Is digoxin really important in treatment of compensated heart failure?

Is digoxin really important in treatment of compensated heart failure?

REPORT ON THERAPY Is Digoxin Really Important in Treatment of Compensated Heart Failure? A Placebo-Controlled Crossover Study in Patients with Sinus ...

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REPORT ON THERAPY

Is Digoxin Really Important in Treatment of Compensated Heart Failure? A Placebo-Controlled Crossover Study in Patients with Sinus Rhythm

JEROME L. FLEG, M.D., F.A.C.C.

SHELDON H. GOTTLIEB, M.D. EDWARD G. LAKATTA, M.D. Baltimore.

Maryland

From the Cardiovascular Section, Gerontology Research Center, National Institute on Aging, and the Division of Cardiology, Baltimore City Hospitals, Baltimore, Maryland. This study was supported in part by the Biomedical Research Support Grant 2S07-RR-0556, Baltimore City Hospitals, Baltimore, Maryland. Requests for reprints should be addressed to Dr. Edward G. Lakatta, Cardiovascular Section, Gerontology Research Center, National Institute on Aging, 4940 Eastern Avenue, Baltimore, Maryland 21224. Manuscript accepted on March 30, 1982.

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To assess the efficacy of digitalis in patients with chronic clinically compensated congestive heart failure and normal sinus rhythm, we performed a double-blind crossover study with digoxin and placebo in 30 consecutive outpatients fullfilling these criteria; serum digoxin levels, clinical symptoms and signs, and objective indexes of cardiac function were monitored. No patient’s clinical condition deteriorated during three months of placebo administration. Discontinuation of digoxin resulted in a small increase in echocardiographicaiiy determined resting left ventricular end-diastolic dimension (1.8 f 0.8 mm, p
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from differences in patient selection, most of these studies had one or more shortcomings: inclusion of patients without convincing evidence of heart failure; failure to separate patients with sinus rhythm from those with atrial fibrillation; no determination of serum digoxin levels; no comparison of glycosides with placebo: no objective measure of cardiac pump or muscle function; and no assessment of changes in exercise capacity. As a result, these studies have produced little definitive evidence on which physicians might base their prescribing habits for cardiac glycosides. Recently, Arnold et al. [8] reported hemodynamic deterioration following digoxin withdrawal, both at rest and with exercise, in nine subjects with congestive heart failure. Although left ventricular function was carefully assessed in this study, the conclusions were limited by the atypical characteristics of the small patient group-relatively young subjects with very high resting pulmonary capillary wedge pressures, in whom idiopathic cardiomyopathy was the most common cardiac diagnosis. The present study was undertaken to assess the efficacy of long-term digoxin therapy in a double-blind placebo-controlled crossover protocol in patients who more closely represent the large ambulatory population with heart failure, i.e., older patients in whom coronary heart disease is predominant [9,10]. Whenever possible, attempts were made to overcome the major shortcomings of previous studies that addressed this question. Only patients with documented chronic stable congestive heart failure and residual cardiomegaly were studied; those subjects with atrial fibrillation were excluded. Serum digoxin levels were monitored throughout the study, and only those patients with therapeutic serum levels of digoxin were included in the data analysis. In addition to assessment of clinical signs and symptoms, the effects of glycoside on cardiac function were measured by echocardiography and systolic time intervals. Finally, the effect of digitalis on work capacity during treadmill exercise was determined in a representative subset of these patients. METHODS The patient population was selected from two sources within the Baltimore City Hospitals: the Chronic Care inpatient facility (nine patients) and the outpatient Cardiac Clinic (21 patients). All patients had at least one radiographically documented episode of left-sided heart failure, not associated with an acute cardiopulmonary or other systemic insult; 10 subjects had associated right-sided failure. Chronic congestive heart failure was documented in each patient by clinical symptoms and/or signs of pulmonary venous hypertension that persisted after treatment of the initial episode of congestive heart failure, plus residual cardiomegaly (cardiothoracic ratio of more than 0.50) and pulmonary vascular redistribution as shown on a chest x-ray film taken within

