dizziness and near syncope with higher doses. Today his laboratory results show that his

SCr is 0.9 mg/dL and his potassium level is 3.5 mEq/L. Is this patient a candidate for aldosterone antagonist

therapy?

Aldosterone contributes to HF through the increased retention of sodium and water

and contributes to the depletion of potassium. Likewise, the diuretic and potassiumsparing actions of spironolactone are attributed to inhibition of aldosterone.

201 At one

time, it was believed that optimal doses of ACEIs fully suppressed the production of

aldosterone. It is now recognized that aldosterone levels can remain elevated through

a combination of nonadrenal production and reduced hepatic clearance. In addition, it

has become clear that both angiotensin II and aldosterone have other negative effects

on the CV system, including myocardial and vascular fibrosis, direct vascular

damage, endothelial dysfunction, oxidative stress, and prevention of NE uptake by the

myocardium.

23,202 This led the RALES investigators to test the hypothesis that low

doses of spironolactone might impart a cardioprotective effect in patients with severe

HF independent of diuresis or potassium retention. In this trial, 1,663 patients with a

history of NYHA class IV HF were randomly assigned to receive either

spironolactone 25 mg or placebo. The dose of spironolactone could be increased to

50 mg if HF worsened without evidence of hyperkalemia.

The study was discontinued prematurely after a mean follow-up of 24 months

when a significant reduction in mortality was observed in the spironolactone group.

Hospitalization rates were lower in the patients treated with spironolactone.

Hyperkalemia developed in 2% of the patients on spironolactone and 1% of those on

placebo. Gynecomastia was reported in 10% of men treated with spironolactone

compared with only 1% of those receiving placebo.

Subsequently, the aldosterone receptor antagonist eplerenone was studied in 6,632

patients with LV dysfunction after MI. In the Eplerenone Post-Acute Myocardial

Infarction Heart Failure Efficacy and Survival Study (EPHESUS), subjects were

randomly assigned to receive either eplerenone or placebo.

65 Concurrent therapy

included diuretics, ACEIs, β-blockers, and aspirin. During a mean follow-up of 16

months, there were 478 deaths (14.4%) in the eplerenone group compared with 554

deaths (16.7%) with placebo (p = 0.008). Most deaths were attributable to CV

causes. More subjects experienced hyperkalemia with eplerenone than with placebo.

Because eplerenone does not block progesterone and androgen receptors,

gynecomastia and sexual dysfunction may be less.

65,202

In 2011, the Eplerenone in Mild Patients Hospitalization and Survival Study in

Heart Failure (EMPHASIS-HF) study was

p. 289

p. 290

published. This study evaluated eplerenone in patients with NYHA class II HF and

an EF of less than 35%.

203

In EMPHASIS-HF, subjects were randomly assigned to

receive either eplerenone or placebo. The primary outcome of the trial was CV death

or HF hospitalization. During a median follow-up of 21 months, 18.3% of

eplerenone-treated patients versus 25.9% of placebo patients had a primary outcome

event (p < 0.001). This study further supported the role of aldosterone antagonists in

HFrEF and expanded the known effectiveness to NYHA class II HF patients.

B.D. has NYHA class II HF based on his current symptom control and fits the

profile of the subjects in the EMPHASIS-HF study, although he is on a low dose of

ACEI. Starting B.D. on an aldosterone antagonist is appropriate because of his

relative intolerance to increasing the dose of ACEI and β-blocker. An initial

spironolactone dose of 25 mg per day should be chosen for B.D. based on the dose

studied in the RALES trial. Spironolactone is chosen based on the likely class effects

of aldosterone antagonists in HF treatment and the lower cost compared with

eplerenone. This dose is safe based on his current potassium of 3.5 mEq/L and SCr

of 0.9 mg/dL. He will need to be followed to determine whether a larger dose of

spironolactone will be tolerated and safe after a measurement of his potassium and

SCr 2 weeks after initiation. Specific monitoring parameters for the management of

hyperkalemia in patients treated with aldosterone antagonists can be found in Table

14-11.

