Cardiovascular Drugs and Therapy 1993;7:893496 Invited Viewpoint © Kluwer Academic Publishers, Boston. Printed in U.S.A.

Digoxin is Effective, But is it safe? F r a n k I. M a r c u s University of Arizona College of Medicine, Tucson, Arizona

Summary. In the last 15 years several double-blind, placebo- controlled clinical trials have unequivocally shown that digi- talis decreases symptoms of cardiac failure, results in a re- duction in the need for hospitalization for treatment of congestive heart failure, and improves cardiac function. The major unresolved question concerning digitalis use is its safety. There are experimental data and clinical evidence that digitalis use may be associated with an increased mortal- ity, particularly in the first year or two after an acute myo- cardial infarction. This increased mortality appears to be present even after adjustment for predictor covariants. This conclusion depends on the ability of statistical methods to account for differences in comorbidity. Since the question of digitalis safety remains after myocardial infarction, the physician should carefully examine the indications for ad- ministration of digitalis. More than the usual surveillance is required during chronic digitalis administration.

Cardiovasc Drugs Ther 1993;7:893-896

Key Words. digoxin, digitalis, digoxin efficacy, digoxin safety, post myocardial infarction, independent risk factor

A recurrent pattern after the introduction of a new drug is that it goes through three major phases. "In the first, it is the cure for everything and it is criminal not to prescribe it; in the second, it is so dangerous that it should be used only by experts, which of course excludes everyone but the speaker; in the third, its sphere of usefulness becomes more clearly defined and the control of dosage and other factors help to mini- mize unwanted effects" [1]. For digitalis, this se- quence of events took nearly 200 years. Just over 50 years ago, the meticulous clinical observations of Wood [2], Gavey [3], and others provided proof that digitalis improved heart failure in patients with sinus rhythm. Still, doubts persisted, but proof of its effi- cacy has been dispelled in the last 15 years by double- blind placebo-controlled clinical trials that have un- equivocally demonstrated that digitalis decreases symptoms of cardiac failure, results in a reduction in the need for hospitalization for treatment of conges- tive heart failure, and improves cardiac function (Ta- ble 1) [4-16]. Some, but not all, studies have demon- strated an increase in exercise tolerance. When compared with angiotensin converting enzyme (ACE) inhibitors, digitalis often compares favorably with these drugs in reducing symptoms; in addition, digi- talis has been shown to have additive cardiovascular

effects when used in conjuction with diuretics and ACE inhibitors [17].

The major unresolved question concerning digitalis use is its safety. Certain characteristics of this drug indicate that it has the potential for mischief. Digitalis has a narrow therapeutic/toxic ratio. Doubling or tri- pling the optimal maintenance dose for an individual can result in adverse effects, including tachyarrhyth- mias, such as atrial or ventricular tachycardia. In ex- cess doses its vagomimetic effect may cause sinus bradycardia or AV block. The presence of severe myo- cardial damage increases the possibility that the ad- verse cardiovascular effects may be manifest as exac- erbation of ventricular arrhythmias rather than its vagomimetic effects. Hypokalemia, frequently pres- ent in patients with congestive heart failure, can sen- sitize to digitalis toxicity at serum levels that other- wise would be innocuous. Decrease in renal function can fluctuate in patients with congestive heart failure, leading to a decrease in total body excretion of digoxin and an increase in serum levels. Numerous drug inter- actions with digoxin, particularly with antiarrhythmic drugs, such as amiodarone, propafenone, quinidine, or verapamil, can result in an increase in serum drug levels [18]. Finally, the observation that other posi- tire inotropic agents such as the phosphodiesterase inhibitors may exert unfavorable effects on survival of patients with chronic heart failure adds to the con- cern that digitalis may have a similar adverse effect on mortality.

There is nagging recurrent evidence that digitalis use may be associated with an increased mortality, particularly in the first year or two after an acute myocardial infarction. Experimental studies suggest there is a physiological basis for this suspicion. A "low risk" conscious postinfarction dog model has been used to demonstrate a significantly enhanced suscepti- bility to the development of ischemia-related lethal ventricular arrhythmias in the presence of therapeutic serum concentrations of digoxin [19]. In this model, acute beta-adrenoceptor blockade with nadalol was

Address for correspondence: Frank I. Marcus, M.D., Section of Car- diology, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724.

