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Association between clinical cardiac status, laboratory parameters, and digoxin usage
Association between clinical cardiac status, laboratory parameters, and digoxin usage David H. Huffman, M.D. James W. Crow, Ph.D. Pertti Pentik~iinen, M.D. Daniel L. Azarnoff, M.D. Kansas City, Kan. and Mo.
The cardiac glycosides are among the most effective drugs available for improving myocardial contractility. Their use, however, is not without hazard since a significant number of patients develop toxicity. 1, ~ Recent improvements in our knowledge of the pharmacology and therapeutic use of the digitalis glycosides should make our use of these drugs in patients more rational and decrease the number of toxic events. ~-3The development of the digoxin radioimmunoassay4, 5 has been particularly useful in this regard. There have been a number of studies which have evaluated the relationship between the serum digoxin concentration and clinical evidence of digoxin intoxication2 -19 With the exception of one study, ~9 all of these have demonstrated a significant positive relationship between the serum digoxin concentration and clinical evidence of glycoside intoxication. The present study was undertaken to evaluate the relationship between serum digoxin concentrations, other laboratory parameters, and the clinical response of patients receiving digoxin. In addition to defining a significant relationship From the Clinical Pharmacology-Toxicology Center, Departments of Medicine and Pharmacology; University of Kansas Medical Center, and College of Health Sciences and Hospital, Kansas City, Kan, and the Kansas City Veterans Administration Hospital, Kansas City, Mo. Supported inpart by grant GM 15956 from the U~ted States Public Health Service. Presented at the Midwest Section of the American Federation for Clinical Research meeting in Chicago, Ill., November, 1974. Received for publication Dec. 9, 1974. Reprint requests: Daniel L. Azarnoff, M.D., Clinical Pharmacology-Toxicology Center, The University of Kansas Medical Center, College of Health Sciences and Hospital, Rainbow Blvd. at 39th, Kansas City, Kan. 66103.
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between the serum digoxin concentration and cardiovascular response, we have also determined a correlation between the clinical cardiac status and a number of routine laboratory tests. Methods
During the period of July, 1971, to June, 1973, the serum digoxin concentration was determined in Over 1,200 patients admitted to the University of Kansas Medical Center. From this group, 143 patients who received a constant maintenance dose of digoxin for a minimum of 1 week were selected for this review. All patients received digoxin (Burroughs-Wellcome} during their hospitalization. Each patient was seen in consultation by one of us at the time the drug level was obtained; however, an extensive chart review was made at a later date by an independent observer who classified the patients without knowledge of the serum digoxin concentration. The patients were divided into four groups on the basis of clinical considerations. The groups were as follows: I, not toxic, in congestive heart failure; II, not toxic, not in congestive heart failure; III, possibly toxic; IV, definitely toxic. The criteria of Beller and associates 13were used for separating the patients into "not toxic," "possibly toxic," and "definitely toxic" groups and were based in part on the electrocardiogram (ECG). The further division of the "not toxic" patients into Group I and I! was based on the clinical status of the patient and the chest x-ray. The following laboratory data were recorded for each patient whenever available: age, sex, weight, diagnosis, blood urea nitrogen (BUN), creatinine, creatinine clearance, Na +, K § CL-, COs, serum
January, 1976, Vol. 9l, No. 1, pp. 28-34
C a r d i a c s t a t u s a n d digoxin usage
Table I. D u n c a n ' s Multiple R a n g e T e s t for significant digoxin p a r a m e t e r s * Group Variable
Weight (Kg.)
3.60
3/142
CRC (ml./min.)
3.01
3/130
3.54
3/142
67.57
3/142
Dose (mg.) Level (ng./ml.) Dose/Kg. (ng./Kg.)
6.245
3/142
I
H
72.7 -+ 14.2~ 62.4 -+ 31.4 0.234 _+ 0.10 0.95 _+ 0.52 0.003 _+ 0.002
65.3 -+ 14.3 60.9 +- 32.8 0.260 _+ 0.09 1.49 _+ 0.46 0.004 _+ 0.002
I
III
64.0
-+ 15.1
47.2
+- 30.3
0.292 --+ 0.08 2.53 +_ 0.64 0.005 + 0:001
IV
60.7 + 12.6 41.5 +- 21.9 0.316 _+ 0.09 3.32 _+ 1.23 0.005 _+ 0.001
*Any two means not underscore d by the s a m e line are significantly different at the 95 per cent level. t M e a n • S.D.
glutamic oxaloacetic t r a n s a m i n a s e (SGOT), bilirubin, alkaline p h o s p h a t a s e , Ca §§ lactic d e h y d r o genase (LDH), albumin, globulin, a n d T4. T h e s e r u m digoxin c o n c e n t r a t i o n was m e a sured by the r a d i o i m m u n o a s s a y p r o c e d u r e of S m i t h and associates 5 as it is used in o u r laboratory. 2~ Venous blood was collected 6 to 8 h o u r s a f t e r drug a d m i n i s t r a t i o n for d e t e r m i n a t i o n of the s e r u m concentration. Digoxin assays were p e r f o r m e d in duplicate within 48 h o u r s of receiving the sample. T h e specificity a n d sensitivity of t h e a n t i b o d y used in this a s s a y were similar to antibodies with high affinity for digoxin previously reported. TM ~ Q u a l i t y control was m a i n t a i n e d b y two i n t e r n a l s t a n d a r d s {1.25 a n d 2.5 ng. per milliliter) which were p r e p a r e d in large b a t c h e s a n d a s s a y e d each d a y t o g e t h e r with the s t a n d a r d curve a n d t h e u n k n o w n samples. T h e coefficient of variation of 30 consecutive i n d e p e n d e n t assays of t h e i n t e r n a l s t a n d a r d s was 4.8 per cent.