Digitalis Glycosides

CASE 14-2, QUESTION 2: B.D. has tolerated spironolactone 25 mg daily for 2 months. His laboratory test

results today show that his potassium is 4.4 mEq/L and his SCr is 1.0 mg/dL. His BP is 124/82 mm Hg and his

pulse is 70 bpm. He has come to the clinic today for a follow-up appointment with his cardiologist who notes

that B.D. has had four HF hospitalizations in the last year. B.D. also reports increased SOB, DOE, and PND,

although his weight is stable and he takes all his medications as prescribed. The medical resident who is also

staffing the clinic asks whether it would be appropriate to add digoxin to B.D.’s medical treatment of HF. He

was told by a colleague that in clinical trials digoxin reduced both HF symptoms and hospitalizations for HF.

What would you recommend?

Debates raged for years about whether digitalis glycosides or vasodilators should

be the drug(s) of first choice for treating HFrEF. By the time the first ACC/AHA

guidelines were published, a clear consensus was evident. Vasodilators are first-line

therapy, with digoxin being added for patients with supraventricular arrhythmias,

failure to achieve symptomatic relief with vasodilators alone, or intolerable side

effects from vasodilators. ACEIs are preferred compared with other vasodilators

because of proven efficacy, convenience of dosing, and fewer side effects. By 1999,

experts also recommended starting β-blocker therapy earlier in the treatment plan.

Digoxin, however, continues to be widely debated.

CONTROVERSY ABOUT EFFICACY OF DIGOXIN

Correction of the underlying defect is a rational approach to the treatment of any

disease. When considering HF solely as “pump failure” with a weakened myocardial

muscle, then digitalis is the logical choice to improve cardiac contractility, CO, and

renal perfusion. If focusing on symptom relief and increased exercise tolerance as

markers of benefit, digoxin is effective. Critics, however, raised concerns that

symptom relief was less in patients with normal sinus rhythm than in those with

supraventricular arrhythmias. The most vocal critics claimed that the risk of digitalis

toxicity did not warrant using this class of drugs in patients with normal sinus rhythm.

Using multivariate analysis, one group of investigators concluded that a third heart

sound (S3 gallop rhythm), an enlarged heart, and a low EF best predict those patients

with normal sinus rhythm who will derive a beneficial response from digoxin.

204

Several other meta-analyses and critical reviews of the literature concurred that

digoxin therapy provides a beneficial effect, especially in patients with severe

symptomatic ventricular systolic dysfunction.

205,206 However these opinions were

based on historical data and when many current therapies were not available.

DIGOXIN WITHDRAWAL TRIALS

In 1993, two digoxin withdrawal trials, PROVED207 and RADIANCE,

208 were

published. Both attempted to determine whether patients with HF who were already

treated with digoxin would show deterioration after discontinuation. In both studies,

patients had documented HFrEF (LVEF <35%), mild to moderate symptoms, were in

normal sinus rhythm and stable for at least 3 months with treatment of a diuretic and

digoxin (baseline digoxin level, 0.9–2.0 ng/mL). Patients in the RADIANCE trial

were also stabilized on an ACEI in addition to the diuretic and digoxin.

207 A 12-

week, double-blind, placebo-controlled treatment period followed initial

stabilization in both studies. Patients in the active treatment groups continued digoxin

at their previous dose. Those in the placebo groups were withdrawn from digoxin

and given placebo.

In PROVED,

207 42 subjects continued digoxin and 46 were given placebo. There

were 29% treatment failures in the withdrawal group compared with 19% in those

taking digoxin. Exercise tolerance worsened in more patients taking placebo. Those

taking digoxin tended to maintain lower body weight and HR as well as higher EF. In

the RADIANCE study, 85 subjects continued digoxin therapy and 93 were switched

to placebo.

208 During the 12-week follow-up period, 4.7% of the subjects taking

digoxin experienced worsening symptoms compared with 24.7% of the placebotreated patients. More of the placebo-treated patients had worsening of EF and lower

quality-of-life scores. When comparing the two trials directly, fewer patients

deteriorated in both arms in the RADIANCE study. Whether this is attributed to a

greater benefit from combining an ACEI with a diuretic compared with using a

diuretic alone (as in PROVED) cannot be established.

