Download The Use of Digitalis Glycosides in Sinus Rhythm

Clinical Scienceand Molecular Medicine (1978) 55,417-421
EDITORIAL REVIEW
The use of digitalis glycosides in sinus rhythm
A. G U Z
AND
D. M C H A F F I E
Department of Medicine, Charing Cross Hospital Medical School, London
Historical perspective
Throughout the last 200 years the use of digitalis
glycosides has constantly revealed the weakness of
the contemporary understanding of congestive
heart failure; in consequence the reputation of these
drugs has either soared or slumped according to
physicians’ prejudices. Withering (1 785) identified
Digitalis purpurea as the diuretic ingredient of the
Shropshire woman’s herbal brew and in his study
of 160 patients he showed that it could relieve
dropsy in most of his cases. Although he knew that
the drug ‘influenced the pulse’, the concept of heart
failure was not recognized, and the primary cardiac
action of the drug was not then known. The
indications for its use were ill-defined and with
more widespread prescription many patients, with
little prospect of improvement, were exposed to
serious risk from toxic side-effects. Withering knew
of no other agent with comparable properties, and
he succeeded where many other failed by adopting
a reliable dosage regimen and using an experimental approach in each case. He was conscious of the
questions that were to inhibit the sustained use of
the drug for over 100 years. How does digitalis
work? What identifies patients who will benefit?
How can the clinical response be measured? How
may the risks of treatment be avoided? All are
lively questions even today!
After the rejection of digitalis as a dangerous
drug of dubious efficacy at the end of the
eighteenth century, and the drug being sidetracked
for much of the nineteenth century as a treatment
for fevers (Keele, 1966), McKenzie (191 1) reintroduced digitalis into cardiovascular therapeutics
because its atrioventricular nodal blocking properties slowed the ventricular response in atrial
Correspondence: Professor A. Guz, Department of
Medicine, Charing Cross Hospital Medical School,
London W.6.
29
fibrillation. He showed that digitalis was particularly beneficial in patients with mitral stenosis
and atrial fibrillation. With Lewis (1942) he
developed the concept that heart failure was caused
by ‘fatigue’ of the ventricular muscle and they
proposed that relief in mitral stenosis resulted from
cardiac slowing because this allowed the muscle to
rest. This controversial aspect of the history of
clinical cardiology has been reviewed by
McMichael (1975), who concluded that there was
evidence from McKenzie’s own work that a factor
independent of heart rate control was contributicg
to clinical benefit. Nonetheless, McKenzie and
Lewis considered atrial fibrillation as the specific
indication for digitalis and were convinced that few
other cases benefited from it. In North America,
some workers attempted to examine systematically
the effects of digitalis in patients with a variety of
cardiac conditions and rhythms. Comparisons of
the action of digitalis in sinus rhythm and in atrial
fibrillation were made by Christian (1922), Luten
(1924) and Marvin (1927). These authors reported
a total of over 130 patients and showed that
digitalis was associated with improvement in about
half the cases in which it was used. They proposed
that patients with sinus rhythm benefited as much
as those with atrial fibrillation. Gavey & Parkinson
(1939) reviewed the controversy, and from their
own work concluded that for patients with nonrheumatic atrial fibrillation or sinus rhythm, there
was a similar beneficial result from use of digitalis.
Patients with rheumatic atrial fibrillation, who
showed the greatest reductions of heart rate,
responded best of all.
With the advent of haemodynamic studies in
man, the place of digitalis as first choice in the
treatment of heart failure became more firmly
established. The glycosides were shown to have an
inotropic action in animals and in man, both with
normal and abnormal hearts (Smith & Haber,
417
418
A . Guz and D. McHafje
1973). The subcellular and ionic mechanisms for
this action were thought by most workers to result
from a glycoside-induced inhibition of membranebound Naf + K+-dependent adenosine triphosphatase (ATPase), which resulted in a rise in the
intracellular pool of free Cazf. The mechanism of
this rise was not understood, but the effect would
be a facilitation of excitation-contraction coupling
(Lee & Klaus, 1971). Intravenous usage was
certainly associated with reductions of intracardiac diastolic pressures and increases in cardiac
output. If the syndrome of heart failure was caused
by reduced contractility of the ventricular muscle,
and if this abnormality was chronically reversible,
there appeared to be every reason why these drugs
should work in the long term. The appeal of this
approach was that the prolonged systolic time
intervals, the diminished velocity of circumferential fibre shortening, the reduced peak rate of
change of ventricular pressure (dpldt) etc. could
all be favourably influenced by digitalis glycosides.
