Need for a Large Randomized Trial to Evaluate the Effects of Digitalis on Morbidity and

Mortality in Congestive Heart Failure Salim Yusuf, MBBS, FRCP, DPhil, Rekha Garg, MD, MS, Peter Held, MD, and Richard Gorlin, MD

Despite major advances in the prevention and tmatmwt of cardiovascular dii tits inci- denceandprevakmceofcongesttveheartfaiture (CHF) have been increasing tn recent years. As tibs average age of the population increases, the prevaknce of CHF is expected to continue to iw crease.7henumberofdeathsinwhkhCHFwas consMeredtheundertyi~orcontributMgcause hwreased from Sl,OOO in 1955 to 274,000 by 1988 in the United States. Even accounting for popuiatton growth and an increase in the number of elderly, this represents a 2-W increase. Awi- tiona5y, CHF was responsWe for about 843,000 hospiiiizations in l988. Digitalis is one of the drugs most commoniy prescribed for CHF and has been used for >200 years. in 1990, dlgoxin was oneofthemostcommoniyprescribeddrugsin the United States, accounting for >21 million pre- scriptions. There has been iittk deciine in the drug’s use over the iast 5 years, indicating that newer trwtmwb for CHF have not replaced the widespread use of diiiis. Desptte these fiml- ings, considerable controversy surrounds the ap pmpriateness of Rs rote and value in treathtg CHF patknts who are in sinus rhythm. A number of recent, uncontroiied studies have arrived at apparemtiyco-orycon-concerning the effects of diiiis on mortaitty in postmyo- card&i hfarcth and heart faihue patients. A brge, doub+e-bMMd, randomized, COntCOYBd cthd- cai trial to evaiuate the effects of digitalis on mortauty, morbidity and quaiity of iife is being sponsored by the Nattonai Heart, Lung, and Biood institute in conjunction wtth the Department of

Veterans Affairs Cooperative Studies Program. Patients with CHF and an ejection fraction 10.45 wiii be randomized to receive digoxin or piacebo aiong wtth other standard therapy. Patiints with an ejection fraction >0.45 aiso vvil be enro5ed in a parallel but separate andlary study. Patii recruitment started in early March 199l, and about 7,500 to 8,000 patients are expected to be enrolled over 3 years and fo5owed for a mhimum of 2 further years or until the end of the study. Resuits are expected to become available in

1995 or 1998. (Am J Cardioi l99&89.-706)

D espite major advances in the prevention and treatment of cardiovascular diseases, as is evident from a substantial decline in

From the National IIeart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (S.Y., R.G.), the Univcr- sity of Goteborg, Goteborg, Sweden (P.H.), and Mount Sinai Hospital, New York, New York (R.G.).

Address for reprints: Salim Yusuf. MBBS, FRO, DPhil, Clinical Trials Branch. Division of Epidemiology and Clinical Applications, National Institutes of Health, National Heart, Lung, and Blood Institute, Federal Building, Room SClO. 7550 Wiscon- sin Avenue, Bethesda, Maryland 20892.

mortality due to acute myocardial infarction and strokes in the United States, national statistics indicate that the incidence and prevalence of congestive heart failure (CHF) have been increas- ing in recent years. About 2.5 to 3 million individu- als are currently estimated to have CHF in the United States. With the continuing increase in the proportion of elderly in the population, the preva- lence of CHF is expected to continue to rise. The number of deaths in which CHF was considered to be the underlying or contributing cause increased from 51,000 in 1955 to 274,000 by 1988 in the United States.’ Even accounting for population growth, this represents a 2-fold increase. The mortality rate among CHF patients is about 50% at 5 years following diagnosis, and the age-adjusted death rate increased 21% in the lo-year period from 1968 to 1978. Additionally, CHF was respon- sible for about 643,000 hospitalizations in 1988 and is currently the leading diagnostic-related group in the United States among hospitalized patients over the age of 65 years. About 30% to 40% of patients with CHF arc hospitalized every year. Approxi- matcly half of these hospitalizations are for worscn- ing CHF. These limited data indicate that CHF is