Received and accepted 11 February 1993.

893

894 Marcus

Table 1. Double-blind, placebo-controlled studies of digoxin in heart failure patients

Dura- Increased Improved cardiac Study No, tion exercise function with

Author Year design p t s ) (weeks) time digoxin

Worsening of heart failure

Digoxin Placebo Misc. positive findings

Dobbs 1977 Crossover 46 6 ? ? 0% 35% Lee 1982 Crossover 225 9 ? 1' LVEF (p = ,49) 24% 56%

Fleg 1982 Crossover 30 12 No $ Systolic time 0% 0% intervals (p < 0.001)

Taggart 1983 Crossover 22 12 ? $ Systolic time 10% 21% intervals (p < 0.001)

Guyatt 1988 Crossover 20 7 6 rain walk 1" Fractional short- 0% 35% (p - 0.06) ening (p = 0.004)

German and 1988 Parallel 213 12 (p = 0.08) ? 4% 5% Austrian Xamoterol

Captopril- 1988 Parallel 196 24 p = ? $ LVEF 15% 29% digoxin (trend) (p = <0.01)

DiBianco 1989 Parallel 111 12 (p = 0.03) T LVEF 15% 47% (p = <0.01)

Pugh 1989 Crossover 44 8 ? ? 11% 25%

Fleg 1991 Crossover 10 4 No 1' LVEF with exer- 0% 10% cise (p < 0.05)

Young 1992 Parallel 88 20 (p = 0.006) I" LVEF (p < 0.05) 19% 39%

Packer 1992 Parallel 178 20 (p = 0.003) I' LVEF (p = 0.01) 6% 28%

Drexler 1992 Parallel 133 52 No ?

Heart failure score improved (p < 0.05)

Reduced body weight (p = 0.01) Decreased LVEDD (p = 0.003) Reduced CT ratio (p = 0.0003) Decreased LVEDD (p = 0,001)

Reduction in dyspnea (p = 0.04) Reduction in heart failure score

(p = 0.001) Reduction in CT ratio (p = 0.04) Reduction in symptoms (p < 0.05) Reduction in peripheral edema

and basilar rales (p < 0.05) Reduction in hospitalization/ER

visits (p = <0.05) Fewer t reatment failures

(p < 0.05) Less need for diuretics (p < 0.05) Reduced need for eointervention

(p < 0.001). Reduced incidence of treatment,

both early (p < 0.05) and late (p < 0.01)

Decreased t reatment failure (p < 0.05)

Reduction in hospitalization/ER visits or need to ~ diuretics (p = O.O2)

Reduction in hospitalization/ER visits or need to t diuretics (p < 0.001)

Improved symptom score and NYHA class (p < 0.05)

1Number of patients in digoxin and placebo groups only. LVEF = left ventricular ejection fraction; LVEDD = left ventricular end-diastolic diameter; CT ratio = cardiothoracic ratio; NYHA class = New York Heart Association functional classification.

found to reduce digitalis-mediated ischemic postin- farction mortality, possibly because of an increase in ventricular refractoriness [20].

Clinical data indicate that digitalis may be an inde- pendent risk factor for mortality after myocardial in- farction. In 1981, Moss and coworkers evaluated 4- month mortality rates after hospital discharge of 978 patients of less than 66 years of age [21]. During this time, 42 patients died, all but one of cardiovascular causes. Twenty-one were receiving digitalis upon dis- charge. Since patients treated with digitalis can be expected to have more serious heart disease, statisti- cal techniques were applied to attempt to adjust for differences between the digitalis and nondigitalis

groups so that the effect of digitalis on mortality could be evaluated. The data suggested that digoxin use contributed to the mortality rate in this high-risk sub- set of patients. Based on the model used, predicted increases in mortality due to digoxin use, adjusted for other variables was 30% (90% confidence interval = 18-42%). This predicted increase in mortality associ- ated with digitalis is of the same magnitude as the benefit from beta-blocker drugs or ACE inhibitors after a myocardial infarction. The conclusion reached was that digitalis therapy may increase mortality in the early posthospital phase after an acute myocardial infarction in a subset of patients with congestive heart failure and complex ventricular premature complexes.