This inotropic activity, considered to be the key to
digitalis action, has reinforced teaching in several
medical textbooks that digoxin is indicated in all
forms of heart failure irrespective of the cause and
whatever the rhythm (Scott, 1973; Beeson &
McDermott, 1975; Goodman & Gilman, 1975).
Although some doubts have been expressed about
the basis for such practice (Editorial, 1976), the
volume of prescriptions for digoxin in the U.K. has
continued to rise steadily for the last 5 years, and in
this decade the digitalis glycosides have become the
fourth most commonly prescribed drug in the
United States (Schick & Scheuer, 1974). For all
this, there has been little evidence that chronic
stimulation of the diseased heart yields clinical
improvement that could not be produced by
alternative means.
dynamic abnormalities in patients with heart failure
could be improved without directly stimulating
cardiac muscle. McMichael & Sharpey-Schafer
(1944) showed that mechanical lowering of right
atrial pressure in such patients produced changes in
central venous pressure and cardiac output similar
to those produced by digitalis. These observations
were extended when Pugh & Wyndham (1949)
provided evidence that the intravenous use of
diuretics produced similar results.
Later, Rader, Smith, Berger & Eichna (1964)
showed that diuretic therapy for heart failure could
be used alone on a chronic basis; clinical improvement occurred in the majority of patients. There
were changes in haemodynamic variables, but little
correlation between such changes and the magnitude of the clinical response; this appeared to
most closely parallel the relief of oedema produced
by the diuretic. When these workers then added
digoxin, increases in cardiac output were seen in
some individuals with sinus rhythm, particularly
where there had been no haemodynamic change
with the mercurial diuretics, but there was no
further diuresis or weight change in this subgroup
and it was not possible to identify digoxin
‘responders’ on purely clinical criteria.
Modern diuretics such as frusemide and bumetanide are very potent agents for the relief of salt
and water retention. These drugs will relieve oedema
and symptoms in the majority of patients; the dose
may be readily adjusted to the clinical response
and the drugs have higher therapeutic/toxic ratios
than does digoxin. It is, however, uncommon to
find them being used alone but rather in combination with long-term digoxin therapy.
Role of diuretics
Does the inotropic action of digitalis persist?
In Gavey & Parkinson’s (1939) study on digitalis,
an examination was made of the response to
diuretics in 16 patients with heart failure in sinus
rhythm who had been refractory to cardiac glycosides. All had a diuresis, including some in whom
oedema was not obvious. It is surprising that the
demonstration that for some patients a diuretic was
more effective than digitalis did not suggest the need
for a comparison of the effects of the two drugs.
Diuretics were regarded as little more than adjuvants to therapy because they did not influence
‘myocardial insufficiency’.
Several observations suggested that the haemo-
This crucial clinically relevant question does not
seem to have been asked until recently. Mahler,
Karliner & O’Rourke (1974) could demonstrate a
maintained improvement in several aspects of myocardial performance in the conscious dog given
intramuscular digoxin for 8 days. Subsequently,
Crawford, Karliner & O’Rourke (1976) showed
similar changes in normal man over a period of
10-14 days: these effects were small, although
significant. Dobbs, Kenyon & Dobbs (1977)
demonstrated a maintained shortening of left
ventricular ejection time over a period of 1 month
in patients with heart disease who were given
Is the long-term usage of digitalis worthwhile?
Use of digitalis glycosides
digoxin. By contrast, Davidson & Gibson (1973),
in a careful study of this question in patients who
had an aortic valve prosthesis, raised some doubts
about whether the inotropic action of digoxin
persists in the abnormal heart. A small inotropic
effect could be detected 4-6 h after an oral dose of
digoxin, but with continued dosage no such effect
could be demonstrated over the remaining 10 days
of therapy, although the plasma concentrations of
the drug were within the therapeutic range. Selzer
(1960) also found that the improvement in cardiac
output diminished over time when digoxin was
given to patients in left ventricular failure with
sinus rhythm. Cohn. Selzer, Kersh, Karpman &
Goldschlager (1975) confirmed these results and
showed that in the majority of such patients there
was partial or total loss of the initial benefit over a
period of 4 h.