646 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69 JUNE 4, 1992

likely to remain a major clinical and public health heart failure score (based on clinical and radio- problem in the United States. Moreover, patients graphic changes) in the digoxin-treated patients, with CHF have impaired quality of life, restrictions although similar numbers of patients deteriorated in functional capacity and a plethora of symptoms. clinically during the control and active treatment Therefore, treatments should be evaluated for phases. Retrospective analyses suggested that a their effects on mortality, hospitalizations, quality third heart sound, an enlarged heart and a low of life and symptoms. Of the commonly used drugs ejection fraction correlated with benefit among for heart failure, only angiotensin-converting en- responders. No improvement in ejection fraction zyme (ACE) inhibitors have been formally evalu- was found with digoxin. Fleg et all3 reported no ated for their effects on all the end points just difference in exercise capacity, physical findings or mentioned. Three independent randomized trials symptoms between the digoxin and placebo arms in

and an overview of the results of several smaller a study of 40 patients. Taggart et all4 found no trials have established that ACE inhibitors reduce clear evidence of a benefit with digoxin in 22 mortality and hospitalizations, improve functional status, relieve symptoms and probably have a small

patients (worsening CHF developed in 4 patients

favorable impact on quality of life.2-5 given placebo vs 2 given digoxin). After screening

Digitalis preparations are among the drugs most 380 patients, Guyatt et all5 included 30 patients in th

commonly prescribed for CHF and has been used eir study and reported results obtained in the 20

for > 200 years. In 1990, digoxin was also one of the who completed treatment. Patients benefited with

most prescribed drugs in the United States, account- respect to symptoms, clinical assessment of CHF,

ing for > 21 million prescriptions.6 There has been exercise capacity (6-minute walking distance) and

little decline in the drug’s use over the last 5 years, ejection fraction during the digoxin period com-

indicating that newer treatments for CHF have not pared with the placebo phase. The large propor-

replaced the widespread use of digoxin, as noted by tion of patients excluded or with missing end point d

Jolly (oral communication, January 1988). In the ata makes interpretation of the results difficult.

treatment trial of the Studies of Left Ventricular In a double-blind crossover study, Pugh et all6

Dysfunction (SOLVD),2 60% of patients with CHF studied 44 patients and observed that 11 (25%)

and an ejection fraction < 0.35 received digoxin at deteriorated clinically while taking placebo com-

entry into the study. In the SOLVD registry of pared with only 5 who deteriorated’ (11%) while

>6,000 patients with heart failure or an ejection receiving digoxin. Most patients who deteriorated,

fraction <0.45, digoxin was used in 45% of pa- however, could be stabilized by increasing the dose

tients.7 Moreover, data from Worcester, Massachu- of diuretics. Only 2 patients required reintroduc-

setts, on the use of various drugs in patients with tion of digoxin. Benefit from digoxin could not be

acute myocardial infarction indicate that about predicted based on a third heart sound, hemody-

40% of discharged patients take digoxin8; this namic criteria, echocardiographic measures or heart

proportion has remained unchanged during the size. Differences in clinical response were paral-

last 10 years. leled by variations in digoxin’s ability to inhibit sodium-potassium adenosine triphosphatase pump activity in the erythrocyte (measured by decreases

TRIALS OF DIGOXIN IN HEART FAIUJRE in rubidium fluxes). Patients who were not clini-

Despite the widespread use of digitalis and its tally responsive to digoxin, for example, demon-

availability for some 2 centuries, considerable con- strated a lack of sustained inhibition of rubidium

troversy surrounds its role in treating CHF patients fluxes despite continued increases in digoxin bind-

and its effect on survival. Table I lists the 15 ing. Thus, there may be an adaptive response by randomized controlled trials of digitalis in CHF which sodium-potassium adenosine triphosphatase

that have been identified.9-z0 The first 2 trials is induced in the red cell membrane, which over-

enrolled patients without clear evidence of CHF,9>10 rides the digoxin effect in some patients. Whether

and the third included patients with atria1 fibrilla- these results apply to the myocytes can be only

tion.ll Several small trials evaluated patients with conjectural at this time. CHF by using a crossover design with treatment Four larger trials17-l9 compared digoxin with

periods of 2 to 3 months each. 12-16,2o Almost all placebo or a second active drug. However, only the patients were withdrawn from previous chronic use results comparing the digoxin group to the placebo

of digitalis and randomized to receive placebo or group will be discussed. In the captopril-digoxin digoxin. trial,17 196 patients were randomized to receive

Lee et all2 found a significant improvement in digoxin or placebo. All patients had an ejection