Statistical Methods An analysis of v a r i a n c e was p e r f o r m e d to determ i n e if a significant difference existed a m o n g the m e a n s of t h e four groups for each of t h e variables. I f t h e r e was a significant difference a t t h e 95 per cent level of confidence, it was f u r t h e r a n a l y z e d b y D u n c a n ' s ~3 M u l t i p l e R a n g e T e s t as modified by K r a m e r 24 for u n e q u a l groups to d e t e r m i n e which of t h e groups were different. Multiple regression analysis. P a t i e n t s with missing l a b o r a t o r y d a t a for weight, age, creatinine, B U N , sodium, p o t a s s i u m , c a r b o n dioxide, chloride or S G O T were deleted; 116 p a t i e n t s r e m a i n e d for the m u l t i p l e regression analyses. T h e s e p a t i e n t s were divided into three groups for this analysis: s u b t h e r a p e u t i c ( G r o u p I, n = 27),
American Heart Journal
t h e r a p e u t i c ( G r o u p II, n = 57), a n d toxic ( G r o u p s I I I a n d IV, n = 32). F o r this analysis, t h e creatinine clearance which was missing for 46 p a t i e n t s was e s t i m a t e d f r o m a n o m o g r a m . 2~ Four stepwise regression a n a l y s e s 26 were performed a t t h e 95 per cent level of confidence: (1) t h e r a p e u t i c vs. s u b t h e r a p e u t i c , (2) t h e r a p e u t i c vs. toxic, (3) t h e r a p e u t i c vs. s u b t h e r a p e u t i c w i t h o u t consideration of the digoxin level, a n d (4) t h e r a peutic vs. toxic w i t h o u t consideration of t h e digoxin level. Discriminant function analysis. Two discrimin a n t function analyses were obtained, one for t h e r a p e u t i c vs. s u b t h e r a p e u t i c a n d t h e o t h e r for t h e r a p e u t i c vs. toxic patients. T h o s e clinical a n d l a b o r a t o r y variables which a b s o r b e d t h e m o s t variance in t h e multiple regression analysis guided the selection of those used in the discrimi n a n t function analyses. A discrimination index ' T ' was c a l c u l a t e d for e a c h p a t i e n t as a f u n c t i o n of the i n d e p e n d e n t variables selected for t h e discriminant analysis: n
Ij =
~ i=1
CiXji
where ci is the discriminant f u n c t i o n coefficient a n d Xji t h e value(s) of t h e i n d e p e n d e n t variable(s) for t h e jth patient. T h e p a t i e n t s were r a n k e d in descending order b y their calculated index. A " d i s c r i m i n a t i o n value" was selected which m i n i m i z e d t h e t o t a l n u m b e r of classification errors. P a t i e n t s with a discrimination index higher t h a n this discrimination value were assigned to t h e t h e r a p e u t i c group. T h o s e p a t i e n t s with a discrimination index l o w e r t h a n the discrimination v a l u e were assigned to either the s u b t h e r a p e u t i c g r o u p or t h e toxic group, depending on which groups were p a r t of
29
Huff-manet al. Table II.Discriminant analysis: therapeutic vs. toxic Run No. 1. 2. 3. 4. 5. 6. 7.
8.
9. 10
Variable included Level Dose Dose/Kg. Level Dose Level Dose/Kg. Level CRC Level Dose CRC Level Bun CRC Wt Dose CRC Dose/Kg. CRC
Type I
Errors* i
Type II
3 9 13 4
5 13 5
3
6
3
5
4
5
2
8
10
10
9
14
Discriminant function coefficients -0.03208 -0.06649 -4.12271 -0.03151 -0.02751 -0.03154 -1.11019 -0.03162 0.00006 -0.03026 -0.04395 0.00012 -0.03540 0.00033 0.O0031 -O.OOO30 -0.10767 0.00033 -5.25804 0.00027
Discrimination value -0.07058 -0.01662 -0.01874 -0.07620 --0.07394 -0.06679 --0.07201
-0.07748
-0.01313 --0.01233
*Misclas~ifications: T y p e I, misclassified a therapeutic p a t i e n t as a toxic patient; T y p e II, misclassified a toxic p a t i e n t as a therapeutic patient.
the analysis. Two types of classification errors were possible. In the analysis between therapeutic and toxic patients, a Type I error resulted when a toxic patient was misclassified as therapeutic, whereas a type II error resulted if a patient in the therapeutic group was misclassified as toxic. All statistical analyses were performed by an IBM 370 model 145 computer. Results
Significant differences between the m e a n s of the four groups at the 95 per cent level of confidence were found among the four clinically different groups for the following variables: digoxin level, dose per kilogram, body weight, dose, and creatinine clearance. The results of the Duncan's Multiple Range test for differences between groups are presented in Table I. The digoxin level had the highest F value (67.57). The mean digoxin level of each group was significantly different from the other three groups. Although there was a progressive decrease in the creatinine clearance from Groups I to IV, the differences among Groups I, II, and III and between Groups III and IV were not significant. However, the creatinine clearance was significantly lower in the
30
"toxic groups" (III and IV) than in "not-toxic" Groups I and II. Patients in Group I weighed significantly more than did all other patients (Groups II, III, and IV). The absolute digoxin maintenance dose as well as the dose per kilogram increased from Group I to Group IV. The not toxic groups (I and II) received significantly less digoxin t h a n those in Group IV. F o u r stepwise multiple regression analyses were performed. In comparing therapeutic and subtherapeutic, the regression equation absorbed 13.7 per cent of the variance (R 2) when drug level was not considered whereas 29.5 per cent was absorbed when level was included. This same trend was more evident between the therapeutic and toxic groups when the digoxin level was included in the regression analysis 55.5 per cent of the variance was absorbed. Of this 55.5 per cent, 50 per cent of the variance was absorbed by the digoxin level alone and only an additional 5 per cent by adding 12 other variables. In con' trast, when the digoxin level was not included only 24.5 per cent of the variance was absorbed. When level is considered, in both therapeutic vs. toxic a n d therapeutic vs. subtherapeutic regression analyses, it carries the greatest weight
January, 1976, Vol. 91, No. 1
Cardiac status a n d digoxin usage
in the regression equation (i.e., highest b' value). Because level is so predictive, 13 variables* in the therapeutic vs. toxic and 10t in the therapeutic vs. subtherapeutic are included in the regression equation as opposed to the comparisons when level is excluded. Only 75 and 5w variables are included at the 95 per cent level in the latter two comparisons without the digoxin level. There is approximately a 1.5- to 2.0-fold increase in the correlation coefficient (R) when level is considered. If level enters the regression equation, creatinine clearance, BUN, and dose weigh heavily in the therapeutic vs. toxic groups whereas patient weight enters significantly in the therapeutic vs. subtherapeutic regression equation. This trend was suggested by Duncan's Multiple Range Study (Table I). In Table II, the results of the discrimination analysis are given for comparison of therapeutic vs. toxic patients for 10 different combinations of the variables which contributed most to the multiple regression analysis. The digoxin level alone was the best predictor of the clinical response of the patient. This table can be used for determining the appropriate classification of a patient into either the therapeutic or toxic group by multiplying the independent variable(s) (e.g., level or dose) by the appropriate discrimination function coefficient(s). If the determined discrimination index is algebraically greater than the "discrimination value" in the table, the patient can be appropriately considered in the therapeutic group. If it is less t h a n the "discrimination value," the patient is in the toxic or possibly toxic group. For example, using the values for run 1, if the patient's steady state digoxin level is 1.4 ng.
