Journal of Clinical Pharmacy and Therapeutics (2003) 28, 347–348
Optimizing digoxin dosage: the long winding road
1A. Li Wan Po* B Pharm PhD and M. J. Kendall MD FRCP
*Centre for Evidence-Based Pharmacotherapy, Aston University, Birmingham, UKand Division of Medical Sciences, University of Birmingham, Birmingham, UK
‘Conclusions of so much moment to the welfare of
receiving digoxin were randomized to continue
mankind cannot be formed from the events of a few
with digoxin or placebo for 12 weeks. Although in
weeks or months. They must depend on an estimate
RADIANCE, the patients also received concurrent
of the greater number of results, from many cases,
angiotensin-converting enzyme inhibitors whereas
under circumstances nearly similar. This is the
in PROVED they did not, both studies showed that
foundation of experience with every rational man,
patients randomized to the placebo group did less
not only in medicine, but in all reasoning concern-
well in terms of maximum exercise tolerance and
ing probable evidence. The mischief of precipitate
treatment failures. While those results provided
conclusions is nowhere more sensibly felt, than in
some rationale for the continued use of digoxin,
they were not powered to detect differences in
While earlier clinical use of digitalis is well
mortality and the design clearly targeted a specific
documented, William Withering is credited with
subgroup of heart failure patients, namely those
formally introducing digitalis into clinical medicine
stable on digoxin. Generalizabilty of the results was
over two centuries ago (2). With the development
therefore limited. The DIG trial (6) was designed to
of chemical techniques, digitoxin was isolated and
overcome those short-comings. It randomized
characterized from Digitalis purpurea and digoxin
patients with ischaemic and non-ischaemic heart
from D. lanata However, since 1785 digitalis gly-
failure, stable sinus rhythm and left ventricular
cosides have been the subject of considerable dis-
ejection fraction of 45% or less; 3397 to digoxin and
cussion and experimentation. Perhaps even Ferriar
3403 to placebo. Both digoxin-naı¨ve patients and
(1799) would have been surprised to find that the
patients withdrawn from digoxin were included in
optimum use of digitalis would be the subject of
the trial. Whereas patients on digoxin had fewer
considerable debate for over 200 years (1). Intro-
hospitalizations for heart failure and improved
duced for the treatment of the dropsy, it was soon
quality of life, compared with those on placebo,
promoted as a treatment for a wide variety of
overall there was no difference in mortality. In fact,
conditions, including mania and pneumonia, with
there was a small increase in cardiac deaths in the
considerable ill-effects (3). The major problem with
digoxin group, which caused considerable unease
digitalis is that appropriate dosing is essential
given that several studies have shown that ino-
given its narrow therapeutic window. As Wither-
tropic drugs such as ibopamine (7), milrinone (8)
ing carefully noted, ‘The foxglove when given in
and vesnarinone (9) increased mortality in heart-
very large and quickly-repeated doses occasions…
slow pulse, even as low as 35 in a minute and, cold
The fact that digoxin can have a beneficial effect
sweats, convulsions, syncope and death.
but may also cause serious harm suggests that it
Two pivotal trials [RADIANCE (4) and PROVED
may be critically important to achieve optimum
(5)] used an unusual, withdrawal from treatment,
plasma concentration. It is therefore of consider-
design to demonstrate digoxin’s efficacy in heart-
able interest that a retrospective analysis of the
failure. Patients with New York Heart Association
RADIANCE and PROVED trials suggested that
(NYHA) class II or III heart failure and with a left
there was little benefit in increasing dosage to reach
ventricular ejection fraction of 35% or less and
blood levels above 0Æ5–0Æ9 ng/mL (10). Further-more, a subgroup analysis of the DIG trial sug-
Correspondence: Professor A. Li Wan Po, Centre for Evidence-Based Pharmacotherapy, Aston University, Birmingham B4 7ET,
gested that there was an increased risk of death as
the blood level of digoxin was increased even
Fig. 1. All-cause mortality rates byserum digoxin concentrationgroups in Drug Investigation Grouptrial [reproduced with permissionfrom Rathmore et al. (12)].
within the generally recognized therapeutic range
assessing the effect of digoxin withdrawal in patients
of 0Æ5–2 ng/mL (11). The latest, more detailed,
with mild to moderate chronic congestive heart
retrospective analysis of the DIG trial data con-
failure: results of the PROVED trial. Journal of the
American College of Cardiology, 22, 955–962.
