Artigo - When, and When Not, to Use Digoxin

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DRUG THERAPY Drugs & Aging 1997 Jun; 10(6); 411-420 
1 170-229X/97/CXXJ6.D41 I/S05.oo/0 
© Adis International Umited. All rights reseNed. 
When, and When Not, to Use Digoxin 
in the Elderly 
A. T. Marcel Gosselink, Dirk J. van Veldhuisen and Harry J.G.M. Crijns 
Department of Cardiology /Thoraxcenter, University Hospital Groningen, Groningen, 
The Netherlands 
Contents 
Summary .............. . .... . 411 
412 
412 
413 
413 
414 
414 
415 
416 
417 
417 
418 
418 
418 
1. Digoxin in Heart Failure . . ......... . 
1 .1 Inotropic versus Neurohumoral Effects . 
1.2 Randomised Trials ... . 
1.3 Disease Severity .... . 
1.4 Dosage Considerations 
1.5 Effect on Mortality . . . 
2. Digoxin in Atrial Fibrillation (AF) . 
2.1 Ventricular Rate Control in Chronic AF . 
2.2 Restoration of Sinus Rhythm .... . 
2.3 Digoxin for Paroxysmal AF ..... . 
2.4 Contraindications for Digoxin in AF . 
3. Digoxin in the Elderly . 
4. Conclusions . . . . . . . . . . . . . . . . . 
Summary Digitalis has been widely used in the treatment of cardiac disease for more 
than 200 years. The present article reviews the current role of digitalis in the 
management of heart failure and atrial fibrillation (AF) in light of recent study 
findings. 
Generally, first-line therapy for the management of heart failure due to systolic 
dysfunction should include an ACE inhibitor and a diuretic. In patients who 
remain symptomatic despite the use of these drugs, the addition of digoxin should 
be considered. Because digoxin has been shown to reduce the number of hospital 
admissions attributable to worsening heart failure, more liberal use of digoxin in 
the management of heart failure may be justified. 
Digoxin may be adequate as monotherapy for ventricular rate control in pa­
tients with chronic AF, particularly in sedentary and elderly patients. A ~-blocker 
or calcium antagonist (either alone or in combination with digoxin) is indicated 
when digoxin is ineffective for ventricular rate control. Digoxin is ineffective in 
restoring sinus rhythm, preventing paroxysms or controlling rate in paroxysmal 
AF. 
The elderly are at an increased risk of digoxin toxicity. Low dosages of digoxin 
appear to be effective in the treatment of heart failure due to systolic dysfunction 
and may reduce the incidence of digitalis toxicity in these patients. In elderly 
412 Gosse/ink et al. 
patients with AF and inadequate rate control who are receiving digitalis mono­
therapy, adding another atrioventricular nodal blocking drug may be more appro­
priate than increasing the digoxin dose, in order to avoid toxic digoxin levels. 
Cardiac glycosides have been widely used in the 
treatment of cardiac disease for more than 200 
years. Nevertheless, controversy has surrounded 
the use of digoxin since its introduction. Although 
the use of cardiac glycosides in the treatment of 
supraventricular tachyarrhythmias, particularly 
atrial fibrillation (AF), has generally been well ac­
cepted, the role of digoxin in the management of 
congestive heart failure with sinus rhythm has been 
the subject of much debate. 
In recent years, intense research efforts have 
been made to elucidate the role of digoxin in the 
treatment of patients with cardiovascular disease. 
These have greatly enhanced our understanding of 
the value and limitations of digoxin therapy. This 
article presents the current state of knowledge re­
garding the role of digoxin in the management of 
AF and in congestive heart failure with sinus 
rhythm in light of recent study findings, with a spe­
cial focus on the elderly. 
1. Digoxin in Heart Failure 
In recent years, the concept of the pathophysi­
ology of heart failure has undergone significant 
changes. Traditionally, heart failure has been con­
sidered a haemodynamic disorder and, as a result, 
drug treatment has primarily attempted to correct 
haemodynamic abnormalities. Evidence has accu­
mulated, however, that disease progression in 
chronic heart failure is related to neurohumoral as 
well as haemodynamic factors.[I) Recent data 
strongly support an important role for neurohu­
moral modulation or inhibition in the treatment of 
heart failure. Moreover, the favourable long term 
effects of some drugs in heart failure, particularly 
ACE inhibitors, have largely been attributed to 
their neurohumoral effectsP) 
In the past, digoxin has been considered a pure 
positive inotropic agent. Thus, the disappointing 
results achieved with positive inotropic agents in 
some large scale trials conducted in the 1980s led 
© Adis International Limited. All rights reserved. 