These studies establish a beneficial effect of digoxin, even in those patients

receiving concurrent ACEIs. At least two factors, however, limit extrapolation to all

patients with HF. First, the investigators only assessed the value of therapy indirectly

by using a withdrawal design instead of initiating therapy in patients previously

untreated with digoxin. Second, the patients had advanced disease as evidenced by

NYHA class II or III symptoms despite triple-drug therapy. Thus, the benefit of

digoxin as initial monotherapy in early disease remains an unanswered question.

EFFECT OF DIGOXIN ON MORTALITY

The seminal study to answer the question of whether treatment with digoxin improves

survival in HF was the Digitalis Intervention Group (DIG) study.

209

In this study,

6,800 patients with HF were randomly assigned to receive either digoxin or placebo.

Eligibility requirements included an EF of 45% or less (mean, 28% in both groups),

normal sinus rhythm, and clinical evidence of HF. Most subjects were in NYHA

class II or III HF, although a small number of class I and class IV subjects were

included. Concurrent therapies included diuretics, ACEIs, and nitrates. In both

groups, 44% were taking digoxin before randomization. The starting digoxin dose (or

placebo) was based on age, weight, and

p. 290

p. 291

renal function, with subsequent adjustments made according to plasma level

measurements. Approximately 70% of subjects in both groups ended up taking 0.25

mg/day. By 1 month, 88.3% of patients receiving digoxin had serum levels between

0.5 and 2.0 ng/mL, with a mean of 0.88 ng/mL. Patients were followed for an average

of 37 months.

For the primary outcome of total mortality from any cause, 34.8% of patients on

digoxin and 35.1% of those on placebo died; corresponding CV deaths were 29.9%

and 29.5%, respectively. Although neither of these differences is statistically

significant, a trend was seen toward fewer HF-associated deaths and statistically

fewer hospitalizations (risk ratio, 0.72) with digoxin. As would be expected, cases

of suspected digoxin toxicity were greater in the active treatment group (11.9% vs.

7.9%), but the incidence of true toxicity was low.

The DIG trial improves on the PROVED and RADIANCE trials because it added

digoxin to other therapy as opposed to being a withdrawal study and also because of

the larger population. However, because nearly all patients were receiving

concurrent vasodilator therapy, the value of digoxin as monotherapy on mortality

rates remains unanswered.

The ACC/AHA guidelines indicate that patients with HF are unlikely to benefit

from the addition of digoxin in stage A or stage B HF. In stage C patients, despite

receiving optimal doses of ACEIs or β-blockers, digoxin may be beneficial to reduce

HF hospitalizations.

Digoxin is prescribed frequently in patients with HF and concurrent AF, but βblockers may be more effective in controlling the ventricular response, especially

during exercise. Digoxin should be avoided if the patient has significant sinus or AV

block, unless the block is treated with a permanent pacemaker. Digoxin should be

used cautiously in patients taking other drugs that can depress sinus or AV nodal

function (amiodarone or β-blockers), although patients usually will tolerate this

combination.

Despite being on maximal tolerated doses of lisinopril and metoprolol, B.D.

continues to have HF symptoms. In patients with persistent HF symptoms, especially

like B.D. who also presents with an EF less than 25%, digoxin can be used as an

additional agent. However, digoxin is not indicated as primary therapy for

stabilization of patients with acutely decompensated HF. Such patients should first

receive appropriate treatment, including IV medications.

SEX DIFFERENCES IN RESPONSE TO DIGOXIN

CASE 14-2, QUESTION 3: If B.D. had been a woman, would it have made any difference in the

consideration to prescribe digoxin?

The retrospective post hoc analysis of the DIG study data reported that the death

rate was lower among women in the placebo group as compared to men (28.9% vs.

36.9%; p < 0.001); however, this difference was not significant between women and

men taking digoxin.

206 Women taking digoxin had a higher death rate than women

taking placebo (33.1% vs. 28.9%), whereas death rates in men were similar in both

groups. The authors speculate that a possible mechanism for the increased risk of

death among women taking digoxin is an interaction between hormone-replacement

therapy and digoxin. Progesterone might increase serum digoxin levels by inhibiting

P-glycoprotein (PGP), thus reducing digoxin renal tubular excretion. Consistent with

this hypothesis, digoxin serum concentrations after 1 month of therapy were higher in

women than in men. The study investigators, however, did not gather data on estrogen

and hormone-replacement therapy or consistently measure serum digoxin levels later

in the trial. However, subsequent reanalysis

210 of the DIG data found lower serum

concentrations (0.5–0.9 ng/mL) of digoxin associated with a decreased risk of

hospitalizations and mortality in women. Serum concentrations greater than 1.2

ng/mL were associated with higher risk of death when compared with the placebo

group. Higher digoxin concentrations resulted in worse clinical outcomes both in men

and in women. Another analysis of patients treated with digoxin in the SOLVD trial

failed to demonstrate a survival difference based on gender.