A different approach to the same problem has
been the study of the effects of the withdrawal of
digoxin administered in the long term to patients
who have been in heart failure, but are in sinus
rhythm. Starr & Luichi (1969) doubted the
maintenance of an inotropic action; they could not
demonstrate any change in ballistocardiographic
recordings after digitoxin withdrawal in a group of
geriatric patients.
Such withdrawal has also been studied by
documenting whether clinical deterioration occurs
in such patients. Dall (1970) found that maintenance digoxin could be stopped without detriment in 75% of a large group of elderly patients;
unfortunately those subjects in sinus rhythm were
not differentiated from those in atrial fibrillation.
Fonrose, Ahlbaum, Bugatch, Cohen, Genovese &
Kelly (1974) thought that ‘slight’ signs of cardiac
‘decompensation’ occurred in 50% of another
geriatric group of patients when digoxin was
withdrawn. Dobbs et al. (1977) in a double-blind
trial substituted placebo for digoxin; 30% of 46
patients deteriorated on placebo, but this included
four with atrial fibrillation. A common feature of
deterioration in these studies was increased salt and
water retention. Hull & MacIntosh (1977) showed
that digoxin withdrawal did not result in deterioration in 17 out of 18 patients in sinus rhythm
provided that diuretic therapy was adjusted to
control any salt and water retention.
Do the biochemical changes accompanying digoxin
action persist in the long term?
Grahame-Smith (1978) has studied digoxin
binding to the Na+ + Kf-dependent ATPase
419
system in the erythrocyte membrane; this system
has been used as a model for digoxin action on
cardiac muscle (Erdman & Hasse, 1975).
During the initial administration of digoxin to
patients in sinus rhythm with heart failure, there
appeared to be a fall in the number of receptors on
the erythrocyte surface available for binding a
[3H]digoxin marker, as a result of the occupation
of receptor sites by unlabelled digoxin. The
associated inhibition of the Na+ + K+-dependent
ATPase system in the erythrocyte membrane could
be correlated with the observed shortening of time
intervals in cardiac systole. However, after treatment for a minimum of 2 months, a reverse trend
was found despite the maintenance of therapeutic
plasma concentrations. [3H1Digoxin binding
increased to pretreatment values, and the inhibition
of the Na+ + K+-dependent ATPase system was
diminished; systolic time intervals lengthened. The
erythrocyte apparently became pharmacologically
tolerant to digoxin during long-term therapy. If the
erythrocyte model is at all relevant to inotropic
action then the results suggest that this pharmacological effect on the heart may also diminish with
time.
Prevalence of digitalis toxicity with long-term use
Digitalis toxicity has been called “one of the
most prevalent adverse drug reactions observed in
clinical medicine” (Smith, 1975). It has been found
in up to 19% of patients admitted to hospital who
are using the drug and there are reports of
mortality in similar patients ranging from 7 to
50%. Measurement of digoxin concentrations in
the blood does not always detect cardiac toxicity
(Ingelfinger & Goldman, 1976).
Does digoxin increase the capacity for exercise in
patients with myocardial disease in sinus rhythm?
It has become apparent that congestive heart
failure is not simply a state of low cardiac output.
It is instead a more complicated syndrome of
impaired cardiac function characterized by salt and
water retention. The signs and symptoms are
predominantly those of intra- and extra-vascular
space congestion and any treatment that relieves
these features produces improvement in the patient
irrespective of the haemodynamic change that
ensues. If direct cardiac stimulation by digoxin is
not required for relief of the signs and symptoms of
heart failure in the majority of cases, if the longterm use of the drug is associated with serious risk
420
A . Guz and D.McHafJie
of toxicity, and if there is doubt about long-term
inotropism, then it is important to examine
whether the drug provides benefits in the form of
improved exercise capacity.
There is remarkably little information available
on this point. Bruce, Lind, Franklin, Muir, McDonald, McNichol & Donald (1968) were unable to
demonstrate any increase in the maximum
dynamic response to exercise in normal subjects
given an intravenous dose of digoxin. Selzer &
Malmborg (1 962) were able to increase the cardiac
output response to exercise in some patients with
‘latent’ heart failure as a result of an intravenous
dose of digoxin; unfortunately these authors do not
report whether these patients were able to do more
exercise as a result.