*The variables in the order they entered the regression equation comparing therapeutic and toxic groups (digoxin level included) were: digoxin level, BUN, creatinine clearance, potassium chloride, age, CO2, creatinine, dose, dose per kilogram, and sodium. #The variables in the order they entered the regression equation comparing therapeutic and subtherapeutic groups (digoxin level included) were: digoxin level, weight, age, creatinine, BUN, SGOT, sodium, chloride, creatinine clearance, and dose per kilogram. SThe variables in the order they entered the regression equation comparing therapeutic and toxic groups (digoxin level not included) were: dose per kilogram, creatinine clearance, dose, creatinine, BUN, potassium, and sodium. w variables in the order they entered the regression equation comparing therapeutic and subtherapeutic groups (digoxin level not included) were: weight, chloride, age, SGOT, and sodium.
American Heart Journal
per milliliter, the "discrimination value" is 1.4 x (-0.03208) -- -0.0448 which is greater than -0.07058 and he is placed in the therapeutic group. Comment
Our observations confirm the majority of previous studies demonstrating t h a t the utility of the serum digoxin concentration in evaluating the clinical response to digoxin has been established. Evidence has been reported ~7, ~8 t h a t the availability of the serum digoxin concentration is associated with a 50 per cent reduction of clinical digoxin intoxication although digoxin continues to be a major cause of drug toxicityY9-3~ From the analyses of the data reported here, we determined that factors in addition to serum digoxin concentration were of value in assessing the relationships between digoxin therapy and clinical cardiac status. A positive correlation was found between the clinical cardiac status of the patient and the serum digoxin concentration, digoxin dose, body weight, and the creatinine clearance. Although other factors contributed to the categorization of patients into therapeutic or toxic groups, differences among the means for these factors were not significantly different. Previous studies relating serum digoxin concentrations to patient response have compared "not toxic" with either "toxic" patients or "potentially toxic" patients. We have attempted to define a therapeutic and subtherapeutic group by dividing the "not toxic" patients into those with and those without congestive heart failure and to determine the importance of other factors such as renal function. Although the lowest mean digoxin concentration occurred in the subtherapeutic group (I), one cannot assume t h a t the poor response was due only to inadequate glycoside levels since other factors such as excess dietary sodium intake, inadequate diuretic therapy, the presence of valvular lesions or infiltrative cardiomyopathies may have a greater effect on cardiac function than the increased inotropic effect induced by digitalis. Another factor commonly implicated in therapeutic failures with digoxin therapy is inadequate patient compliance2 z The patients in the present study were hospitalized and had received a maintenance dose of digoxin for at least 7 days. With these reservations, the therapeutic range predicted from discrimination
31
H u f f m a n et al.
function analyses is 1.0 to 2:2 ng. per mililiter at 6 to 8 hours following a dose and is consistent with previously reported values2 ~ A smaller dose, decreased absorption of digoxin in the presence of congestive heart failure, a n d / o r an increased distribution volume for digoxin in these patients could explain the reduced serum digoxin concentration in Group I. Although the mean digoxin dose was less in Group I t h a n in Group II, the difference was not statistically significant. Except to state that the patients were receiving a relatively bioavailable digoxin product, we do not know whether digoxin absorption is decreased in congestive heart failure. The patients in Group I were significantly heavier than the patients in the other three groups. This is not surprising since most of this group had excess fluid which, perhaps, is associated with an increased volume of distribution for dig0xin. The discriminant function analysis based on level alone resulted in the fewest classification errors (8/89). It is interesting t h a t where the analysis was based on dose alone, one additional total error occurred (9/89) a n d all misclassifications were Type I errors. Digoxin dose w a s the best in minimizing Type II error. It can be argued that the Type II error which consists of the misclassification of a toxic patient as therapeutic is a more serious error. O f the three single independent variables, level, dose, and dose per kilogram, dose per kilogram was a significantly poorer predictor (in terms of total misclassifications) of both subtherapeutic and toxic patients. Level was the best predictor, with dose being intermediate in both cases. When classifying toxic patients the inclusion of level with combinations of other laboratory variables had no better predicting power t h a n did level alone. When level was deleted from the discrimination function of toxic patients the total number of errors is increased twofold as reflected in the dose, creatinine clearance, and dose per kilogram, creatinine clearance studies (Table II). A discriminant function analysis comparing therapeutic and subtherapeutic patients was less encouraging than the comparison of therapeutic and toxic patients. The minimum number of errors made in classifying subtherapeutic was noticeably higher (20 per cent) than those in the toxic study (10 per cent). Also, there was less clustering of the misclassifications in the subther-
32