to the concern that similar disappointing effects 
could be expected with digoxin, particularly be­
cause the deleterious effects of inotropic drugs ap­
peared to be independent of their mechanism of 
action. [3) In recent years, evidence has emerged 
that digoxin exerts its positive inotropic effects 
mainly at higher dosages; at lower dosages, little 
inotropic activity but more pronounced neuro­
humoral effects are observed. (4) 
1.1 Inotropic versus Neurohumoral Effects 
The potential benefit of digoxin in chronic heart 
failure has, until recently, been thought to be re­
lated purely to its haemodynamic (i.e. positive ino­
tropic) effects. Several studies have shown that 
long term digoxin therapy improves ventricular 
performance and is clinically beneficial in patients 
with symptomatic heart failure caused by systolic 
dysfunction, through a sustained positive inotropic 
effect. [5 ,6) 
The neurohumoral and autonomic effects of dig­
oxin have been evaluated in several studies.[7-12) 
Digoxin appears to modulate sympathetic tone)7] 
In heart failure, digoxin generally has an inhibitory 
effect on sympathetic function, probably mediated 
by improvement or normalisation of impaired 
baroreceptor-mediated mechanisms)S,9) Adminis­
tration of digoxin immediately reduces plasma nor­
epinephrine (noradrenaline) levels in heart failure 
patients,[IO) reflecting a reduction in sympathetic 
tone; this effect appears to be sustained after 6 
months of maintenance digoxin therapy.lll) Dig­
oxin may also lower plasma renin[ll] and aldoste­
rone l9) levels, although the latter effect is not very 
pronounced.[II) 
In addition to these neurohumoral actions, the 
effects of digoxin on both cardiopulmonary and ar­
terial baroreceptor function in humans have long 
been recognised.[S,IO) However, the reasons why 
baroreceptor reflex function is impaired in heart 
failure have not been fully elucidated, and neither 
Drugs & Aging 1997 Jun; 10 (6) 
Digoxin 
have the mechanisms by which digoxin improves 
baroreceptor function in this syndrome. Several 
possible explanations for the latter have been sug­
gested, including: (i) a direct receptor effect; (ii) an 
increase in blood pressure; and (iii) inhibition of 
excessive activation of the sodium-potassium 
adenosine triphosphate pump.llO.12] Recently, it 
was demonstrated that digoxin therapy was associ­
ated with an increase in heart rate variability (a 
valuable tool for examining autonomic function), 
both in patients with moderatel13] and mildl14] heart 
failure. 
1.2 Randomised Trials 
Many earlier studies of digoxin in heart failure 
had methodological limitations. However, during 
the last decade several well-designed trials of dig­
oxin have been undertaken (table I). Three of these 
studies,15,6,15] published in the late 1980s, did not 
primarily investigate digoxin itself but included it 
as a reference drug.l5,6,15] In these trials, digoxin 
was found to significantly increase left ventricular 
ejection fraction I5 ,6] and exercise time,16] and to de­
crease the signs and symptoms of heart failure, 
compared with placebo.l 15] 
More recently, 2 placebo-controlled digoxin 
withdrawal studiesI16,17] showed that digoxin had 
a beneficial effect on exercise capacity, ejection 
fraction and clinical variables, both in the pres­
encel16] and in the absence[17] of concomitant ACE 
413 
inhibitor therapy. However,the question remains 
whether these results can be applied to patients in 
whom digoxin treatment is initiated.118] Neverthe­
less, the overall results of these trials provide evi­
dence supporting the use of digoxin for chronic 
heart failure. 
1 .3 Disease Severity 
Although it is generally assumed that patients 
with moderate to severe heart failure benefit more 
from digoxin therapy,119] evidence exists that the 
drug might also be effective in patients with less 
advanced disease. IIO] These findings are supported 
by our own recent datal II ,20] and that of other work­
ers .121 ] In the Dutch Ibopamine Multicenter 
Trial,lll] patients with predominantly mild heart 
failure were randomised to receive digoxin, 
ibopamine or placebo. The results showed that dig­
oxin significantly improved exercise time over that 
achieved with placebo after 6 months. Subgroup 
analysis indicated that the drug was indeed rela­
tively more effective in patients with more ad­
vanced disease; nevertheless, it was also effective 
in patients with mild disease. These results are in 
agreement with data from another recent study in 
patients with mild heart failure. 121 ] 
In the setting of heart failure secondary to acute 
myocardial infarction, digoxin may be associated 
with an unfavourable clinical outcome;122] how­
ever, most studies in this area have been conducted 
Table I. Recent double·blind, randomised, placebo-controlled trials of digoxin in heart failure 
Reference No. of Duration NYHA Mean Improved Worsening of Cardiac mortality 
patients' (wk) class ejection exercise heart failure (%) (%) 
fraction (%) tolerance with digoxin placebo digoxin placebo 
digoxin 
Captopril-Digoxin Multicenter 196 24 II-III 25 No 15 29· 7 6 
Research Group 1988151 
DiBianco et al. 1989[61 111 12 II-III 25 Yes 15 47* 5 6 
van Veldhuisen et al. 1993[111 108 26 II-III 28 Yes 0 4 4 6 
German and Austrian Xamoterol 213 12 I-III NA No 4 6 0 
Study Group 1988[151 
Packer et al. 1993[161 178 12 II-III 26 Yes 5 25· 3.5 
Uretsky et al. 19931171 88 12 II-III 27 Yes· 19 39· 2 4 
a Number of patients in the digoxin plus placebo arm. 