None of these studies answers the fundamental
question about the possibility of a long-sustained
benefit resulting from the inotropic action of
digoxin in patients with symptomatic congestive
cardiac failure. How should this question be
resolved and what are the important specifications
for a study designed to answer it?
The most important principle is to separate those
responses expected with modern diuretics from the
benefits obtained from augmenting myocardial
contraction. The specific benefit of digoxin as a
myocardial stimulant can only be examined after
relief of salt and water retention by diuretics.
Patient selection is crucial; those with atrial
fibrillation cannot be studied, because not only may
much of the benefit from digoxin at rest be due to
the induced atrioventricular nodal block, but also
this block is lessened on exercise. Furthermore, if
the basic physiological action of the glycoside is on
cardiac muscle. it would seem sensible to exclude
non-myocardial causes of heart failure, such as
hypertension and valvular disease.
Haemodynamic variables correlate poorly with
clinical condition, and the study design should
therefore move away from the traditional
evaluation of changes in acute haemodynamics and
focus on the measurement of changes in symptoms
and exercise capacity. Evidence of relief of dyspnoea and fatigue and the demonstration that the
patient can do more work, are of greater importance than detecting improvements in contractility
indices or cardiac output. If the subjective responses of the patient can be quantified and shown
to be reproducible, they should be subjected to the
same statistical analysis as the ‘hard’ data derived
from the exercise test.
Important details of the drug administration
should include the use of sufficient diuretic therapy
to produce normal or near-normal body fluid
volumes. This can be checked by isotope dilution
methods, but in all cases attempts should be made
to produce a basal ‘dry’ body weight, with freedom
from oedema and evidence of vascular congestion.
Adjustments of the digoxin regimen should be
made by an experienced independent clinician, for
the aim should be to use sufficient dose to ensure
maximum physiological activity but avoid toxicity.
The patient should be studied both when taking
digoxin and also when taking a placebo. The trial
should be conducted on a double-blind basis. It is
important to eliminate confounding variables such
as enforced bed rest or changes in the range of
daily activities; such variables may affect
symptoms.
In a recent study (McHaffie, Purcell, MitchellHeggs & Guz, 1978) some of these conditions were
met. Six patients in sinus rhythm had myocardial
disease, either past myocardial infarction or cardiomyopathy, causing heart failure. Oral frusemide
was used to produce a ‘dry’ weight and symptoms
of breathlessness and fatigue were improved as
oedema was eliminated. Three pairs of exercise
tests were done during the study period of 3
months and the responses of each patient when
using digoxin and diuretics were compared with
those when using diuretics alone. Visual analogue
scales were employed to measure symptomatic
changes at each test. Five patients who completed
all tests showed no significant change in symptoms,
no difference in work load achieved or any
difference in the heart rate, respiratory rate,
ventilation or respiratory quotient at each work
load whether digoxin was added to or removed
from the treatment regimen.
With reference to the criteria of adequacy of a
trial suggested above, this study had several
limitations. It was not double-blind and the digoxin
dosage was not adjusted beyond ensuring that
serum digoxin concentrations were within the
accepted therapeutic range. There was also no test
of maximal exercise capacity. Nevertheless, in this
group of patients where salt and water retention
could be controlled with diuretics, digoxin did not
improve the sense of well-being nor the capacity for
exercise. The study showed that diuretics could be
used as drugs of first choice for some patients with
heart failure in sinus rhythm.
Conclusion
There is ample evidence that digoxin, when used in
the short term, stimulates the heart and may relieve
Use of digitalis glycosides
the symptoms of cardiac failure in patients with
normal rhythm. Its role in the treatment of the
chronic heart failure syndrome with sinus rhythm
remains uncertain. There are genuine doubts that
the drug is effective with long-term administration
and there is considerable risk of toxicity. A
characteristic feature of congestive heart failure is
that symptomatic benefit can be obtained by
measures that relieve intra- and extra-vascular
congestion. Since cardiac stimulation may not be
required to achieve this, digoxin may not be
essential treatment for such patients. It seems
rational to suggest that the achievement of a ‘dry’
weight with diuretics should be the first objective in
the treatment of congestive cardiac failure with
sinus rhythm. Digoxin could then be administered
and withdrawn as required, to ascertain whether
the use of this drug further improved the clinical
state.
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