apeutic study leading to a high degree of error scattering. This lack of predictive power m a y be reflecting a lack of patient data homogeneity within Group I. The discrimination function for patient weight and level predicted better t h a n the other variables in the subtherapeutic group as was suggested by the results of Duncan's Multiple Range test. The principle of optimization used in discriminant analysis may give a biased overestimate of the reliability of the method. Therefore, if applied to another group of patients, it may produce a higher rate of misclassification errors than were determined in this study. In the prospective study of Beller and associates, 1~ decreased renal function in the toxic groups compared with therapeutic patients was the most important reason for digoxin intoxication. There were no differences in the dose of digoxin in this study. While renal function is an important factor in our study, it is apparent t h a t the digoxin dose is also an important factor in the development of digoxin intoxication. There has been recent enthusiasm for the use of computer-assisted programs to advise physicians on digoxin dosage regimens24 These programs use pharmacokinetic information and have been shown to decrease the incidence of toxicity25 However, recent studies ~6indicate that the initial enthusiasm for these programs has abated. It appears t h a t a less expensive and more reliable way to evaluate digoxin therapy is to determine the serum digoxin concentration. Since there is an overlap between the serum digoxin concentrations for patients in the various groups and since there are other factors such as age, ~7 thyroid status, 38 acidosis, hypokalemia, hypoxia, etc., which are all important determinants of the response t o digoxin in the individual patient, clinical judgment remains an essential factor in determining appropriate therapy with digoxin. The digoxin serum levels should not be determined routinely in every patient who receives digoxin, particularly when adequate therapeutic benefit has been obtained and there is no evidence of digoxin toxicity. However, of the 15 per cent of patients taking digitalis on admission to a large hospital, 23 per cent were found to be definitely digitalis toxic by serial ECG. 13 Incidences of digitalis toxicity from l0 to 21 per cent have also been reported in other recent studies. 2~, 39 Unfortunately, most of the symptoms and arrhythmias
January, 1976, Vol. 91, No. 1
Cardiac status a n d digoxin usage
s u g g e s t i v e of d i g i t a l i s i n t o x i c a t i o n c a n also b e c a u s e d b y t h e c a r d i a c d y s f u n c t i o n p e r se. P h y s i cians, e v e n a f t e r y e a r s of c l i n i c a l e x p e r i e n c e , c a n n o t a l w a y s d i s c r i m i n a t e b e t w e e n t h e two. O t h e r p r o b l e m s also exist. T w e n t y - f i v e of 323 p a t i e n t s i n a s t u d y were f o u n d t o h a v e zero d i g o x i n b l o o d levels e v e n t h r o u g h t h e y w e r e s u p p o s e d l y t a k i n g t h e i r m e d i c a t i o n r e g u l a r l y . 4~ P a t i e n t c o m p l i a n c e t o d i g i t a l i s d o s a g e r e g i m e n s , 32 bioavailability, drug interactions, and physiologic abnormalities (malabsorption, increased motili t y ) c a n be d e t e c t e d b y b l o o d levels. T h e u s e of d i g o x i n b l o o d levels h a s r e d u c e d d i g i t a l i s t o x i c i t y significantly.~7, 58 T h e c l i n i c i a n will f i n d t h e s e r u m d i g o x i n l e v e l u s e f u l i n d e c i d i n g : (1) if t h e p a t i e n t is t a k i n g t h e glycoside r e g u l a r l y , (2) if b i o a v a i l a b i l i t y p r o b l e m s exist w i t h t h e d o s a g e f o r m , a n d (3) if a n a r r h y t h m i a is d u e t o t h e glycoside or i n t r i n s i c h e a r t disease. T h e level is also u s e f u l i n a p a t i e n t for w h o m a n a d e q u a t e history c a n n o t be o b t a i n e d w h e n t h e p h y s i c i a n wishes t o k n o w w h e t h e r t h e p a t i e n t is r e c e i v i n g d i g o x i n or d i g i t o x i n a n d t o d e t e r m i n e w h e t h e r the p a t i e n t c a n be given m o r e t h a n t h e m a i n t e n a n c e dose. T h e serum digoxin d e t e r m i n a t i o n correlates well w i t h t h e t h e r a p e u t i c a n d toxic r e s p o n s e s o f p a t i e n t s a n d serves a u s e f u l p u r p o s e i n c o n t r o l l i n g digitalis therapy. REFERENCES
1. Smith, T. W.: Contribution of quantitative assay techniques to the understanding of the clinical pharmacology of digitalis, Circulation 46:188, 1972. 2. Smith, T. W.: Digitalis glycosides (Parts I and II), N. Engl. J. Med. 288:719, 943, 1973. 3. Doherty, J. E.: Digitalis glycosides, Ann. Intern. Med. 79:229, 1973. 4. Butler, V. P., Jr., and Chen, J. P.: Digoxin-specific antibodies, Proc. Natl. Acad. Sci. 67:71, 1967. 5. Smith, T. W., Butler, V. P., Jr., and Haber, E: Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay, N. Engl. J. Med. 281:1212, 1969. 6. Smith, T. W., and Haber, E.: Digoxin intoxication: The relationship of clinical presentation to serum digoxin concentration, J. Clin. Invest. 49:2377, 1970. 7. Evered, D. C., Chapman, C., and Hayter, C. J.: Measurement of plasma digoxin concentration by radioimmunoassay, Br. Med. J. 3:427, 1970. 8. Evered, D. C., and Chapman, C.: Plasma digoxin concentrations and digoxin toxicity in hospital patients, Br. Heart J. 33:540, 1971. 9 9. Chamberlain, D. A., White, R. J., Howard, M. R., and Smith, T. W.: Plasma digoxin concentrations in patients with atrial fibrillation, Br. Med. J. 3:429, 1970. 10. Hoeschen, R. J., and Proveda, V: Serum digoxin by
American Heart Journal
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and Melmon, K. L.: Computer-assisted digoxin therapy, N. Engl. J. Med. 289:441, 1973. Ewy, G. A., Kapodia, G. C., Yao, L., Cullen, M., and Marcus, F. L.: Digoxin metabolism in the elderly, Circulation 39:449, 1969. Doherty, J. E., and Perkins, W. H.: Digoxin metabolism in hypo- and hyperthyroidism: Studies with tritiated digoxin in thyroid disease, Ann. Intern. Med. 64:489, 1966. Olgilvie, R. I., and Ruedy, J.: An educational program in digitalis therapy, J. A. M. A. 222:50, 1972. Binnion, P. F.: Zero plasma digoxin levels in patients on oral digoxin therapy, Irish Med. J. 148:346, 1974.
