Saturday I7 March I979 IS MAINTENANCE DIGOXIN NECESSARY IN PATIENTS WITH SINUS RHYTHM? G. D.
JOHNSTON
D. G. MCDEVITT
Department of Therapeutics and Pharmacology, Queen’s University of Belfast and Belfast City Hospital, Belfast, Northern Ireland Discontinuation of digoxin in 56 patients with sinus rhythm who had been taking it for a long time did not produce clinical deterioration in 33 of 34 patients whose pre-withdrawal steadystate plasma-digoxin concentration was less than 0·8 ng/ml; fast atrial fibrillation developed in the other patient. 22 patients had plasma-digoxin levels between 0·8 and 2.0 ng/ml before withdrawal—of these, 7 deteriorated without digoxin (5 had atrial fibrillation, which was associated with congestive heart-failure in 2, and 2 had congestive heart-failure whilst remaining in sinus rhythm). In the latter 2 patients with heart-failure, measurement of the pre-injection period/left-ventricular ejection time (P.E.P./L.V.E.T.) ratio suggested that digoxin did exert a sustained positive inotropic effect. Thus, successful discontinuation of digoxin was possible in 86% of the total group and was more likely when the plasma-digoxin concentration was below 0·8 ng/ml. Unexpected atrial fibrillation was the commonest development in the 8 patients in whom digoxin withdrawal was unsuccessful.
Summary
Introduction THE principal therapeutic action of digoxin in heartfailure is said to be its positive inotropic effect on the myocardium and to be unrelated to its capacity to control heart-rate in atrial fibrillation.’ In support of this it has been shown that patients in sinus rhythm benefited as much as those with atrial fibrillation from the use of cardiac glycosides,2-4 and that inotropic action is demonstrable both in normal and abnormal hearts.5 Despite this, there is little evidence that chronic stimulation of the heart by digoxin is useful in patients with sinus rhythm, and its value has been questioned.6 The present study was undertaken to determine the effects of discontinuing digoxin maintenance therapy in patients with sinus rhythm.
concentration by a radioimmodified ’Lanoxitest’ kit method.7 Bloodmunoassay using samples were taken at least 6 h after the last stated digoxin dose. Patients in sinus rhythm who had no previous history of atrial tachyarrhythmia and did not show clinical evidence of congestive heart-failure were considered suitable for a trial of digoxin withdrawal. 65 patients fulfilled these criteria and, after a full explanation of what was involved, were asked if they were willing to have their digoxin withdrawn. 10 patients declined, but 1 other patient who had had transient atrial fibrillation after a previous myocardial infarction was included. Thus 56 patients volunteered, and they were reassessed 2 weeks later, at which time a chest X-ray was taken. The "usual" range of plasma-digoxin concentration is 0.8-2.0 ng/ml.8 Levels below 08 ng/ml may, therefore, be counted as subtherapeutic. Patients were divided into two measurement
of
plasma-digoxin a
°
groups
according
to two
"steady-state" plasma-digoxin
con-
centration measurements done 2 weeks apart in each patient. The 34 patients whose plasma-levels on each of the two occasions were less than 08 ng/ml (subtherapeutic group) had their digoxin discontinued as outpatients, all other medications remaining unchanged. For 3 months, each patient was assessed monthly for his degree of dyspnoea, signs of heart-failure, and evidence of rhythm disturbance. An E.c.G. was recorded at each visit, and the chest X-ray was repeated at 3 months. The 22 patients whose steady-state plasma-digoxin concentrations were 0-8-2.0 ng/ml (therapeutic group) had their digoxin withdrawn under hospital supervision for the first 6 days. All other drugs were continued unchanged. Each patient was weighed daily and assessed daily for clinical signs of heartfailure or rhythm disturbance; in addition, systolic-time intervals of the left ventricle were measured by simultaneous fastspeed recordings (100 mm/s) of E.c.G., phonocardiography, and carotid-artery pulse-tracing. All recordings were done in the early afternoon after a 15 min rest. The mean of ten consecutive intervals, each corrected for heart-rate,? was calculated. Plasma-digoxin concentrations in the patients in hospital were measured 6 h after the last dose and daily for another 4 .days. Patients were reviewed 1 and 3 weeks after discharge (i.e., 2 and 4 weeks after withdrawal) and, thereafter, monthly for up to 3 months. On each visit, signs of heart-failure were sought and the tests were repeated. Criteria for reintroduction of digoxin were the development of heart-failure, increases in the pre-ejection period/left-ventricular ejection time (P.E.P./L.v.E.T.) ratio, or the development of atrial fibrillation or tachycardia. Further evidence of the value of digoxin was afforded if these abnormalities returned to their pre-withdrawal state after digoxin had been reintroduced. Statistical analyses were done by the Student’s paired t test and the exact probability test. Results are expressed as mean± S.E.M.