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three months of the study. Patients with atrial fibrillation

and those with a history of atrial tachyarrhythmia were excluded from the study as were those who had had myocardial infarction within the previous six months. Only subjects whose condition was clinically stable and whose cardiac medication had remained unchanged for at least three months were studied. Before a patient entered the study, we adjusted the digoxin dosage as necessary to achieve a therapeutic serum level of 1.0 to 2.0 ng/ml at least six hours after the last dose. The 30 subjects who constituted the study population ranged in age from 37 to 89 years (mean 69.2 f 2.1 years). There were 14 men and 16 women. Twenty-six of the 30 were receiving maintenance digoxin (mean daily dose 0.24 f 0.02 mg, range 0.125 to 0.50 mg, and mean plasma level 1.4 f 0.1 ng/ml). which they had been taking for one to 16 years. The cause of congestive heart failure was coronary artery disease in 19 patients, aortic or mitral valvular disease in five, hypertension in three, and cardiomyopathy in three. Sixteen subjects were in New York Heart Association Class II for congestive heart failure, 13 were in Class Ill, and one was in Class IV. An S3 gallop was present in one subject, rales in five, and signs of right-sided heart failure in five subjects at the time of study. Twenty-four of the 30 subjects were taking other cardiovascular drugs, which are delineated in Table I. Control subjects, matched for age and sex and free from overt cardiovascular disease, were derived from the Baltimore Longitudinal Population [ 1 l] and used to define normal indexes of cardiac size and function. Each of these control subjects had a normal response to maximal treadmill exercise electrocardiography. The study was carried out in three visits to the laboratory. During the initial visit, informed consent was obtained after the protocol was thoroughly explained. The patient received a standard posteroanterior chest roentgenogram to ascertain cardiothoracic ratio and status of pulmonary vascularity. An M-mode echocardiogram of the left ventricle was performed with the patient in the left lateral decubitus position with a Smith-Kline Instruments Ekoline 20A echocardiograph interfaced with a Honeywell 1856 recorder at a paper speed of 50 mm/set. Three sets of systolic time intervals were then recorded 10 minutes apart on a Honeywell 1856 recorder at a paper speed of 100 mm/set with the patient supine. Resting heart rate and systolic, diastolic, and pulse pressures were determined from the average of three recumbent heart rate and blood pressure readings during systolic time interval recordings. Maximal symptom-limited treadmill exercise capacity was determined in subjects free of orthopedic limitations under continuous electrocardiographic monitoring, using a modified

TABLE I

Concurrent Cardiovascular Medications Medicalion

No. 23 5 4 5 5

Diuretics Long-acting nitrates Beta-blockers Antiarrhythmics Antihypertensives

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TABLE II

ET AL.

Resting Heart Size and Function on Placebo in Subjects with Heart Failure and Age- and Sex-Matched Control Subjects CHF Subjects No.

CTR LVED/m* (mm) FS V,r (circkec) PEPILVET

30 21 19 19 26

Value 0.54 32.5 0.23 0.82 0.47

No.

f 0.01 f 1.5 f 0.02 f 0.06 f 0.02

22 17 17 17 14

Control Subjects Value 0.46 26.2 0.36 1.22 0.37

f f f f f

0.01 0.7 0.01 0.06 0.02

D
Values represent mean f standard error of the mean. CHF = congestive heart failure; CTR = cardiothoracic ratio. Other abbreviations defined in text.

Balke protocol. Tests were terminated by fatigue, dyspnea, or unequivocal angina pectoris. Systolic blood pressure and heart rate were measured during the final 30 seconds of each exercise stage and every two minutes during a six-minute recovery period. At the end of the visit, the patient received a bottle containing 100 tablets of either digoxin or placebo and was instructed to take them in place of regular digoxin. The identity of the drug was unknown to both the patient and physician. Patients returned for the second visit approximately three months (IL two weeks) later, and were studied in a manner identical to that of the initial visit, including interval history and repeated physical examination. Particular attention was paid to any changes in symptoms or signs of heart failure. At the end of the visit, the patient returned his unused “study pills” and was crossed over to the other regimen for three more months. The third visit was scheduled three months after the second visit and was identical in format. On all follow-up visits, care was taken to record the echocardiogram and systolic time intervals with the echo transducer, carotid pickup, and heart sound microphone in the same locations as during the initial visit. Likewise, the dosages of all other cardiac and antihypertensive medications were kept constant throughout the entire study. All patients remained under the care of their personal physicians during this period. Serum digoxin determinations were made during each visit to insure compliance. After each visit, the chest x-ray films were read by the same radiologist, and a single physician, unaware of digoxin and placebo status, made the following measurements: cardiothoracic ratio, determined from posteroanterior chest x-ray films in the standard manner [12]; left ventricular end-diastolicdimension (LED), measured at the onset of the QRS complex by the leading-edgemethod [ 131; fractional shortening of the minor hemi-axis of the left ventricle (FS), calculatedas (LVED - LVES)/LVED, where LVES is the left ventricular end-systolic dimension measured at the peak downward excursion of the interventricular septum [ 131; velocity of circumf&entia/ fiber shortening ( VCr),calculated as FS/LVET, where LVET is left ventricular ejection time determined from the left ventricular posterior wall echogram; systolic time intervals, calculated from mean values of three recordings of 10 beats each taken 10 minutes apart, and corrected for heart rate by the regression equations of Weissler et al. [ 141; PEPi, LVETi and Q&i represent these heart rate-corrected values for PEP (pre-ejection period),