January, 1976, Vol. 91, No. 1
The cardiac glycosides are among the most effective drugs available for improving myocardial contractility. Their use, however, is not without hazard since a significant number of patients develop toxicity. 1, ~ Recent improvements in our knowledge of the pharmacology and therapeutic use of the digitalis glycosides should make our use of these drugs in patients more rational and decrease the number of toxic events. ~-3The development of the digoxin radioimmunoassay4, 5 has been particularly useful in this regard. There have been a number of studies which have evaluated the relationship between the serum digoxin concentration and clinical evidence of digoxin intoxication2 -19 With the exception of one study, ~9 all of these have demonstrated a significant positive relationship between the serum digoxin concentration and clinical evidence of glycoside intoxication. The present study was undertaken to evaluate the relationship between serum digoxin concentrations, other laboratory parameters, and the clinical response of patients receiving digoxin. In addition to defining a significant relationship From the Clinical Pharmacology-Toxicology Center, Departments of Medicine and Pharmacology; University of Kansas Medical Center, and College of Health Sciences and Hospital, Kansas City, Kan, and the Kansas City Veterans Administration Hospital, Kansas City, Mo. Supported inpart by grant GM 15956 from the U~ted States Public Health Service. Presented at the Midwest Section of the American Federation for Clinical Research meeting in Chicago, Ill., November, 1974. Received for publication Dec. 9, 1974. Reprint requests: Daniel L. Azarnoff, M.D., Clinical Pharmacology-Toxicology Center, The University of Kansas Medical Center, College of Health Sciences and Hospital, Rainbow Blvd. at 39th, Kansas City, Kan. 66103.
28
between the serum digoxin concentration and cardiovascular response, we have also determined a correlation between the clinical cardiac status and a number of routine laboratory tests. Methods
During the period of July, 1971, to June, 1973, the serum digoxin concentration was determined in Over 1,200 patients admitted to the University of Kansas Medical Center. From this group, 143 patients who received a constant maintenance dose of digoxin for a minimum of 1 week were selected for this review. All patients received digoxin (Burroughs-Wellcome} during their hospitalization. Each patient was seen in consultation by one of us at the time the drug level was obtained; however, an extensive chart review was made at a later date by an independent observer who classified the patients without knowledge of the serum digoxin concentration. The patients were divided into four groups on the basis of clinical considerations. The groups were as follows: I, not toxic, in congestive heart failure; II, not toxic, not in congestive heart failure; III, possibly toxic; IV, definitely toxic. The criteria of Beller and associates 13were used for separating the patients into "not toxic," "possibly toxic," and "definitely toxic" groups and were based in part on the electrocardiogram (ECG). The further division of the "not toxic" patients into Group I and I! was based on the clinical status of the patient and the chest x-ray. The following laboratory data were recorded for each patient whenever available: age, sex, weight, diagnosis, blood urea nitrogen (BUN), creatinine, creatinine clearance, Na +, K § CL-, COs, serum
January, 1976, Vol. 9l, No. 1, pp. 28-34
C a r d i a c s t a t u s a n d digoxin usage
Table I. D u n c a n ' s Multiple R a n g e T e s t for significant digoxin p a r a m e t e r s * Group Variable
Weight (Kg.)
3.60
3/142
CRC (ml./min.)
3.01
3/130
3.54
3/142
67.57
3/142
Dose (mg.) Level (ng./ml.) Dose/Kg. (ng./Kg.)
6.245
3/142
I
H
72.7 -+ 14.2~ 62.4 -+ 31.4 0.234 _+ 0.10 0.95 _+ 0.52 0.003 _+ 0.002
65.3 -+ 14.3 60.9 +- 32.8 0.260 _+ 0.09 1.49 _+ 0.46 0.004 _+ 0.002
I
III
64.0
-+ 15.1
47.2
+- 30.3
0.292 --+ 0.08 2.53 +_ 0.64 0.005 + 0:001
IV
60.7 + 12.6 41.5 +- 21.9 0.316 _+ 0.09 3.32 _+ 1.23 0.005 _+ 0.001
*Any two means not underscore d by the s a m e line are significantly different at the 95 per cent level. t M e a n • S.D.
glutamic oxaloacetic t r a n s a m i n a s e (SGOT), bilirubin, alkaline p h o s p h a t a s e , Ca §§ lactic d e h y d r o genase (LDH), albumin, globulin, a n d T4. T h e s e r u m digoxin c o n c e n t r a t i o n was m e a sured by the r a d i o i m m u n o a s s a y p r o c e d u r e of S m i t h and associates 5 as it is used in o u r laboratory. 2~ Venous blood was collected 6 to 8 h o u r s a f t e r drug a d m i n i s t r a t i o n for d e t e r m i n a t i o n of the s e r u m concentration. Digoxin assays were p e r f o r m e d in duplicate within 48 h o u r s of receiving the sample. T h e specificity a n d sensitivity of t h e a n t i b o d y used in this a s s a y were similar to antibodies with high affinity for digoxin previously reported. TM ~ Q u a l i t y control was m a i n t a i n e d b y two i n t e r n a l s t a n d a r d s {1.25 a n d 2.5 ng. per milliliter) which were p r e p a r e d in large b a t c h e s a n d a s s a y e d each d a y t o g e t h e r with the s t a n d a r d curve a n d t h e u n k n o w n samples. T h e coefficient of variation of 30 consecutive i n d e p e n d e n t assays of t h e i n t e r n a l s t a n d a r d s was 4.8 per cent.