Patieyats and Methods Patients taking maintenance digoxin therapy were assessed at either a cardiac or general medical outpatient clinic. In each patient the reason for starting digoxin was determined (where possible), the grade of dyspnoea was noted, clinical evidence of heart-failure was looked for, a 12-lead electrocardiogram E.c.G.) was recorded, and a blood-sample was taken for
Results Of the 56 patients studied, 26 were male and 30 female. Their mean age was 65-2+1-1years, and their mean blood-urea concentration was 7-2±0-9 mmol/1. In most patients (70%) the reason for initiating 8116
568
digoxin therapy was congestive heart-failure, usually secondary to ischsemic heart-disease (52%), but which could also have been due to hypertensive, valvular, or respiratory disease; in 18% digoxin had been given for "non-congestive" heart-failure complicating an acute myocardial infarction; and in the remainder (12%) the reason could not be determined (table I). 44 (80%) patients, 27 in the subtherapeutic and 17 in the therapeutic group received diuretics throughout the study. In the 34 patients with steady-state plasma-digoxin concentrations of less than 0-8 ng/ml, digoxin was successfully withdrawn in 33 without deterioration of cardiac function (table n). 1 patient with a steady-state plasma-concentration of 0-7ng/ml on two occasions had fast atrial fibrillation after withdrawal of digoxin (table TABLE I-INDICATIONS FOR INITIAL DIGOXIN THERAPY IN
56
PATIENTS IN WHOM THE DRUG WAS WITHDRAWN
TABLE II-RESULTS OF DIGOXIN WITHDRAWAL IN
p=0’0043
56
PATIENTS
(exact probability).
TABLE III-REASONS FOR UNSUCCESSFUL DIGOXIN WITHDRAWAL
*1
patient had plasma-digoxin concentration
JOHNSTON
D. G. MCDEVITT
Department of Therapeutics and Pharmacology, Queen’s University of Belfast and Belfast City Hospital, Belfast, Northern Ireland Discontinuation of digoxin in 56 patients with sinus rhythm who had been taking it for a long time did not produce clinical deterioration in 33 of 34 patients whose pre-withdrawal steadystate plasma-digoxin concentration was less than 0·8 ng/ml; fast atrial fibrillation developed in the other patient. 22 patients had plasma-digoxin levels between 0·8 and 2.0 ng/ml before withdrawal—of these, 7 deteriorated without digoxin (5 had atrial fibrillation, which was associated with congestive heart-failure in 2, and 2 had congestive heart-failure whilst remaining in sinus rhythm). In the latter 2 patients with heart-failure, measurement of the pre-injection period/left-ventricular ejection time (P.E.P./L.V.E.T.) ratio suggested that digoxin did exert a sustained positive inotropic effect. Thus, successful discontinuation of digoxin was possible in 86% of the total group and was more likely when the plasma-digoxin concentration was below 0·8 ng/ml. Unexpected atrial fibrillation was the commonest development in the 8 patients in whom digoxin withdrawal was unsuccessful.
Summary
Introduction THE principal therapeutic action of digoxin in heartfailure is said to be its positive inotropic effect on the myocardium and to be unrelated to its capacity to control heart-rate in atrial fibrillation.’ In support of this it has been shown that patients in sinus rhythm benefited as much as those with atrial fibrillation from the use of cardiac glycosides,2-4 and that inotropic action is demonstrable both in normal and abnormal hearts.5 Despite this, there is little evidence that chronic stimulation of the heart by digoxin is useful in patients with sinus rhythm, and its value has been questioned.6 The present study was undertaken to determine the effects of discontinuing digoxin maintenance therapy in patients with sinus rhythm.