Abbreviations and symbols: NA = not available; NYHA = New York Heart Association; • p 1.2 IlglL may be of 
questionable clinical benefit. It should be noted, 
however, that comparing serum digoxin concentra-
1 PROVED = Prospective Randomised Study of Ventric­
ular Failure and the Efficacy of Digoxin; RADIANCE = 
Randomised Assessment of Digoxin or Inhibitors of the 
Angiotensin Converting Enzyme. 
© Adls Internaftonal Limited. All rights reserved. 
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Norepinephrine Aldosterone 
(noradrenaline) 
Neurohormone 
Gosselink et al. 
o Placebo 
• Digoxin 
Renin 
Fig. 1. Changes in plasma neurohormone levels after 3 months 
of monotherapy with digoxin (n = 22) or placebo (n = 18) in 
patients with mild to moderate heart failure, expressed as a 
percentage of the baseline value (after Brouwer et al. ,[141 with 
permission). Symbol: * p 0.45 . 
The primary end-point of the study was the ef­
fect of digoxin on total mortality; secondary end­
points included a (first) hospital admission for 
Drugs & Aging 1997 Jun; 10 (6) 
Digoxin 
III 
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• Digoxin 
o Placebo 
HF 
415 
Fig. 2. Effects of digoxin on time domain and frequency domain heart rate variability indices after 3 months of monotherapy with 
digoxin (n = 22) or placebo (n = 18) in patients with mild to moderate heart failure. Changes are expressed as a percentage of the 
baseline value (after Brouwer et al.,114) with permission), Abbreviations and symbols: HF = high frequency power; LF = low frequency 
power; pNN50 = percentage difference between successive normal R-R intervals >50ms; rMSSD = root mean square of successive 
difference; SDNN '= standard deviation of normal R-R intervals; • p 3 years, although there was a 
trend towards a decrease in the risk of death attrib­
utable to worsening heart failure,l26] However, the 
number of hospital admissions both overall and for 
worsening heart failure were significantly reduced 
by digoxin. With regard to the combined end-point 
of mortality from worsening heart failure or a 
hospitalisation relating to that diagnosis, the bene­
fit of digoxin appeared to be greater among pa­
tients at high risk; that is, those with lower ejection 
fractionsor enlarged hearts, and those in New York 
Heart Association (NYHA) functional class III or 
IV. 
© Adis International Limited. All rights reserved. 
Most patients in the DIG studyl26] were taking 
0.25 mg/day of digoxin, and almost 30% of pa­
tients had a serum digoxin concentration of > 1.0 
fJ.g/L (measured >6 hours after each dose). How­
ever, no data were presented concerning the influ­
ence of digoxin dosage or serum concentrations on 
clinical outcome. Overall, the incidence of digoxin 
toxicity was low, although the incidence of 
hospitalisation for suspected digoxin toxicity was 
significantly higher in the digoxin than in the pla­
cebo group (2.0 vs 0.9%; P 5% in 
those aged >75 years.l27] Approximately 50% of 
patients with AF are aged> 75 years. I27] 
Drugs & Aging 1997 Jun: 10 (6) 
416 
AF is associated with considerable excess mor­
bidity and mortality. In particular, the increased 
risk of thromboembolic stroke poses a major threat 
to patients with AF. In recent years, anti thrombotic 
strategies in AF have undergone extensive clinical 
evaluation. 
Two treatment strategies have evolved in the 
management of patients with AF: (i) restoration 
and maintenance of sinus rhythm; or (ii) ventricu­
lar rate control. Determining the appropriate treat­
ment strategy for an individual patient requires a 
thorough assessment of symptomatology, aetiol­
ogy, the presence of underlying heart disease, and 
the duration and temporal pattern of the arrhyth­
mia. Restoration of sinus rhythm improves exer­
cise capacity, as indicated by an increase in peak 
oxygen consumption (fig. 3),[28] and peripheral 
blood flow,[29] and is associated with a decrease in 
atrial size[30] compared with ventricular rate con­
trol. Unfortunately, at the present time, data from 
randomised studies comparing both treatment 
strategies are not available, although such studies 
are now under way.[31] 
Digoxin is the oldest therapy for AF and is still 
the most frequently prescribed drug for ventricular 
rate control in patients with this arrhythmia. De-
30 
25 
c;; 
~ 20 
.§ 
I 15 
o 
> 
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'" Cl.. 