Statistical Methods An analysis of v a r i a n c e was p e r f o r m e d to determ i n e if a significant difference existed a m o n g the m e a n s of t h e four groups for each of t h e variables. I f t h e r e was a significant difference a t t h e 95 per cent level of confidence, it was f u r t h e r a n a l y z e d b y D u n c a n ' s ~3 M u l t i p l e R a n g e T e s t as modified by K r a m e r 24 for u n e q u a l groups to d e t e r m i n e which of t h e groups were different. Multiple regression analysis. P a t i e n t s with missing l a b o r a t o r y d a t a for weight, age, creatinine, B U N , sodium, p o t a s s i u m , c a r b o n dioxide, chloride or S G O T were deleted; 116 p a t i e n t s r e m a i n e d for the m u l t i p l e regression analyses. T h e s e p a t i e n t s were divided into three groups for this analysis: s u b t h e r a p e u t i c ( G r o u p I, n = 27),
American Heart Journal
t h e r a p e u t i c ( G r o u p II, n = 57), a n d toxic ( G r o u p s I I I a n d IV, n = 32). F o r this analysis, t h e creatinine clearance which was missing for 46 p a t i e n t s was e s t i m a t e d f r o m a n o m o g r a m . 2~ Four stepwise regression a n a l y s e s 26 were performed a t t h e 95 per cent level of confidence: (1) t h e r a p e u t i c vs. s u b t h e r a p e u t i c , (2) t h e r a p e u t i c vs. toxic, (3) t h e r a p e u t i c vs. s u b t h e r a p e u t i c w i t h o u t consideration of the digoxin level, a n d (4) t h e r a peutic vs. toxic w i t h o u t consideration of t h e digoxin level. Discriminant function analysis. Two discrimin a n t function analyses were obtained, one for t h e r a p e u t i c vs. s u b t h e r a p e u t i c a n d t h e o t h e r for t h e r a p e u t i c vs. toxic patients. T h o s e clinical a n d l a b o r a t o r y variables which a b s o r b e d t h e m o s t variance in t h e multiple regression analysis guided the selection of those used in the discrimi n a n t function analyses. A discrimination index ' T ' was c a l c u l a t e d for e a c h p a t i e n t as a f u n c t i o n of the i n d e p e n d e n t variables selected for t h e discriminant analysis: n
Ij =
~ i=1
CiXji
where ci is the discriminant f u n c t i o n coefficient a n d Xji t h e value(s) of t h e i n d e p e n d e n t variable(s) for t h e jth patient. T h e p a t i e n t s were r a n k e d in descending order b y their calculated index. A " d i s c r i m i n a t i o n value" was selected which m i n i m i z e d t h e t o t a l n u m b e r of classification errors. P a t i e n t s with a discrimination index higher t h a n this discrimination value were assigned to t h e t h e r a p e u t i c group. T h o s e p a t i e n t s with a discrimination index l o w e r t h a n the discrimination v a l u e were assigned to either the s u b t h e r a p e u t i c g r o u p or t h e toxic group, depending on which groups were p a r t of
29
Huff-manet al. Table II.Discriminant analysis: therapeutic vs. toxic Run No. 1. 2. 3. 4. 5. 6. 7.
8.
9. 10
Variable included Level Dose Dose/Kg. Level Dose Level Dose/Kg. Level CRC Level Dose CRC Level Bun CRC Wt Dose CRC Dose/Kg. CRC
Type I
Errors* i
Type II
3 9 13 4
5 13 5
3
6
3
5
4
5
2
8
10
10
9
14
Discriminant function coefficients -0.03208 -0.06649 -4.12271 -0.03151 -0.02751 -0.03154 -1.11019 -0.03162 0.00006 -0.03026 -0.04395 0.00012 -0.03540 0.00033 0.O0031 -O.OOO30 -0.10767 0.00033 -5.25804 0.00027
Discrimination value -0.07058 -0.01662 -0.01874 -0.07620 --0.07394 -0.06679 --0.07201
-0.07748
-0.01313 --0.01233
*Misclas~ifications: T y p e I, misclassified a therapeutic p a t i e n t as a toxic patient; T y p e II, misclassified a toxic p a t i e n t as a therapeutic patient.
the analysis. Two types of classification errors were possible. In the analysis between therapeutic and toxic patients, a Type I error resulted when a toxic patient was misclassified as therapeutic, whereas a type II error resulted if a patient in the therapeutic group was misclassified as toxic. All statistical analyses were performed by an IBM 370 model 145 computer. Results
Significant differences between the m e a n s of the four groups at the 95 per cent level of confidence were found among the four clinically different groups for the following variables: digoxin level, dose per kilogram, body weight, dose, and creatinine clearance. The results of the Duncan's Multiple Range test for differences between groups are presented in Table I. The digoxin level had the highest F value (67.57). The mean digoxin level of each group was significantly different from the other three groups. Although there was a progressive decrease in the creatinine clearance from Groups I to IV, the differences among Groups I, II, and III and between Groups III and IV were not significant. However, the creatinine clearance was significantly lower in the
30
"toxic groups" (III and IV) than in "not-toxic" Groups I and II. Patients in Group I weighed significantly more than did all other patients (Groups II, III, and IV). The absolute digoxin maintenance dose as well as the dose per kilogram increased from Group I to Group IV. The not toxic groups (I and II) received significantly less digoxin t h a n those in Group IV. F o u r stepwise multiple regression analyses were performed. In comparing therapeutic and subtherapeutic, the regression equation absorbed 13.7 per cent of the variance (R 2) when drug level was not considered whereas 29.5 per cent was absorbed when level was included. This same trend was more evident between the therapeutic and toxic groups when the digoxin level was included in the regression analysis 55.5 per cent of the variance was absorbed. Of this 55.5 per cent, 50 per cent of the variance was absorbed by the digoxin level alone and only an additional 5 per cent by adding 12 other variables. In con' trast, when the digoxin level was not included only 24.5 per cent of the variance was absorbed. When level is considered, in both therapeutic vs. toxic a n d therapeutic vs. subtherapeutic regression analyses, it carries the greatest weight
January, 1976, Vol. 91, No. 1
Cardiac status a n d digoxin usage
in the regression equation (i.e., highest b' value). Because level is so predictive, 13 variables* in the therapeutic vs. toxic and 10t in the therapeutic vs. subtherapeutic are included in the regression equation as opposed to the comparisons when level is excluded. Only 75 and 5w variables are included at the 95 per cent level in the latter two comparisons without the digoxin level. There is approximately a 1.5- to 2.0-fold increase in the correlation coefficient (R) when level is considered. If level enters the regression equation, creatinine clearance, BUN, and dose weigh heavily in the therapeutic vs. toxic groups whereas patient weight enters significantly in the therapeutic vs. subtherapeutic regression equation. This trend was suggested by Duncan's Multiple Range Study (Table I). In Table II, the results of the discrimination analysis are given for comparison of therapeutic vs. toxic patients for 10 different combinations of the variables which contributed most to the multiple regression analysis. The digoxin level alone was the best predictor of the clinical response of the patient. This table can be used for determining the appropriate classification of a patient into either the therapeutic or toxic group by multiplying the independent variable(s) (e.g., level or dose) by the appropriate discrimination function coefficient(s). If the determined discrimination index is algebraically greater than the "discrimination value" in the table, the patient can be appropriately considered in the therapeutic group. If it is less t h a n the "discrimination value," the patient is in the toxic or possibly toxic group. For example, using the values for run 1, if the patient's steady state digoxin level is 1.4 ng.