concentration by a radioimmodified ’Lanoxitest’ kit method.7 Bloodmunoassay using samples were taken at least 6 h after the last stated digoxin dose. Patients in sinus rhythm who had no previous history of atrial tachyarrhythmia and did not show clinical evidence of congestive heart-failure were considered suitable for a trial of digoxin withdrawal. 65 patients fulfilled these criteria and, after a full explanation of what was involved, were asked if they were willing to have their digoxin withdrawn. 10 patients declined, but 1 other patient who had had transient atrial fibrillation after a previous myocardial infarction was included. Thus 56 patients volunteered, and they were reassessed 2 weeks later, at which time a chest X-ray was taken. The "usual" range of plasma-digoxin concentration is 0.8-2.0 ng/ml.8 Levels below 08 ng/ml may, therefore, be counted as subtherapeutic. Patients were divided into two measurement
of
plasma-digoxin a
°
groups
according
to two
"steady-state" plasma-digoxin
con-
centration measurements done 2 weeks apart in each patient. The 34 patients whose plasma-levels on each of the two occasions were less than 08 ng/ml (subtherapeutic group) had their digoxin discontinued as outpatients, all other medications remaining unchanged. For 3 months, each patient was assessed monthly for his degree of dyspnoea, signs of heart-failure, and evidence of rhythm disturbance. An E.c.G. was recorded at each visit, and the chest X-ray was repeated at 3 months. The 22 patients whose steady-state plasma-digoxin concentrations were 0-8-2.0 ng/ml (therapeutic group) had their digoxin withdrawn under hospital supervision for the first 6 days. All other drugs were continued unchanged. Each patient was weighed daily and assessed daily for clinical signs of heartfailure or rhythm disturbance; in addition, systolic-time intervals of the left ventricle were measured by simultaneous fastspeed recordings (100 mm/s) of E.c.G., phonocardiography, and carotid-artery pulse-tracing. All recordings were done in the early afternoon after a 15 min rest. The mean of ten consecutive intervals, each corrected for heart-rate,? was calculated. Plasma-digoxin concentrations in the patients in hospital were measured 6 h after the last dose and daily for another 4 .days. Patients were reviewed 1 and 3 weeks after discharge (i.e., 2 and 4 weeks after withdrawal) and, thereafter, monthly for up to 3 months. On each visit, signs of heart-failure were sought and the tests were repeated. Criteria for reintroduction of digoxin were the development of heart-failure, increases in the pre-ejection period/left-ventricular ejection time (P.E.P./L.v.E.T.) ratio, or the development of atrial fibrillation or tachycardia. Further evidence of the value of digoxin was afforded if these abnormalities returned to their pre-withdrawal state after digoxin had been reintroduced. Statistical analyses were done by the Student’s paired t test and the exact probability test. Results are expressed as mean± S.E.M.
Patieyats and Methods Patients taking maintenance digoxin therapy were assessed at either a cardiac or general medical outpatient clinic. In each patient the reason for starting digoxin was determined (where possible), the grade of dyspnoea was noted, clinical evidence of heart-failure was looked for, a 12-lead electrocardiogram E.c.G.) was recorded, and a blood-sample was taken for
Results Of the 56 patients studied, 26 were male and 30 female. Their mean age was 65-2+1-1years, and their mean blood-urea concentration was 7-2±0-9 mmol/1. In most patients (70%) the reason for initiating 8116
568
digoxin therapy was congestive heart-failure, usually secondary to ischsemic heart-disease (52%), but which could also have been due to hypertensive, valvular, or respiratory disease; in 18% digoxin had been given for "non-congestive" heart-failure complicating an acute myocardial infarction; and in the remainder (12%) the reason could not be determined (table I). 44 (80%) patients, 27 in the subtherapeutic and 17 in the therapeutic group received diuretics throughout the study. In the 34 patients with steady-state plasma-digoxin concentrations of less than 0-8 ng/ml, digoxin was successfully withdrawn in 33 without deterioration of cardiac function (table n). 1 patient with a steady-state plasma-concentration of 0-7ng/ml on two occasions had fast atrial fibrillation after withdrawal of digoxin (table TABLE I-INDICATIONS FOR INITIAL DIGOXIN THERAPY IN
56
PATIENTS IN WHOM THE DRUG WAS WITHDRAWN
TABLE II-RESULTS OF DIGOXIN WITHDRAWAL IN
p=0’0043
56
PATIENTS
(exact probability).
TABLE III-REASONS FOR UNSUCCESSFUL DIGOXIN WITHDRAWAL
*1
patient had plasma-digoxin concentration
