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JUNE 2015
DIGOXIN
D
igoxin is a cardiac glycoside extracted from
foxglove leaves. Since 1785, when Sir William
Withering published his textbook on the “An
Account of the Foxglove and Some of Its Medicinal
Uses”, digoxin has been used in the treatment of
heart conditions such as heart failure (HF) and atrial
fibrillation (AF). In more recent times, digoxin is
no longer considered first-line therapy for these
conditions. The latest evidence suggests that digoxin
has a very limited place in therapy due to a high
incidence of toxicity and side effects, drug interactions
and risk of death.
Use in older people
Mechanism of action
The generally accepted therapeutic range of serum
digoxin is 0.5–2 microgram/L. In residents with heart
failure, lower concentrations of 0.5–0.8 microgram/L
should be the target. Blood samples should be taken
at least 6 hours after a dose to allow for distribution in
the body system.
Digoxin belongs to the class of medicines called
digitalis glycosides. It is used to improve the strength
and efficiency of the heart, or to control the rate and
rhythm of the heartbeat. This leads to better blood
circulation, slower heart rate and reduced swelling of
the hands and ankles in patients with heart problems.
Indications
The Australian Medicine Handbook 2015 lists the
following indications for digoxin:
■■
AF and atrial flutter
■■
Heart failure
The National Heart Foundation of Australia guideline
for chronic heart failure recommends ACE inhibitors,
unless not tolerated or contraindicated, for all patients
with systolic heart failure, whether symptoms are
mild, moderate or severe. Diuretics should be used
with ACE inhibitors to reduce fluid overload. Betablockers are recommended, unless not tolerated or
contraindicated, for all patients with systolic heart
failure who remain mildly to moderately symptomatic
despite appropriate doses of an ACE inhibitor. A 2011
update of these guidelines recommends low dose
digoxin (62.5 μg/day) for relief of symptoms in people
with advanced heart failure and people with AF.
Digoxin is used mainly as add-on therapy in people
with AF whose heart rates are not adequately
controlled on beta-blockers alone.
Renal function declines with ageing. As digoxin is
predominantly renally cleared (about 70%), the dose
needs to be reduced in renal impairment.
Older people may also be more sensitive to digoxin.
The dose of digoxin in older people is usually within
the range of 62.5–125 micrograms once daily.
Monitoring
Digoxin has a narrow therapeutic range, meaning there
is only a small difference in the blood concentration to
be effective and the level to be toxic.
Residents on digoxin should be monitored for clinical
effect and toxicity. Routine blood level monitoring is
no longer recommended.
For patients with atrial fibrillation, the target should
be control of symptoms at the lowest dose, rather
than aiming for a specific range. When used to control
ventricular rate in AF, a ventricular rate less than 110
beats/minute should be the aim.
Routine measurement of pulse rate before giving next
dose of digoxin is not necessary.
Side effects
The major side effect of digoxin include cardiac
arrhythmias (ectopic and heart block), gastrointestinal
symptoms (nausea, vomiting, anorexia), and
neurologic complaints (visual disturbances,
disorientation, confusion).
Clinical signs of acute digoxin toxicity include
arrhythmias, anorexia, confusion, and hyperkalaemia.
Chronic digoxin toxicity presents similarly, with the
addition of halos, green-yellow vision, blindness,
lethargy, and fatigue.
DIGOXIN
Toxicity may occur at lower serum digoxin levels
when electrolyte disturbances such as hypokalaemia,
hypercalcaemia or hypomagnesaemia coexist.
Hypothyroidism may increase digoxin concentrations.
Drug interactions
St John’s wort, a complementary medicine used for
depression, may reduce the blood concentration of
digoxin by 25%, resulting in reduced effectiveness.
Verapamil may increase digoxin levels resulting in
toxicity. A number of antibiotics and antifungals
can increase digoxin levels, including azithromycin,
clarithromycin, erythromycin, itraconazole and
ketoconazole.
Shifting evidence
The one and only randomised controlled trial (RCT)
trial on digoxin in heart failure by the Digitalis
Investigation Group (DIG) studied the effect of digoxin
on mortality and hospitalisation over a period of
three to five years. People with concomitant AF were
excluded from the trial. Digoxin did not reduce overall
mortality, but it reduced the rate of hospitalisation
both overall and for worsening heart failure. Patients
with more severe symptoms appeared to obtain
symptomatic benefit from the introduction of digoxin,
leading to improved quality of life. It is important to
note that this study was performed before routine use
of beta-blockers; however 94% of patients were taking
ACE inhibitors.
Subsequent analysis of data from the DIG trial showed
the effect of digoxin therapy differs between men
and women. Digoxin therapy is associated with an
increased risk of death from any cause among women,
but not men, with heart failure. After further analysis
of this trial, the optimal range for serum digoxin in
heart failure was decreased to 0.5–0.8 microgram/L.
In 2013 the impact of digoxin on death rates was
further examined. Introduction of digoxin therapy in
patients with new systolic heart failure was associated
with a significant 72% jump in all-cause mortality but
no effect on HF-hospitalisation risk.
Recent analysis confirms that digoxin may increase the
risk of death. A systematic review and meta-analysis of
the current literature published last month indicates
that digoxin therapy is associated with increased
mortality in patients treated for atrial fibrillation or for
heart failure. In patients prescribed digoxin for AF or
heart failure there was a 21% increased risk of death
from any cause. Digoxin was associated with a 29%
increased risk of death in patients with AF, and 14%
increased mortality in patients with heart failure.
Digoxin withdrawal
Withdrawal of digoxin in the presence of an ACE
inhibitor may lead to progressive deterioration
in symptoms and physical activity tolerance, and
increased hospitalisation. Discontinuation has no
effect on mortality.
Summary
The use of digoxin has declined markedly over the
last two decades. Digoxin is now only considered as
adjunctive therapy, rather than first-line therapy for
heart failure or atrial fibrillation. The body of current
evidence suggests that digoxin therapy in patients
with heart failure or atrial fibrillation increases the risk
of death. Digoxin remains a useful therapy in patients
with heart failure with concomitant AF.
References
N Engl J Med. 1997 Feb 20;336(8):525-33.
N Engl J Med. 2002 Oct 31;347(18):1403-11.
JAMA 2003;289(7):871–8.
Circ Cardiovasc Qual Outcomes. 2013 Sep 1;6(5):525-33.
European Heart Journal 2015.