Cardiovascular Drugs and Therapy 1993;7:897-898 © Kluwer Academic Publishers, Boston. Printed in U.S.A.

Digoxin

Letter

to

the Editor

Doubts to Dampen Enthusiasm Philip A. Poole Wilson National Heart and Lung Instituteand RoyalBromptonNational Heart and Lung Hospital, London, UK

Key Words. digoxin,

heart failure

Dear Sir: Controversy concerning the use of digoxin in patients with heart failure in sinus rhythm has existed for almost the whole of the present century [1-4]. The debate is not finished. Several recent withdrawal studies [5-7] have revived enthusiasm for the use of digoxin, and the results of the large mortality study currently being undertaken by the National Institute of Health in America are awaited. The article by F.I. Marcus [8] in this journal puts forward an optimistic view. He believes that several clinical trials have shown unequivocally that digoxin decreases symptoms of cardiac failure and declares that the major unresolved question concerning digoxin is safety. I beg to differ. The first issue is to identify what are the key clinical questions concerning the use of digoxin. No physician doubts the value of digoxin in controlling the fast heart rate of patients with atrial fibrillation with or without heart failure. The question is not whether digoxin in patients with heart failure and in sinus rhythm is positively inotropic either acutely or chronically. Nor is the question whether digoxin in selected groups of patients under particular circumstances can be shown to be beneficial for heart failure. Such an argument could be used to justify the continual use of leaches. The key question for the clinician is whether, after a patient has received optimal treatment with ACE inhibitors and a combination of diuretics, the addition of digoxin confers further advantage. The reason that this question is key is that the current initial treatment for overt heart failure is the careful and thoughtful use of [9] an ACE inhibitor combined with a diuretic. The results from the study by Lee et al. in 1982 showed that patients with fluid overload and a third heart sound benefitted from the use of digoxin. That is to be expected, but exactly the same result might have been obtained by the propitious use of an ACE inhibitor and a diuretic. Indeed the clinical and hemodynamic benefit [10] in patients is probably related to change in total body weight [11]. There may be subgroups of patients in whom digoxin is particu-

larly useful, but those subgroups need to be identified in carefully controlled clinical trials. Physicians may well have their own suspicions of who those particular groups might be. There have been a very large number of studies on the use of digoxin in the last century [3,4,12,13]. Most have been withdrawal or observational studies. Some included patients in atrial fibrillation. Very few of these studies would fulfill current criteria for a proper clinical trial. The historical data have been reviewed. One meta-analysis [4] and one overview have been published recently [3]. The meta-analysis found seven trials in the world literature that fulfill the criteria for a modern study but only six of these were included in the overview. The one additional study [5] was rejected from the overview because it was a withdrawal study and did not fulfill the appropriate criteria. The meta-analysis came to the conclusion that there was evidence that the number of patients in the control group who were withdrawn from studies was statistically different from those withdrawn in the group on digoxin. The overview was unable to show any benefit to patients in terms of symptoms or exercise capacity. The numbers are far too small to show any benefit in terms of mortality. These data do not lie easily with the claim by Dr. Marcus that digoxin unequivocally decreases symptoms of heart failure. Furthermore, withdrawal is not a rigorous or robust endpoint for a trial, nor does it answer the question as to whether the patients would be more appropriately treated with diuretics and ACE inhibitors. In one recent trial, withdrawal gave an advantage to patients because those patients were not then exposed to the risk of continuing with the drug [14]. Recently three withdrawal studies have been reported. One has been published as a full paper [5] and the other two as abstracts [6,7]. The problem with this approach is that it does not answer the clinical

Address for correspondence: Philip A. Poole Wilson, Royal Brompton National Heart and Lung Hospital, Dovehouse Street, London, SW3 6LY, UK.

