Correspondence
Digoxin in Patients with Heart Failure
N Engl J Med 1997; 337:129-131July 10, 1997
- Article
To the Editor:
The report by the Digitalis Investigation Group (Feb. 20 issue)1 on the effect of digitalis on mortality and morbidity in patients with heart failure raises several questions. The Digitalis Investigation Group chose a strategy of discontinuing digoxin in 44 percent of their patients with chronic heart failure who were treated with diuretics, angiotensin-converting–enzyme (ACE) inhibitors, and digoxin. Therefore, a positive bias toward a favorable effect of digoxin may have been introduced because those patients were treated successfully with digitalis. Concomitantly, Packer et al.2 have unequivocally demonstrated that the discontinuation of digoxin is associated with worsening heart failure in patients who remained clinically stable while being treated with digoxin, ACE inhibitors, and diuretics. In fact, the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin-Converting Enzyme (RADIANCE) study2 showed a need for hospitalization or emergency care for 13 percent of the patients who discontinued digoxin but only 2 percent of those who continued the drug.
To evaluate this potential bias, we encourage the authors to provide the mortality and morbidity data for patients in whom digoxin was discontinued and compare those with patients who had not previously been treated with digoxin.
2 ReferencesVictor A. Umans, M.D., Ph.D.
Jan H. Cornel, M.D., Ph.D.
Chris Hic, M.D.
Alkmaar Medical Center, 1815 JD Alkmaar, the Netherlands1
The Digitalis Investigation Group
Full Text | Web of Science | Medline2
Packer M ,Gheorghiade M ,Young JB , et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. N Engl J Med 1993;329:1-7
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To the Editor:
In recent years, evidence has accumulated showing that low serum levels of digoxin produce clinical effects in patients with chronic heart failure,1 but higher serum digoxin levels (around 1.2 ng per milliliter) seem to be necessary to achieve improvement in left ventricular ejection fraction.2-4
However, in the clinical trial by the Digitalis Investigation Group, serum digoxin levels were measured in less than half the patients. The mean serum digoxin level was less than 1.0 ng per milliliter, and we do not know what proportion of patients had levels below 1.2 ng per milliliter. Moreover, the authors did not attempt to elucidate the possible influence of different serum digoxin levels on clinical outcomes. Before we assume that digoxin has no effect on mortality in patients with heart failure, it is essential to clarify the possible relation between the mortality rate and serum digoxin levels. It could be that digoxin reduces mortality in patients with chronic heart failure only if it reaches a serum level within a target therapeutic range but not at lower or higher serum levels.
4 ReferencesJavier Soto, M.D.
Cristina Avendaño, M.D.
Puerta de Hierro Hospital, 28035 Madrid, SpainFrancisco G. Vilchez, M.D.
General Yagüe Hospital, 09005 Burgos, Spain1
van Veldhuisen DJ ,de Graeff PA ,Remme WJ ,Lie KI . Value of digoxin in heart failure and sinus rhythm: new features of an old drug? J Am Coll Cardiol 1996;28:813-819
CrossRef | Web of Science | Medline2
Packer M . The development of positive inotropic agents for chronic heart failure: how have we gone astray? J Am Coll Cardiol 1993;22:Suppl A:119A-126A
CrossRef | Web of Science | Medline3
Gheorghiade M ,Hall VB ,Jacobsen G ,Alam M ,Rosman H ,Goldstein S . Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors. Circulation 1995;92:1801-1807
Web of Science | Medline4
Guyatt GH ,Sullivan MJ ,Fallen EL , et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol 1988;61:371-375
CrossRef | Web of Science | Medline
To the Editor:
In the report by the Digitalis Investigation Group, the list of concomitant medications unfortunately does not include beta-blockers. Thus, it is very important to know whether patients with bradyarrhythmias or atrioventricular block were receiving beta-blockers and whether those who had ventricular arrhythmias were not. Since many patients had mild-to-moderate heart failure due to ischemic heart disease, treatment with beta-blockers may have been prescribed for indications other than heart failure. In the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial,1 beta-blockers were used to treat 23.7 percent and 24.3 percent of the patients in the placebo and enalapril groups, respectively, and in the SOLVD treatment trial,2 7 percent and 8.3 percent. Since beta-blocker treatment has been suggested to have beneficial effects on outcome,3 information on beta-blockers in combination with digitalis and on the effects on arrhythmias would be important to have.