What then are the implications for practice?
6. The Digitalis Investigation Group (1997) The effect of
digoxin on mortality and morbidity in patients with
Despite the retrospective nature of the analyses
heart failure. New England Journal of Medicine, 336,
(10–12), it would seem prudent to revise the
recommended therapeutic range for digoxin to
7. Hampton JR, van Veldhuisen DJ, Kleber FX et al.
0Æ5–0Æ9 ng/mL, as has already been suggested
(1997) Randomised study of effect of ibopamine on
(Fig. 1). Digoxin is still widely used in general
survival in patients with advanced severe heart
practice and over 4 million prescriptions for digoxin
are dispensed annually in the United Kingdom.
8. Packer M, Carver JR, Rodenheffer RJ et al. (1991)
Given the latest evidence and the fact that digoxin is
Effect of oral milrinone on mortalioty in severe
susceptible to many drug–drug interactions (13)
chronic heart failure. NEJM, 325, 1468–1475.
and inadvertent overdosing (14), we advise careful
9. Cohn, JN, Goldstein SO, Greenberg BH et al. (1998) A
prescribing and periodic blood level monitoring
dose-dependent increase in mortality with vesnari-
when digoxin is used. As Ferriar (1) further noted,
none among patients with severe heart failure. NEJM, 339, 1810–1816.
‘Let me observe, once for all, that nothing is less
10. Adams KF, Gheorghiade M, Uretsky BF, Patterson
accurately fixed in medicine, than one of its most
JH, Schwartz TA, Young JB (1999) Clinical benefits of
important objects, the dose of medicine’.
low serum digoxin concentrations in heart failure[abstr]. Journal of the American College of Cardiology,
11. Gheorghiade M, Pitt B (1997) Digitalis investigation
1. Ferriar J (1799) An essay on the medical properties of the
group (DIG) trial: a stimulus for further research.
Digitalis purpurea, or Foxglove. Manchester: Cadell
American Heart Journal, 134, 3–12.
12. Rathmore SS, Curtis JP, Wang Y, Bristow MR,
2. Withering W (1785) An account of the foxglove, and
Krumholz HM (2003) Association of serum digoxin
some of its medical uses with practical remarks on dropsy,
concentration and outcomes in patients with heart
and other diseases. Birmingham: M Swinney.
failure. Journal of the American Medical Association,
3. Wyckoff J, Du Bois EF, Woodruff IG (1930) The
therapeutic value of digitalis in pneumonia. JAMA,
13. Li Wan Po A (2002) Digoxin-drug interactions: study
design and generalizability. Journal of Clinical Phar-
4. Packer MP, Gheorghiade M, Young JB et al. (1993)
Withdrawal of digoxin from patients with chronic
14. Gurwitz JH, Field TS, Harrold LR et al. (2003) Inci-
heart failure treated with angiotensin-converting
dence and preventability of adverse drug events
enzyme inhibitors. NEJM, 329, 1–7.
among older persons in the ambulatory setting.
5. Uretsky BF, Young JB, Shahidi E, Yellen LG,
Harrison MC, Jolly MK (1993) Randoized study
Ó 2003 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 28, 347–348
and generous support of NJIT, Peter was honored with the uni-versity’s 2008 Edward F. Weston Medal. 1989 and today is president and principal of the firm. Based in Brooklyn, New York, JF Con-tracting works with city, state and federal agencies, as well as Anastasia, Peter and Elsa Papanicolaou with clients in the private sector. The firm’s expertise encompasses Weston honor inte