*The variables in the order they entered the regression equation comparing therapeutic and toxic groups (digoxin level included) were: digoxin level, BUN, creatinine clearance, potassium chloride, age, CO2, creatinine, dose, dose per kilogram, and sodium. #The variables in the order they entered the regression equation comparing therapeutic and subtherapeutic groups (digoxin level included) were: digoxin level, weight, age, creatinine, BUN, SGOT, sodium, chloride, creatinine clearance, and dose per kilogram. SThe variables in the order they entered the regression equation comparing therapeutic and toxic groups (digoxin level not included) were: dose per kilogram, creatinine clearance, dose, creatinine, BUN, potassium, and sodium. w variables in the order they entered the regression equation comparing therapeutic and subtherapeutic groups (digoxin level not included) were: weight, chloride, age, SGOT, and sodium.
American Heart Journal
per milliliter, the "discrimination value" is 1.4 x (-0.03208) -- -0.0448 which is greater than -0.07058 and he is placed in the therapeutic group. Comment
Our observations confirm the majority of previous studies demonstrating t h a t the utility of the serum digoxin concentration in evaluating the clinical response to digoxin has been established. Evidence has been reported ~7, ~8 t h a t the availability of the serum digoxin concentration is associated with a 50 per cent reduction of clinical digoxin intoxication although digoxin continues to be a major cause of drug toxicityY9-3~ From the analyses of the data reported here, we determined that factors in addition to serum digoxin concentration were of value in assessing the relationships between digoxin therapy and clinical cardiac status. A positive correlation was found between the clinical cardiac status of the patient and the serum digoxin concentration, digoxin dose, body weight, and the creatinine clearance. Although other factors contributed to the categorization of patients into therapeutic or toxic groups, differences among the means for these factors were not significantly different. Previous studies relating serum digoxin concentrations to patient response have compared "not toxic" with either "toxic" patients or "potentially toxic" patients. We have attempted to define a therapeutic and subtherapeutic group by dividing the "not toxic" patients into those with and those without congestive heart failure and to determine the importance of other factors such as renal function. Although the lowest mean digoxin concentration occurred in the subtherapeutic group (I), one cannot assume t h a t the poor response was due only to inadequate glycoside levels since other factors such as excess dietary sodium intake, inadequate diuretic therapy, the presence of valvular lesions or infiltrative cardiomyopathies may have a greater effect on cardiac function than the increased inotropic effect induced by digitalis. Another factor commonly implicated in therapeutic failures with digoxin therapy is inadequate patient compliance2 z The patients in the present study were hospitalized and had received a maintenance dose of digoxin for at least 7 days. With these reservations, the therapeutic range predicted from discrimination
31
H u f f m a n et al.
function analyses is 1.0 to 2:2 ng. per mililiter at 6 to 8 hours following a dose and is consistent with previously reported values2 ~ A smaller dose, decreased absorption of digoxin in the presence of congestive heart failure, a n d / o r an increased distribution volume for digoxin in these patients could explain the reduced serum digoxin concentration in Group I. Although the mean digoxin dose was less in Group I t h a n in Group II, the difference was not statistically significant. Except to state that the patients were receiving a relatively bioavailable digoxin product, we do not know whether digoxin absorption is decreased in congestive heart failure. The patients in Group I were significantly heavier than the patients in the other three groups. This is not surprising since most of this group had excess fluid which, perhaps, is associated with an increased volume of distribution for dig0xin. The discriminant function analysis based on level alone resulted in the fewest classification errors (8/89). It is interesting t h a t where the analysis was based on dose alone, one additional total error occurred (9/89) a n d all misclassifications were Type I errors. Digoxin dose w a s the best in minimizing Type II error. It can be argued that the Type II error which consists of the misclassification of a toxic patient as therapeutic is a more serious error. O f the three single independent variables, level, dose, and dose per kilogram, dose per kilogram was a significantly poorer predictor (in terms of total misclassifications) of both subtherapeutic and toxic patients. Level was the best predictor, with dose being intermediate in both cases. When classifying toxic patients the inclusion of level with combinations of other laboratory variables had no better predicting power t h a n did level alone. When level was deleted from the discrimination function of toxic patients the total number of errors is increased twofold as reflected in the dose, creatinine clearance, and dose per kilogram, creatinine clearance studies (Table II). A discriminant function analysis comparing therapeutic and subtherapeutic patients was less encouraging than the comparison of therapeutic and toxic patients. The minimum number of errors made in classifying subtherapeutic was noticeably higher (20 per cent) than those in the toxic study (10 per cent). Also, there was less clustering of the misclassifications in the subther-
32