3 ReferencesMichael Böhm, M.D.
University of Cologne, D-50924 Köln, Germany1
The SOLVD Investigators
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The SOLVD Investigators
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Packer M ,Bristow MR ,Cohn JN , et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-1355
Full Text | Web of Science | Medline
To the Editor:
In his editorial “End of the Oldest Controversy in Medicine,”1 Dr. Milton Packer predicts that in the coming years the use of digoxin will gradually but inevitably diminish and that the controversy over the use of digoxin will come to an end. We strongly disagree. The prediction that the days of doom and gloom for digitalis have arrived is unfounded. The Digitalis Investigation Group's study limited its goal, as the title states, to the effect of digoxin on mortality and morbidity in patients with heart failure. The study failed to demonstrate a reduction in mortality, but it superbly demonstrated that digoxin reduces the rate of hospitalization among these patients both overall and for worsening heart failure. Furthermore, digoxin was more beneficial to patients at high risk, to patients with low ejection fractions or large hearts, and to patients in New York Heart Association functional class 3 or 4.
In contrast to digitalis, the newer drugs, such as dobutamine, beta-agonists, milrinone, and enoximone, have shown increased mortality.
The favorable effects of digitalis are not limited to the results reported in this study. Digoxin has been shown to improve functional capacity, hemodynamics, and the left ventricular ejection fraction, lower diuretic requirements, and reduce the frequency of physicians' visits. Diuretics and captopril added to digoxin not only improved hemodynamic measurements and exercise performance, but also decreased plasma norepinephrine and aldosterone.2,3
The captopril–digoxin trial, in which patients were randomly assigned to captopril, placebo, or digoxin, demonstrated that whereas only captopril increased the exercise duration, digoxin increased the left ventricular ejection fraction, shortened hospitalization, reduced the number of physicians' visits, and lowered diuretic requirements. Digoxin is now the most commonly prescribed cardiac glycoside owing to its convenient pharmacokinetic alternative routes of administration and the widespread availability of serum drug-level measurements.4
4 ReferencesSamuel Zoneraich, M.D.
New York Flushing Hospital Medical Center, Flushing, NY 113551
Packer M . End of the oldest controversy in medicine -- are we ready to conclude the debate on digitalis? N Engl J Med 1997;336:575-576
Full Text | Web of Science | Medline2
Gheorghiade M ,Hall V ,Lakier JB ,Goldstein S . Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure. J Am Coll Cardiol 1989;13:134-142
CrossRef | Web of Science | Medline3
Pugh SE ,White NJ ,Aronson JK ,Grahame-Smith DG ,Bloomfield JG . Clinical, haemodynamic, and pharmacological effects of withdrawal and reintroduction of digoxin in patients with heart failure in sinus rhythm after long term treatment. Br Heart J 1989;61:529-539
CrossRef | Web of Science | Medline4
Kelly RA, Smith TW. Drugs used in the treatment of heart failure. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 5th ed. Philadelphia: W.B. Saunders, 1997:480-4.
Author/Editor Response
The authors reply:
To the Editor: Umans et al. ask whether there was any bias introduced by including patients in our study who were taking digoxin before randomization. It was precisely to assess the effects on mortality and morbidity of continued treatment with digoxin versus its withdrawal, as well as of initiating versus not initiating digoxin, that both subgroups of patients were deliberately included. There was a neutral effect on mortality in both subgroups. The effects on mortality and on hospitalizations for heart failure were similar in both subgroups (odds ratio for mortality, 0.74; 95 percent confidence interval, 0.66 to 0.83; for hospitalization, 0.77; 95 percent confidence interval, 0.68 to 0.86) (Table 4 of our report). However, in the subgroup of patients from whom digoxin treatment was withdrawn, the prevention of worsening heart failure by digoxin was evident earlier.
Soto et al. inquire whether higher digoxin levels were associated with a greater degree of efficacy. Within the constraints of our study, there was no relation between digoxin levels and clinical efficacy. An observational analysis of the active groups of our trial is potentially confounded, since digoxin levels are affected not only by the dose of the drug but also by renal function and concomitant medications. Therefore, to answer such a question reliably, we would have to randomly assign patients prospectively to different doses or different target levels of digoxin.
We did not collect information about the use of beta-blockers in this trial, and so we are unable to answer Dr. Böhm's question.