A SYMPOSIUM: CONGESTIVE HEART FAILURE 666

TABLE I Randomized, Controlled Trials of Digitalis in CHF

Reference Design

Digoxin

No. Dose, mg/day Mean Plasma Treatment

Pts. (mean) Concentration Duration Comments Results

Starr, Luchi,a

1969 Kirsten et aLI0

1973

Withdrawal 12

crossover

Withdrawal 22

crossover

Dobbs et al,” 1977 Withdrawal 46 0. ,l crossover

Lee et al,12 1982 Withdrawal 35 0. .l

crossover

0.1* -

0.25 -

25-0.5 1.4 na/mL

4wk Probably not No effect on cardiac function

CHF patients

6mo Not all patients Five of 22 patients had recurrence of heart

with CHF failure or arrhythmia after digoxin with-

drawal

6wk Thirteen patients with Sixteen of 46 patients developed signs or

atrial fibrillation

25-1.0 > 1.2 ng/mL 2.5 mo NYHA I-III

Fleget al,‘3 1982 Withdrawal 40 0.125-0.5 1.4 ng/mL 3 mo NYHA II-IV

crossover (0.24)

Taggart et ai,l4

1983 Withdrawal 22

crossover

1 1.2 ng/mL 3mo 95% NYHA l-11

Guyatt et al,l5 1988 Withdrawal 30 (0.39) 1.75 nmoliL 7wk NYHA I-III

crossover

Captopril-Digoxin,” Withdrawal 196 0.125-0.375 0.7-2.5 ng/mL 6mo 85% NYHA I-II

1988 parallel

Xamoterol-Digoxin,l* Withdrawal 204

1988 parallel

0.25 0.87 ng/mL 3 mo 87% NYHA I-II

Milrinone-Digoxin,lg Withdrawal 111 0.125-0.5 1.2 ng/mL 3mo NYHA II-IV

1989 parallel

Pugh et al,16 1989 Withdrawal 44 ? 0.8-2.0 ng/mL 8wk NYHA ll-lll

crossover

FlegetaLzO 1991 Withdrawal 10 0.125-0.50 1.4 ng/mL 4wk 80% NYHA II

crossover (0.28)

Youngetal,sl 1992 Withdrawal 88 0.125-0.50 0.7-2.0 ng/mL 12 wk Not on ACE-I

parallel In sinus rhythm

Packer et al,*2 1992 Withdrawal 178 0.125-0.50 0.9-2.0 ng/mL 12 wks EF <35%

parallel NYHA I-III

All on ACE-I

Drexler et al,*3 1992 Parallel 133 0.25 ? 1 year mean EF = 53%

NYHA ll-lll

No diuretics

or ACE-l

symptoms of CHF after digoxin withdrawal

Fourteen of 25 patients had reduction in se-

verity of CHF. Response to digoxin corre-

lated with the presence of Ss and dilated

heart

Withdrawal of digoxin produced a small in-

crease in cardiac size and decrease in ve-

locity of circumferential fiber shortening.

No effect on exercise tolerance or symp-

toms of CHF

Digoxin exerted a sustained positive ino-

tropic effect during maintenance therapy

but did not appear clinically to benefit the

majority of patients

Digoxin improved quality of life and exercise

capacity

Small nonsignificant improvements in exer-

cise time and NYHA class but significant

increase in ejection fraction with digoxin

compared to placebo

Nonsignificant increase in exercise duration

in the digoxin group compared to placebo

group. Also, digoxin reduced signs of CHF

with a marked reduction in weight

Digoxin increased exercise time and EF and

reduced frequency of worsening CHF

Withdrawal of digoxin resulted in clinical

deterioration of 25% of patients and oc-

currence could not be predicted by any

clinical, hemodynamic or pharmacologic

measurements made prior to withdrawal

Digoxin did not increase exercise capacity

despite improvements in left ventricular

function

Patients withdrawn from digoxin showed

deterioration of EF and exercise capacity

on treadmill but no effect on NYHA class

or 6-min walk distance. Reduced fre-

quency of worsening CHF with digoxin

Significant favorable effect on treadmill exer-

cise capacity, 6-min walk test distance,

EF, and frequency of worsening CHF with

digoxin

Improved quality of life and NYHA class with

digoxin

*Digitoxin used. ACE-I = angiotensin converting enzyme inhibitors. CHF = congestive heart failure; EF = ejection fraction; NYHA = New York Heart Association.