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LVET, and QSz (electromechanical systole), respectively. The ratio of PEP to LVET was calculated using the uncorrected values of PEP and LVET. Statistical Analysis. The paired t test was used to compare indexes of cardiac size and function during digoxin and placebo treatment periods. The unpaired t test was used to compare subjects who had heart failure with normal control subjects and to compare patients who performed treadmill exercise with those who did not. A p value 50.05 by twotailed analysis was required for statistical significance. RESULTS Of 40 consecutive patients who entered the study, three had serum digoxin levels of less than 1.O ng/ml despite dose adjustment; three elected not to return for the second visit; two had acute myocardial infarction during the study; one had progressive aortic valvular insufficiency and intractable congestive heart failure that was unresponsive to reinstitution of digoxin and marked increases in diuretic and vasodilator doses; pneumonia developed in one patient and he was restarted on digoxin by his private physician before the second study visit. The resting heart size and functional indexes in the 30 patients who constituted the study population are compared with those of control subjects matched for age and sex (Table II). The patient group demonstrated a significantly higher cardiothoracic ratio (17 percent) and LVED (15 percent) adjusted for body surface area than the normal subjects. In addition, FS and V,r were reduced (36 and 32 percent, respectively) and the PEP/LVET ratio was increased 30 percent in congestive heart failure patients relative to control subjects. No patient had echocardiographic evidence of hypettrophic cardiomyopathy. Digitalis had no demonstrable clinical effect on any of the 30 patients. Specifically, no changes were noted in the history for orthopnea, paroxysmal nocturnal dyspnea, or exercise capacity between the digoxin and placebo regimens. Physical findings were essentially identical on the two regimens: during digoxin therapy, rales developed in two subjects and mild peripheral edema developed in one; during placebo administration, rales developed in two additional subjects and mild

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TABLE III

Effect of Digoxin Withdrawal on Resting Indexes of Cardiac Size and Function N’

HR (beatslmin) SBP (mm Hg) DBP (mm Hg) CTR LVED (mm) FS V,r (circkec) QSPi (msec) PEPi (msec) LVETi (msec) PEPILVET

---

30 30 30 30 21 19 19 28 28 28 28

Digoxin

68.0 135.5 71.9 0.537 55.8 0.25 0.90 526 150 375 0.467

f f f f f f f f f f f

A

Placebo

-_I

69.8 133.0 72.8 0 540 57.6 0.23 0.82 549 157 391 0.467

2.5 3.7 1.6 0.01 2.3 0.02 0.08 4.6 4.8 3.4 0.02

zt f f f f f f f f f f.

2.5 3.6 16 0.01 2.2 0.02 0.06 4.5 4.4 3.5 0.02

t1.8f -2.5 +0.9 to.002 +1.8 -0.015 -0.08 +22.9 +7.3 +15.6 0.000

P NS NS NS NS
1.0 0.9 0.5

f f f f f f f f f f

0.004

0.59 0.009 0.04 2.9 1.8 2.9 0.012

’ N was determined by the number of patients in whom technically adequate data were obtained. Values represent mean f standard error of the mean. HR = heat rate: NS = not significant: SBP = systolic blood pressure; DBP = diastolic blood pressure; CTR = cardiothoracic ratio. Other abbreviations defined in text.