Received 30 June 1993; accepted 5 J u l y 1993. 897

898

Poole Wilson

question of whether adding digoxin to the treatment of a patient confers advantage. The question that is answered is whether the patient, having been started on the drug, should have that drug stopped. The difference is crucially important when considering positive inotropic drugs. F o r example, it has been claimed that amrinone brings about damage to the myocardium because of its positive inotropic effect but that the harm is only seen after the drug is withdrawn, when deterioration in myocardial function is observed. Thus, if after the withdrawal of digoxin the patient deteriorates, the conclusion might be that digoxin was doing good because of its positive inotropic effect or it was doing harm because it had damaged the myocardium during the period of treatment. This problem is particularly evident in the milrinone digoxin study [5]. In that study the patients who increased their exercise tests most were those who remained on digoxin. No alteration was made to their treatment whatsoever, and yet they had a large increase in their exercise capacity. The patients in whom digoxin was withdrawn did not change their exercise capacity. This is not the expected result and presents very real difficulties in interpretation. A further difficulty is that withdrawal studies are limited to those patients who have been able to be placed on digoxin in the first instance. Digoxin is known to cause arrhythmias and may be harmful in the context of acute myocardial infarction. Several analyses of observational data have hinted that digoxin is harmful in the year following acute myocardial infarction [3,15,16]. Drugs in heart failure can be advantageous for three reasons. H e a r t failure may be prevented, symptoms may be minimized, or mortality may be reduced. The evidence for benefit from digoxin for prevention or the treatment of symptoms is not strong, particularly since the recent data on the use of ACE inhibitors and diuretics (or combinations of diuretics) has appeared in the medical literature [17,18]. The large trial from the National Institute of Health should resolve many of these problems. That study is aiming to obtain 10,000 patients, and at least half may be patients in whom digoxin has been introduced de novo rather than withdrawn. The study should answer the issue of whether digoxin modifies mortality. Unless the results from this trial are markedly positive, there may be reasons for limiting the use of digoxin. Trials can only be guides to clinical care. Within the confines of a study such as the N I H study, there may be a tendency not to optimize t r e a t m e n t with other drugs (ACE inhibitors, diuretics, aspirin, lipid-lowering agents, and beta-blockers). Digoxin is an ancient drug and has many friends. Loyalty is an admirable characteristic but physicians should at least consider the possibility that they might be wrong and a change of policy towards a more limited use of digoxin could be appropriate.

References

1. Petch MC. Digoxin for heart failure in sinus rhythm [editorial]. Thorax 1979;34:147-149. 2. Smith TW. Should digoxin be the drug of first choice after diuretics in chronic congestive heart failure? Protagonist's viewpoint. J A m CoU Cardiol 1988;12:267-271. 3. Poole-Wilson PA, Robinson K. Digoxin--a redundant drug in the treatment of congestive heart failure. Cardiovasc Drugs Ther 1989;2:733-741. 4. Jaeschke R, Oxman AD, Guyatt GH. To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and metaanalysis. A m J Med 1990;88:279-286. 5. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989;320:677-683. 6. YoungJB, Uretsky BF, Shahidi FE, et al. on behalf of the PROVED Study Investigators. Multicenter, double-blind, placebo-controlled randomized withdrawal trial of the efficacy and safety of digoxin in patients with mild to moderate chronic heart failure not treated with converting enzyme inhibitors (abstr). J A m Coll Cardiol 1992;19:259. 7. Packer M, Gheorghiade M, Young JB, et al. on behalf of the RADIANCE Study. Randomized, double-blind, placebo-controlled, withdrawal study of digoxin in patients with chronic heart failure treated with converting-enzyme inhibitors (abstr). J A m Coll Cardiol 1992;19:260. 8. Marcus FI. Digoxin is effective, but is it safe? Cardiovasc Drugs Ther 1993;7. 9. Lee DC, Johnson RA, Bingham JB, et al. Heart failure in outpatients: A randomized trial of digoxin versus placebo. N Engl J Med 1982;306:699-705. 10. Arnold SB, Byrd RC, Meister W, et al. Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 1980;303:1443-1448. 11. Meister W, Arnold SB, Byrd RC, Cheitlin MD, Chatterjee K. Intraindividual discrepancy of the clinical and haemodynamic effects of digoxin. Eur Heart J 1983;4(Suppl E):109. 12. Poole-WilsonPA. Digitalis: Dead or alive? Cardiology 1988; 75(Suppl 1):103-109. 13. KulickDL, RahimtoolaSH. Current role of digitalis therapy in patients with congestive heart failure. JAMA 1991;265: 2995-2997. 14. Packer M, Carver JR, Rodefeffer RJ, et al. for the PROMISE Study Research Group. Effect of milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325: 1468-1475. 15. Yusuf S, Wittes J, Bailey K, Furberg C. Digitalis--a new controversy regarding an old drug. The pitfalls of inappropriate methods. Circulation 1986;73:14-18. 16. Fleiss JL, Bigger JTJ, Rolnitzky LM. Is catch-22 alive and well and living at NHLBI? Reactions to "Digitalis--a new controversy regarding an old drug." Circulation 1986;73: 19-20. 17. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325: 293-302. 18. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-691.