fraction < 0.40 and 85% of patients had New York the digoxin group and 6 in the placebo group. In Heart Association (NYHA) class I-II heart failure. the xamoterol-digoxin trial,i* 204 patients were After 6 months, there was a favorable nonsignifi- randomized to receive digoxin or placebo; 80% cant improvement in exercise time in the digoxin were in NYHA class I-II. A fixed dose of 0.25 mg group compared with placebo, and ejection frac- digoxinlday was administered. In patients who tion increased by 4.1% in the digoxin groupvs 1.3% completed the 3-month double-blind phase, there in the placebo group (p <0.05). Eight patients was no difference in exercise duration between given digoxin and 19 given placebo had to be treatment groups. There was no difference in hospitalized due to CHF. There were 7 deaths in symptoms between groups, although decreases in

660 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69 JUNE 4. 1992

peripheral edema and rales were found among digoxin-treated patients. No deaths occurred in the digoxin group compared with 1 in the placebo group. In the milrinone-digoxin trial,19 111 patients were randomized to receive digoxin or placebo. After 3 months, ejection fraction increased by 1.7% in the digoxin group and decreased by 2% in the placebo group (p < 0.01). Exercise tolerance in patients receiving digoxin increased by 14% com- pared with those given placebo (p <0.05). Three patients in the digoxin group and 4 in the placebo group died during treatment. None of the trials just mentioned reported a preferential benefit in any particular subgroup. In another multicenter study,2l 133 patients with documented myocardial infarc- tion resulting in regional wall motion abnormalities and mild heart failure were randomized to digoxin or placebo. Most patients had little impairment of ejection fraction. After 1 year of treatment, digoxin resulted in improvement in quality of life and NYHA class compared with the placebo group (p < 0.05). No differences in exercise tolerance were observed.

The results from 2 parallel trials of digoxin withdrawal versus placebo were recently re- ported.22>23 In a study of 88 heart failure patients in sinus rhythm who were not on ACE inhibitors, Young et a122 reported that patients withdrawn from digoxin showed deterioration of ejection frac- tion and exercise capacity on the treadmill. How- ever, digoxin withdrawal had no effect on NYHA class or the 6-minute walk test. In a larger study of 178 patients with a low ejection fraction and on ACE inhibitors, Packer et a123 reported a signifi- cant favorable effect of digoxin on ejection frac- tion, exercise capacity on the treadmill, the 6-minute walk test, and the frequency of worsening of CHF, compared with the placebo group.

Although there have been a large number of randomized trials conducted to evaluate the effect of digoxin, these trials have had several limitations. First, all of these trials except one have been withdrawal trials; therefore it would not be possi- ble to evaluate the impact of initiation of digoxin compared with placebo. Second, none of these trials was of sufficient size or duration to provide reliable information on mortality. Third, patients with relatively preserved ejection fraction have not been included in most of these trials and therefore extrapolations of the available data are limited. Fourth, patients received concomitant ACE inhibi- tor therapy in only one of these trials. Therefore, given these limitations, there is still a need for a trial to evaluate the effect of digoxin on morbidity

, CABLE II Summary of Eight Studies Examining the Association

3f Digoxin Use and Mortality in Postinfarction and Heart Failure

Patients Given Digitalis

Reference Mortality Risk

Postinfarction studies

Moss et aLz4 1981 Higher mortality among patients on digoxin

overall, but differences compared with

those not on digoxin not significant. Statis-

tically significant excess in retrospectively

identified subgroup of patients with heart

failure and complex VPDs. This subgroup

comprised only 8.4% of total population

Bigger et al,*5 1985 Nonsignificant higher mortality with digoxin

overall and in the subgroup identified by

Moss et alzl Sweeney et a1,26 Significant excess in sudden death in group

1991 recerving digitalis. Overall mortality not

provided

Ryan et al,a7 1983 Nonsignificant higher mortality with digoxin

overall and in several subgroups examined

Byington and Gold- Nonsignificant higher mortality with digoxin

stein,*a 1985 overall and in several subgroups examined

Muller et aLz9 1986 Nonsignificant higher mortality with digoxin

overall Madsen et al,30 1984 Nonsignificant higher mortality with digoxin

overall and in several subgroups examined

Heartfailure studies

Mancini et al,31 1984 High serum digoxin levels associated with

significant increase in mortality after ad-

justment for various risk factors

Sackner-Bernstein et Nonsignificant higher mortality with digoxin

al,32 1991 overall

VPD = ventricular premature depolarization. Nonsignificant refers to a comparison not achieving statistical significance.

and mortality in a broad spectrum of patients with heart failure and concurrent ACE inhibitor ther-

apy.