Pleural effusions or overt pulmonary edema did not occur in any patient during the study. A consistent increase in LVED occurred during placebo therapy; although this change was statistically significant, the magnitude of the change ‘was only 3 percent. FS of the left ventricle did not differ between digoxin and placebo regimens. V,r significantly diminished during placebo treatment, but like LVED, the difference in V,r evidenced by withdrawal of digoxin was small (10 percent). In patients with more severe left ventricular dilatation and dysfunction as indexed by these parameters, digoxin did not exert a greater effect by linear regression analysis than in subjects with less abnormality (Figure 1). PEPi, LVETi, and their sum, Q!$i,

jugular venous distension developed in one. Body weight

was not affected by digoxin (70.8 f 2.6 kg on digoxin versus 70.7 f 2.6 kg on placebo). It was not necessary to alter the dosage of diuretic, vasodilator, or other cardiac medication in any patient during placebo administration. Resting heart rate and systolic, diastolic, and pulse pressures were unaffected by withdrawal of digitalis (Table III). The effect of digoxin on the resting indexes of cardiac size and function is presented in Table Ill. Digoxin did not change the cardiothoracic ratio. Minor radiographic increases in pulmonary vascular congestion were observed in five subjects during placebo administration, and in two during digitalis treatment.

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VU ON PLACEBO Icirchcl F@ure 1. Len, e&ocardiographically#etermi~ left ventricular end-diastolicdimension (LED) on placebo versus tha change in L VED e/i&d by digoxin. No significant relationship was found by linear regression analysis. Right, echocardiographicallydeterminedvelocityof circumferential fiber shortening (Vcr) on placeboversus the changeelicited by digoxin.Again, no significant relationship was found.

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2. Effect of digoxin withdrawal and readministration on the duration of electromechanical systole, corrected for heart rate (QS~i) in six patients. Q&i lengthened significantly during placebo administration and shortened to initial leveis when digoxin therapy was resumed.

all increased during placebo treatment, but the magnitude of these changes was small (Table Ill); there was no change in the PEP/LVET ratio. No relationship was found between the serum digoxin level and the magnitude of change in QSpi, LVED, or V,r. In six subjects, an additional crossover (i.e., digoxin to placebo to digoxin) was accomplished. As shown in Figure 2, the significant prolongation of QSpi that occurred during digoxin withdrawal was reversed when digoxin was reinstituted (p
Maximal treadmill exercise was performed during both digoxin and placebo regimens in a subgroup of 12 subjects. Although the patients who underwent exercise testing were younger than those who did not (62.6 f 3.4 versus 73.8 f 2.2 years), the LVED (58.0 f 3.5 versus 54.9 f 3.5 mm) and V,r (0.80 f 0.08 versus 0.86 f 0.15 circ/sec) of the two groups during placeba administration did not differ. Three of the patients were limited by the development of angina pectoris during exercise testing; the remaining nine subjects exercised until incapacitated by fatigue or dyspnea. No difference in maximal exercise duration was observed between digoxin and placebo regimens (7.64 f 0.75 versus 7.80 f 0.80 min). Similarly there was no difference in maximal heart rate (124.5 f 6.3 versus 127.8 f 5.9) peak systolic blood pressure (154.5 f 6.4 versus 148.0 f 6.4 mm Hg), or maximal rate-pressure product [( 19.2 f 1.3 versus 18.9 f 1.4) X 103]. As illustrated in Figure 3, heart rate and systolic blood pressure at all submaximal levels of exercise were similar during digoxin and placebo regimens. During long-term follow-up of the 26 patients who had received maintenance digoxin therapy prior to the study, no exacerbation of congestive heart failure attributable to digoxin withdrawal occurred. In 17 subjects, digoxin was not resumed, with no clinical worsening of heart failure for a mean follow-up of 18.9 f 1.6 months (range 11 to 33 months). In three subjects, digoxin therapy was resumed immediately upon completion of the study at the wishes of the attending physician, despite the absence of clinical deterioration during placebo administration. Three other patients required reinstitution of digoxin after an acute event: Myocardial infarction complicated by cardiac failure occurred in one patient, and supraventricular tachyarrhythmias occurred in association with pulmonary embolus in the second patient and with myocardial infarction in the third. Digoxin therapy was resumed after an exacerbation of heart failure in three additional patients whose maintenance diuretic therapy was stopped or reduced in dose after completion of the study. Clinical deterioration in these subjects occurred three months, four months, and 11 months after cessation of digoxin; no attempt was made by the patients’ physicians to control the exacerbations with diuretics alone. COMMENTS

EXERCISE DURATIONlminl

Figure 3. Comparison of heart rate and systolic blood pressure between digoxin and placebo regimens during each stage of treadmill exercise in 12 patients. No difference was found in either parameter for any exercise stage.