211 The available data

suggest that serum digoxin concentrations in the range of 0.5 to 0.9 ng/mL are safe,

improve LVEF, hemodynamics, and reduce hospitalizations irrespective of gender.

MAINTENANCE DOSE

CASE 14-2, QUESTION 4: What is the appropriate maintenance dose of digoxin for B.D.?

The usual maintenance doses of digoxin have traditionally ranged from 0.125 to

0.25 mg/day. With the increased emphasis on targeting lower serum concentrations

(0.5–0.9 ng/mL), more patients are now empirically started at 0.125 mg/day. It is

safer to start with a conservative dose and assess his needs after 1 to 2 weeks.

In all cases, smaller doses of digoxin are given to patients with impaired excretion

rates (those with renal failure, older patients) or small-framed individuals. For

example, a totally anuric patient may receive only 0.0625 mg 3 or 4 days/week.

Loading doses of digoxin are rarely necessary. Slow initiation of therapy with

maintenance doses of digoxin is the method of choice for ambulatory or nonacutely ill

patients with normal renal function. Even in the acute-care setting, no indication

exists for loading doses of digoxin for HF alone. The exception might be if the patient

has AF and it is desired to control ventricular response as quickly as possible. Even

then, alternative drugs are likely to be used (see Chapter 15, Cardiac Arrhythmias).

MONITORING PARAMETERS

CASE 14-2, QUESTION 5: How should B.D.’s digitalis therapy be monitored? How useful are digoxin

serum levels in monitoring therapy?

No clear therapeutic end point exists for digoxin therapy. Nonspecific

electrocardiographic (ECG) changes (ST depression, T-wave abnormalities, and

shortening of the QT interval) correlate poorly with both toxic and therapeutic effects

of the drug.

212,213 Although digoxin serum levels are readily available from most

clinical laboratories, no “therapeutic level” and corresponding “toxic level” are

clearly defined.

A few patients, especially if they are hypokalemic or hypomagnesemic, will

manifest apparent signs of toxicity when serum digoxin concentrations are less than 1

ng/mL. At the other extreme, some patients tolerate concentrations greater than 2

ng/mL with no signs of overt toxicity. Such overlap between therapeutic

concentrations and toxic levels limits the value of serum level monitoring. Serum

levels can be used as a guide in confirming suspected toxicity or in explaining a poor

therapeutic response, but clinical evaluation ultimately remains the best therapeutic

guide.

Clinical Evaluation

As with diuretic and vasodilator therapy, clinical monitoring is the key to evaluating

adequacy of digitalis therapy. As B.D. begins to improve, he should have less

dyspnea and complain less of PND, and a lower HR may be observed.

p. 291

p. 292

TREATMENT OF SUPRAVENTRICULAR ARRHYTHMIAS IN HEART

FAILURE

CASE 14-2, QUESTION 6: B.D. did well for the next 6 months until he noted the onset of palpitations, which

were diagnosed by ECG as AF. A month ago his primary care physician increased his digoxin dose to 0.25 mg

every day. How should we treat his AF?

Supraventricular arrhythmias are frequently encountered in HF because volume or

pressure overload can cause atrial distension and irritability. Specifically, AF is

present in 10% to 30% of patients with advanced HF,

100 contributing to reduced

exercise capacity, increased risk of pulmonary or systemic emboli, and worse longterm prognosis. Drug therapy should be aimed at controlling ventricular rate and

preventing thromboembolic events. Cardioversion to normal sinus rhythm in patients

with low EF and dilated cardiomyopathy is often unsuccessful.

Digoxin slows the ventricular response associated with AF and is a logical choice

in patients with concurrent HFrEF. A potential limiting factor is that digoxin’s AVblocking properties are most evident at rest, and are less effective during exercise.