EFFECT OF DlGffAUS ON MORTALITY The effect of digitalis on survival among patients

following myocardial infarction or with heart fail- ure has been analyzed by several investigators using existing data bases. 24-32 As shown in Table II, several studies suggested that digitalis might in- crease the risk of sudden death or mortality among subgroups of patients with frequent ventricular ectopy. In some of these studies,26,31 digitalis use was associated with a significantly higher risk of death compared with those not using digitalis, after adjustment for differences in risk factors. However, other studies suggested that the higher mortality seen among digitalis-treated patients was largely due to a higher incidence of adverse risk factors. In these studies, after statistical adjustments, the apparently higher mortality associated with digoxin use was not statistically significant.

A critical review of these studies indicates that the effect of digitalis on survival cannot be assessed reliably by retrospective analyses of data bases, but rather requires large, randomized, controlled tri- als.33 In this context, it is worth noting that an

A SYMPOSIUM: CONGESTIVE HEART FAILURE 676

TABLE III Overview of Mortality Among Phosphodiesterase Inhibitors and p Agonists

No. Deaths/Total

No. Patients

Odds P

Agent/Trial Active Control Ratio 95% Cl Value

Phosphodiesterase 67/642 351482 1.58 1.04,2.41 0.03 inhibitors

(PDEl)35 PROMISE= 169/562 1261526 1.36 1.04, 1.78 0.04

Subtotal for 236/1,204 161/1,008 1.39 1.11, 1.74 0.01 all PDEI

p agonists*js 551810 17/424 2.07 1.23,3.49 0.001

*Includes xamoterol, which has both p agonist and antagonistic effects. Cl = confidence interval; PROMISE = Prospective Randomized Milri-

none Survival Evaluation. Adapted from Circulation.35

overview of all randomized trials with inotropic agents other than digitalis shows excessive mortal- ity with each class of agent and, overall, a 2-fold excess death rate in treated versus control patients (p < 0.001).34 Table III notes this adverse effect of nondigitalis inotropic agents has been observed with dobutamine, a B agonist, milrinone and enoxi- mone, both phosphodiesterase inhibitors, and xam- oterol, a B agonist with p-blocking properties.35T36 These data may arouse concerns that an increase in mortality is also possible with digitalis. It should be borne in mind, however, that most nondigitalis agents work through the cyclic adenosine mono- phosphate mechanism, whereas cardiac glycosides like digoxin work via a cell-membrane inhibitory effect on the ion exchange pump. The latter en- hances contractility, presumably by inducing shifts in intracellular calcium.37

All the data base studies of digoxin that came to apparently contradictory conclusions were based on retrospective analyses of data collected prima- rily for other purposes, rather than data from randomized trials. Since such methods also have moderate inherent biases, they are generally not capable of evaluating reliably whether digoxin has a moderate beneficial or harmful effect on mortal- ity. Therefore, based on currently available data, it is completely uncertain what effect digitalis is likely to have on mortality.

It is quite possible that digitalis-induced improve- ments in ejection fraction and exercise tolerance may be associated with less deterioration of clinical status, fewer hospitalizations for worsening CHF and fewer deaths due to progressive CHF. Another likelihood is that its positive inotropic effects are of secondary importance, and its actions on the auto- nomic nervous system are either of primary or equal importance. In addition to vagal enhance- ment, there is augmented baroreceptor reflex sen- sitization and reduced sympathetic outflow. For

example, there is an increase in forearm blood flow, a reduction in venous tone and acute inhibi- tion of renin, angiotensin and aldosterone output. On the other hand, equivocal and small improve- ments in ejection fraction, exercise tolerance, or both, as well as alteration of autonomic function, may not be associated with reduced mortality. Further, digitalis has been shown experimentally to increase infarct size and to reduce the threshold for the development of ventricular fibrillation and ventricular tachycardia in myocardial infarction.38,39 The tendency toward an increase in arrhythmias may be potentiated by hypokalemia or coexisting ischemia. Another issue is depression; reports of depression associated with digitalis use following myocardial infarction have appeared sporadically over the past 2 decades. 40,41 Therefore, there are theoretical reasons to expect digitalis to have a beneficial effect on some outcomes and harmful effects on other outcomes. At present, the balance between the potential for benefit and that for harm is impossible to estimate without a large random- ized trial.