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The present study demonstrates that in an ambulatory cardiac population with stable chronic congestive heart failure and normal sinus rhythm, digoxin can be successfully discontinued for at least one to two years without a change in clinical status in the majority of patients, as long as other cardiac medications are maintained. Although an increase in LVED, decrease in V,r and prolongation of systolic time intervals oc-

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curred during placebo administration, the magnitude of these changes was small. Furthermore, maximal exercise capacity as well as maximal exercise heart rate and systolic blood pressure were unaffected by withdrawal of digitalis. Epidemiologic studies have shown (1) that the prevalence and incidence of congestive heart failure increase exponentially with age [9,10] and that, not surprisingly, the majority of patients who use digoxin and become toxic from it are elderly [ 15,161; (2) coronary heart disease is the most common cardiac diagnosis in patients who receive digitalis; (3) most patients who are treated with cardiac glycosides have sinus rhythm [16]; and (4) patients receiving digoxin usually receive diuretics concomitantly [ 161. Thus, the population studied was representative of the majority of ambulatory patients treated with glycosides, i.e., a predominantly elderly population with Class II or III congestive heart failure, which was due most commonly to coronary artery disease. Most of these patients were simultaneously receiving diuretics. The present results are concordant with those of several previous studies [4-7] and further suggest ,that most patients who are receiving digoxin can safely discontinue the drug for at least one year without clinical deterioration. Although symptoms and functional capacity are clinically useful descriptors, their correlation with resting ventricular size and function is frequently poor [ 171. In patients in whom digitalis was successfully discontinued in previous studies, it might therefore be argued that the drug may have exerted a significant effect on cardiac function that was not clinically apparent. The few such studies in which a noninvasive index of cardiac function was monitored have noted only small effects of cardiac glycosides. A small prolongation of systolic time intervals similar to that in the present study has been observed in subjects in whom digoxin was successfully discontinued [5,7]. No change in heart rate, ventilation, oxygen consumption, respiratory quotient, or symptoms at submaximal exercise workloads was found in five subjects tested before and after digoxin withdrawal [ 181. Rader et al. [ 191 showed that diuretics alone elicited improvement in cardiac output and arteriovenous oxygen difference in half of their patients with congestive heart failure; the addition of digitalis produces no further hemodynamics improvement in these patients. On the other hand, selected populations exist in whom digoxin has been shown to be of both hemodynamic and clinical benefit for up to several weeks [8,20]. In general those subjects benefiting from digitalis are younger than our subjects and appear to have more severe pump dysfunction. Given these variables and the fact that congestive heart failure may develop from diverse cardiac pathologies and may vary in se-

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verity among patients with the same pathology, it would be surprising if a given drug were equally effective in all patients with signs and symptoms of congestive heart failure, as suggested by Cohn [21]. It is also possible that beneficial effects of cardiac glycosides apparent after several weeks might no longer be evident after a period of years, the goal of long-term therapy. The present study demonstrates that the long-term effect of digoxin on noninvasive indexes of ventricular function in our population, although statistically significant, is very small. While radionuclide ventriculography may be superior to the tests used here for the evaluation of global left ventricular function the sensitivity of our methods, in which each patient served as his own control, would seem to be confirmed by the small but consistent changes in left ventricular size, V,.r, and systolic time intervals induced by digitalis withdrawal. The fact that these changes lack clinical importance is supported by the absence of clinical exacerbations of heart failure in our patients during the observation period. Although these indexes are sensitive to changes in inotropic state, they may reflect changes in cardiac preload and afterload; to infer inotropic changes solely from these measurements is tenuous. Thus, the present results are not necessarily indicative of the effect of digoxin on cardiac muscle per se, but rather on the status of pump function, improvement of which is the primary goal of glycoside therapy. Finally, it is important to note that although greater changes in cardiac function might be elicited by increasing the dose of digoxin, the risk of drug toxicity would certainly be heightened by such a maneuver. It should be emphasized that the present results pertain only to clinically stable patients with normal sinus rhythm, most of whom continue to receive other cardiac medications. Available data suggest that in many patients with atrial fibrillation, symptoms of congestive heart failure are exacerbated when glycoside therapy is discontinued [3,6]. One should also bear in mind that the present study was designed to compare digoxin and placebo for only three months. Although the majority of patients were successfully maintained without digoxin for an average follow-up of one and a half years, the effect of discontinuation of digitalis on the long-term natural history of congestive heart failure remains unknown. Because every patient except one was in New York Heart Association Class II or III, the present results do not necessarily apply to those patients with severe functional limitation, i.e., Class IV congestive heart failure. Finally, it is possible that maintenance digoxin therapy in patients with congestive heart failure may prevent de novo atrial fibrillation [ 71 or prevent exacerbation of congestive heart failure symptoms during intercurrent illness. The potential benefits in these instances must be weighed against the

