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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 Both digoxin-naı¨ve patients and (1799) would have been surprised to find that the patients withdrawn from digoxin were included in optimum use of digitalis would be the subject of the trial.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

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