Hence, digoxin may be ineffective at controlling exercise-induced tachycardia that

limits the patient’s functional capacity. β-Blockers are more effective than digoxin

during exercise.

214–216

If digoxin, β-blockers, or both are ineffective, amiodarone is

another useful alternative. Verapamil and diltiazem are not appropriate choices for

rate control in patients with HFrEF due to their negative inotropic effects.

Some studies suggest that AF is an independent predictor of mortality in HF

patients, and restoration of sinus rhythm may reduce mortality and prevent

recurrences. Most patients who are electrically cardioverted revert to AF in a short

time. In CHF-STAT (Congestive Heart Failure: Survival Trial of Antiarrhythmic

Therapy),

217 a subset of patients who were converted to normal sinus rhythm with

amiodarone treatment had significantly lower mortality than those who remained in

AF. Similar results were observed in a substudy of the DIAMOND (Danish

Investigations of Arrhythmia and Mortality on Dofetilide) trial,

218

in which HF

patients with AF treated with dofetilide had significantly improved survival if the

sinus rhythm was maintained. However, AF-CHF (Atrial Fibrillation in Congestive

Heart Failure)

219 showed no mortality or morbidity benefits of rhythm control

compared with rate control. The lack of mortality benefits seen in the AF-CHF might

be explained by the high frequency of β-blocker use (88%). Antiarrhythmic agents

are frequently unsuccessful in maintaining sinus rhythm.

220 Patients who benefit the

most from conversion to sinus rhythm are the hemodynamically compromised.

Maintaining sinus rhythm can potentially improve their quality of life.

The use of most antiarrhythmic agents, except amiodarone and dofetilide, is

associated with worse prognosis due to proarrhythmic or negative inotropic effects

and should be avoided in HF patients. Although amiodarone and dofetilide do not

increase mortality in HF patients, they are associated with increased

hospitalizations.

219 Current treatment guidelines do not support the routine use of

anticoagulants in HF unless patients have concomitant AF or evidence of active

thrombus. Finally, AV nodal ablation may be needed if tachycardia or bothersome

symptoms persist despite aggressive pharmacologic intervention.

B.D. experienced AF while already taking a relatively high dose of digoxin (0.25

mg/day) and metoprolol. If his AF-associated palpitations persist, amiodarone

should be started (see Chapter 15, Cardiac Arrhythmias). Amiodarone is a PGP

inhibitor. The net effect of inhibition of gut PGP by amiodarone is increased

bioavailability of digoxin. B.D.’s digoxin dose will need to be lowered by ~50% if

amiodarone is started.

213,221

If digoxin is continued, serum levels should be closely

monitored and patients observed for clinical evidence of toxicity.

DIGOXIN DRUG INTERACTIONS

CASE 14-2, QUESTION 7: What are other potential drug interactions with digoxin?

Two reviews of cardiac glycoside drug interactions have been compiled.

222,223

Since publication of these early reviews, a greater understanding of PGP-mediated

drug interactions has evolved.

221,224 A brief summary of all digoxin interactions is

found in Table 14-12. Drugs recently recognized as raising digoxin serum

concentrations through PGP inhibition include atorvastatin.

225 CCBs (especially

verapamil and diltiazem),

226 erythromycin and clarithromycin,

227,228 and cyclosporine.

Conversely, rifampin

195 and St. John’s wort

229

reduce oral digoxin bioavailability and

serum concentrations via induction of intestinal PGP.

DIGITALIS TOXICITY

Signs and Symptoms

CASE 14-2, QUESTION 8: If B.D. presents with digoxin toxicity, what would be the common signs and

symptoms of toxicity?

Digoxin has a narrow therapeutic index, and there is concern for morbidity and

death associated with its use. The most important signs of digoxin toxicity are those

relating to the heart. A common misperception is that gastrointestinal or other

noncardiac signs will precede cardiac toxicity. To the contrary, cardiac symptoms

precede noncardiac symptoms of digitalis toxicity in up to 47% of cases. Frequently

nonspecific arrhythmias are the only manifestation of toxicity, with estimates that

rhythm disturbances occur in 80% to 90% of all patients with digitalis toxicity.