Even a moderate effect on mortality would have substantial public health and medical importance. A trial that showed a reduction in mortality of perhaps 10% or 20%, for example, would appropri- ately encourage widespread use of digoxin. If, however, the trial showed that treatment had no detectable effect on mortality or major morbidity, the numbers of patients receiving the drug would decline. Moreover, even if digoxin were shown to increase the risk of death by only 10% or 15%, it might prove to be responsible for 10,000 to 15,000 premature deaths annually in the United States alone. A trial that clearly demonstrated such an adverse effect would lead to a major reevaluation of the role of digoxin. In addition to determining the effects of digoxin on mortality, it would be important to assess its effects on morbidity (e.g., hospitalization) and quality of life. For example, if digoxin had a neutral effect on mortality but reduced the number of hospitalizations or im- proved quality of life, it would still be considered clinically useful.

DESIGN OF A LARGE TRW OF b1~0mN IN HEART FAILURE

A large randomized trial to evaluate the effects of digoxin on mortality is being sponsored by the National Heart, Lung, and Blood Institute in conjunction with the Department of Veterans Af- fairs Cooperative Studies Program. The primary aim of this study is to determine whether digoxin

666 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69 JUNE 4, 1992

has beneficial, harmful or no effects on total 8. Goldberg RJ, Gore JM, Alpert JS, Dalen JE. Therapeutic trends in the

mortality among 7,000 patients with clinical heart management of patients with acute myocardiil infarction (1975-1984): the Worcester Heart Attack Study. Clin Car& 1987;10%%

failure who are in sinus rhythm and have moderate 9. Starr J, Luchi RJ. Blind study on the action of digitoxin on elderly women.

or severe impairment of left ventricular systolic Am He’* J 1969;78’740-751, function (ejection fraction ~0.45). The diagnosis

10. Kirsten E, Rodstein M, Iuster Z. Digoxin in the aged. G&tics 1973$):95- 101.

of clinical heart failure is based on current or past IL Dobbs SM, Kenyon WI, Dobbs RJ. Maintenance digoxin after an episode

evidence of low cardiac output (e.g., limitation of of heart failure: placebo-controlled trial in outpatients. Br Med J 1977;1:749- 752, activity) or congestion (edema, elevated jugular 12. Lee C, Johnson RA, Bingham JB. Heart failure in outpatients. N En@ J

venous pulse, rales or radiologic evidence of pulmo- Med 198~3m:699-705. nary congestion). Patients with an ejection fraction

13. Fleg JL, Gottlieb SH, Lakatta EG. Is digoxin really important in treatment

> 0.45 (expected number of 500 to 1,000 patients) of compensated heart failure? Am JMed 1982;73:24&?.50, 14. Taggart AJ, Johnston GD, McDevitt DG. Digoxin withdrawal after cardiac

will be entered into a parallel but separate ancil- failure in patients with sinus rhythm. J Cardiovasc Pharmcol 1983;5:22%234.

lary study. Patients will be randomized to receive 15. Guyatt GH, Sullivan MJ, Fallen EL, Tiial H, Rideout E, Halcrow S, N ogradi S, Townsend M, Taylor DW. A controlled trial of digoxin in conges-

digoxin or placebo in addition to other standard tive heart failure. Am J Car&! 1988;61:371-375.

therapy (i.e., ACE inhibitors, diuretics, other va- 16. Pugh SE, White NJ, Aronson JK, Grahame-Smith DG, Bloomlield JG.

sodilators). The study also will assess the effects of clinical, hemodynamic, and pharmacologic effects of withdrawal and reintroduc- t’ Ion of digoxin in patients with heart failure in sinus rhythm after long term

digoxin on cardiovascular mortality, deaths due to progressive heart failure, deaths presumed to be due to arrhythmias, hospitalization for worsening heart failure and several other causes, including digoxin toxicity and arrhythmias; and quality of life. The effects of treatment on mortality and other outcomes will also be evaluated in subgroups based on ejection fraction, heart size on chest radio- graph, etiology, previous use of digoxin and base- line NYHA classes.