5 
o 
1 ' 1 
AF SR 
• V02 before cardioversion 
o V02 after cardioversion 
AF AF 
Fig. 3. Peak oxygen consumption (VO,) before and 1 month 
after electrical cardioversion in patients who, after cardioversion 
of atrial fibrillation (AF), were still in sinus rhythm (SA; n = 37) 
or experienced a relapse (n = 26). All patients received negative 
chronotropic drugs before cardioversion, and some were also 
receiving antiarrhythmic agents. Drug therapy remained un­
changed throughout the study. Adapted from Gosselink et alPS) 
Symbol: * pof Sinus Rhythm 
Contrary to widespread belief, digoxin is not 
efficacious for the restoration of sinus rhythm in 
AF. In a double-blind, randomised study in patients 
with recent-onset AF, digoxin was found to have 
no benefit over placebo in inducing sinus 
rhythm.(42) This finding is in agreement with the 
observation that digoxin shortens the atrial refrac­
tory period and increases dispersion of refractori­
ness,(43) an effect that would actually tend to in­
crease the fibrillatory rate and therefore lessen the 
likelihood of conversion to sinus rhythm. How­
ever, in patients with left ventricular dysfunction, 
digoxin may promote conversion to sinus rhythm 
by improving the overall haemodynamic situation 
owing to its negative chronotropic and positive 
inotropic effects. 
2.3 Digoxin for Paroxysmal AF 
The aim of treatment in paroxysmal AF is 2-
fold: to prevent paroxysms from occurring, and to 
control the ventricular rate during a paroxysm. 
There are currently no data to suggest that digoxin 
is helpful in achieving either of these goals. In a 
study by Rawles et aJ.f44J that compared outcomes 
in patients taking digoxin (n = 31) with those in 
patients who were not (n = 41), digoxin reduced 
neither the frequency of paroxysms nor the ventric­
ular rate during paroxysms, but was associated 
with longer attacks. In an another study, digoxin 
Drugs & Aging 1997 Jun; 10 (6) 
418 
also failed to control ventricular rate in paroxysmal 
AF.[451 
Although neither of the 2 aforementioned stud­
ies[44,451 were randomised, thus potentially intro­
ducing selection bias, on the basis of the available 
data digoxin cannot be recommended for paroxys­
mal AF. The observation that digoxin has no effect 
on ventricular rate during paroxysmal AF, yet con­
trols heart rate in chronic AF, may be explained by 
the high sympathetic tone at the onset of a parox­
ysm, a situation in which digoxin is ineffective.[461 
2.4 Contraindications for Digoxin in AF 
Digoxin is contraindicated in certain subsets of 
patients with AF. In patients with hypertrophic car­
diomyopathy, the positive inotropic action of dig­
oxin may increase the subaortic obstruction, dimin­
ish the effective orifice of the left ventricular 
outflow tract and contribute to 'cavitory oblitera­
tion' .147) Digoxin should therefore be avoided in 
these patients. Patients with Wolff-Parkinson­
White syndrome and AF associated with rapid ven­
tricular response are at risk of developing ventric­
ular fibrillation because of rapid ventricular 
conduction via the accessory pathway. Digoxin 
may shorten the refractory period of the accessory 
pathway, thereby facilitating the development of 
ventricular fibrillation.l481 Therefore, digoxin 
should be avoided in patients with Wolff-Parkinson­
White syndrome, particularly in those with R-R in­
tervalsstudy of ibopamine and 
. digoxin in patients with mild to moderate heart failure: results 
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© Adls International Limited. All rights reserved. 
419 
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partment of Cardiology /Thoraxcenter, University Hospital 
Groningen, P.O. Box 30.001, 9700 RB Groningen, The Neth­
erlands. 
Drugs & Aging 1997 Jun; 10 (6) 
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 /KOR/LTH 
 /LVI 
 /NLD (Gebruik deze instellingen om Adobe PDF-documenten te maken waarmee zakelijke documenten betrouwbaar kunnen worden weergegeven en afgedrukt. De gemaakte PDF-documenten kunnen worden geopend met Acrobat en Adobe Reader 6.0 en hoger.)
 /NOR 
 /POL 
 /PTB 
 /RUM 
 /RUS 
 /SKY/SLV 
 /SUO 
 /SVE 
 /TUR 
 /UKR 
 /ENU 
 >>
>> setdistillerparams
> setpagedevice