Dr. Packer's editorial incorrectly states that only nine hospitalizations would be prevented by the use of digoxin in 1000 person-years of treatment. After consideration of the multiplicity of hospitalizations and actual rates of use of digoxin in the two randomized groups, we concluded that about 50 hospitalizations per 1000 person-years of treatment would be prevented by the use of digoxin against a background of diuretics and ACE inhibitors. Furthermore, our trial included a substantial number of patients with ejection fractions greater than 0.35. The absolute benefits were about one third greater in those with ejection fractions of up to 0.35 (a population that has commonly been included in trials of other treatments, such as ACE inhibitors and beta-blockers), so that during long-term treatment with digoxin, the average number of hospitalizations prevented per 1000 person-years of treatment would be approximately 65. Reliable evidence of benefit during long-term treatment (>1 year) to large numbers of patients is not currently available for any agent except ACE inhibitors and digoxin. Packer speculates that the availability of newer inotropic agents may make digoxin obsolete. This ignores the disappointing and even adverse experiences with all other positive inotropic agents that have been tested.1,2 Therefore, digoxin, along with ACE inhibitors, should continue to have an important place in the treatment of patients with heart failure in the foreseeable future.
2 ReferencesSalim Yusuf, M.D.
McMaster University, Hamilton, ON L8L 2X2, CanadaRichard Gorlin, M.D.
Mount Sinai Health Systems, New York, NY 10029Rehka Garg, M.D.
Merck–Medco Managed Care, Montvale, NJ 076451
Packer M ,Bristow MR ,Cohn JN , et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-1355
Full Text | Web of Science | Medline2
Yusuf S ,Teo K . Inotropic agents increase mortality in patients with congestive heart failure. Circulation 1990;82:Suppl 3:III-673 abstract.
Author/Editor Response
I agree with Dr. Zoneraich that the results of clinical trials support the use of digitalis to relieve symptoms in patients with chronic heart failure. Therefore, most physicians will not (and should not) change the way they prescribe this drug in clinical practice. My editorial did not question whether digitalis should be used; it questioned whether digitalis should be used before other drugs for heart failure.
If heart failure were only a symptomatic disease, then physicians would start treatment with the drugs that relieved symptoms most effectively with the fewest adverse reactions. However, heart failure is not only symptomatic; it is a progressive disorder that ultimately leads to the death of the patient. As a result, drugs that prolong life carry a moral imperative that requires physicians to use them first before turning to drugs that act only to relieve symptoms. The main finding of the study by the Digitalis Investigation Group — that digitalis has no effect on survival — effectively eliminates any mandate to prescribe digitalis before drugs that prolong life. This conclusion is not changed by the fact that digitalis reduced the combined risk of morbidity and mortality in the trial, because this effect (as emphasized in the editorial) was quite small.
Because of their beneficial effects on survival,1 clinicians now routinely recommend the use of ACE inhibitors before digitalis. Recently, an advisory committee of the U.S. Food and Drug Administration recommended the approval of carvedilol for the treatment of heart failure on the basis of its ability to reduce substantially the risk of death and hospitalizations2,3 — an effect that was seen even when the majority of patients were not receiving digitalis.3 Both ACE inhibitors and carvedilol improve symptoms,1,4 and thus, if they were prescribed first (because of their effects on survival), the use of digitalis would necessarily be confined to patients whose symptoms were not satisfactorily relieved by these drugs. As the list of therapeutic agents that prolong life grows, the use of digitalis will inevitably wane — just as the use of diuretics in patients with mitral stenosis decreased after the advent of mitral-valve replacement. This is not a prediction of doom and gloom; it is merely a reflection of the natural evolution of medical practice.
4 ReferencesMilton Packer, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 100321
The CONSENSUS Trial Study Group
Full Text | Web of Science | Medline2
Packer M ,Bristow MR ,Cohn JN , et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-1355
Full Text | Web of Science | Medline3
Australia/New Zealand Heart Failure Research Collaborative Group
CrossRef | Web of Science | Medline4
Packer M ,Colucci WS ,Sackner-Bernstein JD , et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. Circulation 1996;94:2793-2799
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Dirk J van Veldhuisen. (2002) Low-dose digoxin in patients with heart failure. Journal of the American College of Cardiology 39:6, 954-956
CrossRef