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potential risks of maintenance therapy. Additional studies in large numbers of patients followed up for extended periods of time are required to determine the long-term risk-benefit ratio of maintenance digoxin. In summary, discontinuation of maintenance digoxin therapy had no demonstrable clinical effect, either at rest or during exercise, in 30 consecutive outpatients with stable congestive heart failure and normal sinus rhythm. Long-term digoxin administration elicited small Improvements in noninvasive resting indexes of cardiac pump and muscle function; despite their statistical significance, however, these changes had no apparent clinical importance. Our findings suggest that the majority of ambulatory patients with compensated con-

gestive heart failure and sinus rhythm can be successfully maintained without digitalis glycosides. ACKNOWLEDGMENT We are indebted to the physicians in the Cardiology Clinic at Baltimore City Hospitals, and to Dr. Edmund G. Beacham and his colleagues from the Division of Chronic Medicine of Baltimore City Hospitals for referring patients for this study, to Mrs. Catherine Dent for technical assistance and to Mrs. Elsie Beard for statistical analyses. We also wish to thank the Department of Radiology at Baltimore City Hospitals for interpreting all chest x-ray films in this study.

REFERENCES

2. 3. 4.

5.

6. 7. 8.

9. 10.

11.

12.

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Schick D, Scheuar J: Curent concepts of therapy with digitalis glycosides. Part I. Am Heart J 1974; 87: 253-258. Gold H: Digitalis, its actii and usage. Med Ann DC 194 1; 10: 127-133. 162. Rogen AS: Maintenance treatment with digitalis. Br Med J 1943; 1: 694-695. Hull SM. Mackintosh A: Discontinuation of maintenance digoxin therapy in general practice. Lancet 1977; II: 1054-1055. Dobbs SM, Kenyon WI, Dobbs RJ: Maintenance digoxin after an episode of heart failwe: placebo-controlled trial in outpatients. Br Med J 1977; 1: 749-752. Perez GL: Discontinuation of digitalis in the elderly. Pratt Cardiol 1978; 4: 161-163. Johnston GD. McDevttt DG: Is maintenance diixin necessary in patients with sinus rhythm? Lancet 1979; I: 567-570. Arnold SB. Byrd RD. Meister W, et al.: Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 1980: 303: 1443-1448. Klainer LM, Gibson TC. white KL: The epidemiology of cardiac failure. J Chronic Dis 1965; 18: 797-814. McKee PA, Castelli WP, McNamara PM, Kannel WB: The natural history of congestive heart failure: the Framingham Study. N Engl J Med 1971; 285: 1441-1446. Stone JL. Norris AH: Activities and attitudes of participants in the Baltknore Longitudinal Study. J Gerontol 1966; 21: 575-580. Felson B: Chest roentgenology. Philadelphia: WB Saunders, 1973.

Auguet 1982

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Jeemd

ol Medklm

Vdetne

13.

14.

15.

16.

17.

18.

19.

20.

21.

73

Sahn DJ. DeMaria A. Kisslo J. Weyman A: Recommendations regarding quantitation in Mmode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072-1083. Weissler AM, Harris WS, Schoenfeld CD: Systolic time intervals in heart failure in man. Circulation 1968; 37: 149-159. Shapiro S, Slone D, Lewis GP. Jick l-t: The epidemiology of digoxin: a study in three Boston hospitals. J Chronic Dis 1969; 22: 361-371. Beller GA, Smith TW. Abelmann WH, Haber E, Hood WB Jr: Digitalis intoxication: a prospective clinical study with serum level correlations. N Engl J Med 1971; 284: 989-997. Benge W. Litchfield RL. Marcus ML: Exercise capacity in patients with severe left ventricular dysfunction. Circulation 1980; 61: 955-959. McHaffie D. Purcell H, Mitchell-Heggs P, Guz A: The clinical value of digoxin in patients with heart failure and sinus rhythm. Cl J Med 1978; 47: 401-419. Rader B, Smith WW, Berger AR, Eichna LW: Comparison of the hemodynamic effects of merctrtal diuretics and digitalis in congestive heart failure. Circulation 1964; 29: 328345. Lee DC-S, Johnson RA. Bingham JB. et al.: Digitalis vs. placebo in outpatients with heart failure (abstr). Circulation 1980; 62: 111-325. Cohn JN: Indications for digitalis therapy. A new look. JAMA 1974; 229: 1911-1914.