Is Digoxin Safe? 895

In 1985, Bigger et al. [22] reported that there was an association between digitalis and decreased sur- viral. Using a Cox regression model, the relative risk was 1.3 and was of borderline significance (p < 0.07) in 504 postinfarction patients. When Bigger et al. pooled the data from their study and the two prior studies that used the Cox regression model, digitalis contributed a significant mortality risk (chi square = 15.2; df = 6, p < 0.025) [22].

In 1987, the Digitalis Subcommittee of the Multi- center Post-infarction Research Group examined the effect of digitalis therapy on mortality throughout the 24-48 month follow-up in 867 patients who survived an acute myocardial infarction. Survival analysis in 728 patients utilized the Cox regression model. Digi- talis therapy was associated with a significantly in- creased postinfarction mortality risk after adjustment for the predictor covariants (relative risk = 2.3, 95% confidence interval = 1.4-3.7, p < 0.001) [23].

The evidence from the above-mentioned studies im- plicating digitalis as an independent risk was criticized by Yusuf et al [24]. They pointed out that this conclu- sion depends critically on the ability of statistical methods, such as Cox regression, to account for differ- ences in comorbidity. The statistical methods can ac- count for known and recorded risk factors but not for unmeasured prognostic features. They indicated that physicians may prescribe digitalis to patients based on their assessment of the severity of the disease. This assessment may well be based on both recorded and unrecorded features. In other words, the possibil- ity of underadjustment cannot be excluded. A rebuttal was then offered by Fleiss et al. in support of the retrospective analysis performed by Bigger and asso- ciates [25].

In a more recent publication from Moss and col- leagues utilizing data from the Multicenter Diltiazem Post-infarction trial, they identified three indepen- dent factors that differentiated instantaneous from noninstantaneous death: presence of frequent ventric- ular ectopic beats, digitalis, and absence of beta- blocker therapy. The relative risk of digitalis use was 2.57 with a confidence interval of 1.31-5.06 [26]. Pos- sible enhanced mortality with digoxin after myocar- dial infarction has also been reported for digitoxin. The relative risk ratio for patients taking digitoxin with regard to mortality was 2.33 [27].

Other studies have not confirmed that digoxin use after infarction is a significant independent risk factor [28-30]. In each of these studies, the effect of digitalis was of borderline statistical significance after com- pounding variables were controlled. A retrospective study of patients receiving digitalis in the beta- blocker heart attack trial concluded that most of the increased mortality risk associated with digitalis ther- apy was probably due to the nature of the cardiac disease being treated [31].

It is clear that only a large randomized controlled trial can resolve this important issue of the safety of

digitalis. This trial is now underway. It is called the Digitalis Investigation Group and is sponsored by the National Heart, Lung, and Blood Institute. The objec- tives are to determine the effects of digoxin on sur- rival, hospitalization frequency, and 6-minute walking distance. It is designed as a parallel, randomized, dou- ble-blind placebo-controlled study. Ten thousand pa- tients will be enrolled. It is the largest heart failure trial in history. It is expected that the results will be announced in 1995. Even so, the controversy of digi- talis safety may not be resolved, since the patients who are enrolled are not limited to those receiving digitalis in the first year or two after myocardial in- farction.

It can be concluded that there is a serious question regarding the safety of digitalis after myocardial in- farction. However, it is now perfectly clear that digi- talis improves myocardial function and relieves symp- toms of congestive heart failure, and may increase exercise capacity. It would seem reasonable, there- fore, to carefully examine indications for administra- tion of digitalis, particularly in the first year after a myocardial infarction, to exercise more than the usual surveillance during chronic digitalis administration, including measurement of serum digoxin levels after initiation of this drug when indicated and to repeat these levels if there are concomitant drugs that may alter digitalis levels and to be exceedingly careful to maintain serum potassium level >4 mEq/1. If digoxin has been administered for t reatment of heart failure that has a remediable cause, such as pulmonary infec- tion, the drug should subsequently be withdrawn.

A c k n o w l e d g m e n t s

I thank Drs. J. Thomas Bigger, Jr., Professor of Medicine and Pharmacology, and Arthur J. Moss, Professor of Medicine, for their reviews of the manuscript.

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