United States have agreed to participate. The More than 300 hospitals in Canada and the

study started recruiting patients in early March on behalf of the PROVED Study Investigators. Multicenter, double blind, placebo controlled randomized withdrawal trial of the efficacy and safety of

1991, and the rate of recruitment has been gradu- digoxin in patients witi mild to moderate chronic heart failure not treated with

ally increasing and is now between 330 and 350 converting enzyme inhibitors. JAm Coil Car&l 1992;19:259A

treatment. Br Heart .I 1989;61:529-539. 17. Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart faiiure. JAMA 1988;259:539-544. 18. The German and Austrian Xamoterol Study Group. Double blind placebo- controlled comparison of digoxin and xamoterol in chronic heart failure. Lancet

PL Young JB, Uretsky BF, Shahidi FE, Yellen LG, Harrison MC, JoUy Mg

1988;i:48%493. 19. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R, for the Milrinone Multicenter Trial Group. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engi J Med 1989;320:677683. 20. Fleg JL, Rothfeld B, Gottlieb SH, Wright J. Effect of maintenance dioxin therapy on aerobic performance and exercise left ventricular function in mild to moderate heart failure due to coronary artery disease: a randomized, pla- cebo, controlled crossover trial. JAm Co11 Cardiol1991;17:743-757.

patients per month. By the end of May 1992, 22. Packer M, Gheorghiade M, Young JB, Smith LK, Constantini PJ, Adams KF, Cody RJ, Butman SM, Gourley LA, Jolly MK. Randomized, double blind,

> 4,200 patients had been randomized from about placebo controlled, withdrawal study of digoxin in patients with chronic heart failure treated with converting enzyme inhibitors. J Am Coil Cardtil 1992;19:

250 hospitals. Recruitment is scheduled to be 260A. completed by December 1993, and all patients Will 23. Drexler H, Schumacher M, Siegrist J, Just H, for the CADS Multicenter

be followed for a further 2 years. The results are Study Group. Effect of captopril and digoxin on quality of lie and clinical

expected to become available in 1995 or 1996. symptoms in patients with coronary artery disease and mild heart failure. JAm

Cd Cardiol1992;19%OA

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DISCUSSION Dr. Creager: What is your rationale for includ-

ing patients with ejection fractions (EFs) > 0.45 in your randomized trial of digoxin in heart failure?

Dr. Ywuf: If the effect of digoxin is at least to some degree mediated through factors indepen- dent of inotropism, e.g., an effect on the harore- flexes, then one might expect an effect in these patients. Suppose we only study patients with low EFs. Then we would have to either extrapolate our findings to patients with higher EFs or perform another study to find out the effects of digitalis in these patients.

Dr. Creagec Do these patients with preserved EF have restrictive cardiomyopathics, heart failure secondary to mitral stenosis or right-sided heart failure secondary to cardiovascular disease? Have you defined this group?

Dr. Yusufz Yes, we have. Patients with severe

uncorrected valvular problems are not included in this group. We do have documentation of the primary and secondary etiologies from the pa- tients’ physicians. About 50% of our group of patients with EF > 0.45 has ischemic heart disease. Patients with restrictive cardiomyopathies, amyloid or mitral stenosis are excluded.

Dr. Packer: We participated in an analysis of prognostic factors in the PROMISE trial. We took all of the baseline variables that were measured in that trial and determined whether they were univariate predictors of mortality. Then we created a model to see which were independent. It turned out that the serum digoxin concentration was, when adjusting for all other variables, an indepen- dent predictor of mortality. The higher the serum digoxin concentration, the higher the mortality, and this was independent of EF, arrhythmias, every severity of heart failure. The one thing we did not and could not adjust for, howcvcr, was the fact that PROMISE was a noninvasive study. So we did not measure invasive hemodynamic variables.

Then we went back to our own data base of invasively monitored patients. When we took the invasive measurements out of our model, serum digoxin concentration was an independent predic- tor of mortality. When we put the hemodynamic variables back in, it was no longer an independent predictor. The implication is that you cannot com- pletely adjust for all variables, because you cannot possibly measure everything.

Dr.Yusuf: I fully agree with you. But adjustment is totally appropriate for most of our interventions, where the effect is either moderate or small to nonexistent. The effect of penicillin on pneumococ- cal pneumonias is so large that one does not need a trial nor does one have to adjust. At the other end, when the effects are small, adjustments probably will not help detect an effect.

Dr. Manciat I think it takes a lot of courage to do these studies because there are a very high number of complex factors one cannot control.

Dr. Yusti That is exactly why one does random- ized trials. If such trials are large all important prognostic factors tend to equalize between the 2 groups.

706 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69 JUNE 4, 1992