apeutic study leading to a high degree of error scattering. This lack of predictive power m a y be reflecting a lack of patient data homogeneity within Group I. The discrimination function for patient weight and level predicted better t h a n the other variables in the subtherapeutic group as was suggested by the results of Duncan's Multiple Range test. The principle of optimization used in discriminant analysis may give a biased overestimate of the reliability of the method. Therefore, if applied to another group of patients, it may produce a higher rate of misclassification errors than were determined in this study. In the prospective study of Beller and associates, 1~ decreased renal function in the toxic groups compared with therapeutic patients was the most important reason for digoxin intoxication. There were no differences in the dose of digoxin in this study. While renal function is an important factor in our study, it is apparent t h a t the digoxin dose is also an important factor in the development of digoxin intoxication. There has been recent enthusiasm for the use of computer-assisted programs to advise physicians on digoxin dosage regimens24 These programs use pharmacokinetic information and have been shown to decrease the incidence of toxicity25 However, recent studies ~6indicate that the initial enthusiasm for these programs has abated. It appears t h a t a less expensive and more reliable way to evaluate digoxin therapy is to determine the serum digoxin concentration. Since there is an overlap between the serum digoxin concentrations for patients in the various groups and since there are other factors such as age, ~7 thyroid status, 38 acidosis, hypokalemia, hypoxia, etc., which are all important determinants of the response t o digoxin in the individual patient, clinical judgment remains an essential factor in determining appropriate therapy with digoxin. The digoxin serum levels should not be determined routinely in every patient who receives digoxin, particularly when adequate therapeutic benefit has been obtained and there is no evidence of digoxin toxicity. However, of the 15 per cent of patients taking digitalis on admission to a large hospital, 23 per cent were found to be definitely digitalis toxic by serial ECG. 13 Incidences of digitalis toxicity from l0 to 21 per cent have also been reported in other recent studies. 2~, 39 Unfortunately, most of the symptoms and arrhythmias
January, 1976, Vol. 91, No. 1
Cardiac status a n d digoxin usage
s u g g e s t i v e of d i g i t a l i s i n t o x i c a t i o n c a n also b e c a u s e d b y t h e c a r d i a c d y s f u n c t i o n p e r se. P h y s i cians, e v e n a f t e r y e a r s of c l i n i c a l e x p e r i e n c e , c a n n o t a l w a y s d i s c r i m i n a t e b e t w e e n t h e two. O t h e r p r o b l e m s also exist. T w e n t y - f i v e of 323 p a t i e n t s i n a s t u d y were f o u n d t o h a v e zero d i g o x i n b l o o d levels e v e n t h r o u g h t h e y w e r e s u p p o s e d l y t a k i n g t h e i r m e d i c a t i o n r e g u l a r l y . 4~ P a t i e n t c o m p l i a n c e t o d i g i t a l i s d o s a g e r e g i m e n s , 32 bioavailability, drug interactions, and physiologic abnormalities (malabsorption, increased motili t y ) c a n be d e t e c t e d b y b l o o d levels. T h e u s e of d i g o x i n b l o o d levels h a s r e d u c e d d i g i t a l i s t o x i c i t y significantly.~7, 58 T h e c l i n i c i a n will f i n d t h e s e r u m d i g o x i n l e v e l u s e f u l i n d e c i d i n g : (1) if t h e p a t i e n t is t a k i n g t h e glycoside r e g u l a r l y , (2) if b i o a v a i l a b i l i t y p r o b l e m s exist w i t h t h e d o s a g e f o r m , a n d (3) if a n a r r h y t h m i a is d u e t o t h e glycoside or i n t r i n s i c h e a r t disease. T h e level is also u s e f u l i n a p a t i e n t for w h o m a n a d e q u a t e history c a n n o t be o b t a i n e d w h e n t h e p h y s i c i a n wishes t o k n o w w h e t h e r t h e p a t i e n t is r e c e i v i n g d i g o x i n or d i g i t o x i n a n d t o d e t e r m i n e w h e t h e r the p a t i e n t c a n be given m o r e t h a n t h e m a i n t e n a n c e dose. T h e serum digoxin d e t e r m i n a t i o n correlates well w i t h t h e t h e r a p e u t i c a n d toxic r e s p o n s e s o f p a t i e n t s a n d serves a u s e f u l p u r p o s e i n c o n t r o l l i n g digitalis therapy. REFERENCES
1. Smith, T. W.: Contribution of quantitative assay techniques to the understanding of the clinical pharmacology of digitalis, Circulation 46:188, 1972. 2. Smith, T. W.: Digitalis glycosides (Parts I and II), N. Engl. J. Med. 288:719, 943, 1973. 3. Doherty, J. E.: Digitalis glycosides, Ann. Intern. Med. 79:229, 1973. 4. Butler, V. P., Jr., and Chen, J. P.: Digoxin-specific antibodies, Proc. Natl. Acad. Sci. 67:71, 1967. 5. Smith, T. W., Butler, V. P., Jr., and Haber, E: Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay, N. Engl. J. Med. 281:1212, 1969. 6. Smith, T. W., and Haber, E.: Digoxin intoxication: The relationship of clinical presentation to serum digoxin concentration, J. Clin. Invest. 49:2377, 1970. 7. Evered, D. C., Chapman, C., and Hayter, C. J.: Measurement of plasma digoxin concentration by radioimmunoassay, Br. Med. J. 3:427, 1970. 8. Evered, D. C., and Chapman, C.: Plasma digoxin concentrations and digoxin toxicity in hospital patients, Br. Heart J. 33:540, 1971. 9 9. Chamberlain, D. A., White, R. J., Howard, M. R., and Smith, T. W.: Plasma digoxin concentrations in patients with atrial fibrillation, Br. Med. J. 3:429, 1970. 10. Hoeschen, R. J., and Proveda, V: Serum digoxin by
American Heart Journal
radioimmunoassay, Can. Med. Assoc. J. 105:170, 1971. 11. Shapiro, W., Taubert, K., and Narahara, K.: Non radioactive serum digoxin and digitoxin levels, Arch. Intern. Med. 130:31, 1972. 12. Whiting, B., Sumner, D. J., and Goldberg, A.: An assessment of the digoxin radio-immunoassay. Scot. Med. J. 18:69, 1973. 13. Beller, G. A., Smith, T. W., Abelmann, W. H., Haber, E., and Hood, W. B.: Digitalis intoxication: A prospective clinical study with serum level correlations, N. Engl. J. Med. 284:989, 1971. 14. Ritzman, L. W., Bangs, C. C., and Conner, D.: Serum glycoside levels in digitalis toxicity, Circulation 40 (Suppl. III):170, 1969. 15. Grahame-Smith, D. G., and Everest, M. S.: Measurement of digoxin in plasma and its use in the diagnosis of digoxin intoxication, Br. Med. J. 1:286, 1969. 16. Binnion, P. F., Morgan, L. M., Stevenson, H. M., and Fletcher, E: Plasma and myocardial digoxin concentrations in patients on oral therapy, Br. Heart J. 31:636, 1969. 17. Redfors, A.: Plasma digoxin concentration-its relation to digoxin dosage and clinical effects in patients with atrial fibrillation, Br. Heart J. 34:383, 1972. 18. Bertler, A., and Redfors, A.: Plasma levels of digoxin in relation to toxicity, Acta Pharmacol. Toxicol. 29:281, 1971. 19. Fogelman, A. M., La Mont, J. T., Finkeistein, S., Rado, E., and Pearce, M. L.: Fallibility of plasma digoxin in differentiating toxic from non-toxic patients, Lancet 2:727, 1971. 20. Huffman, D. H., and Azarnoff, D. L.: The absorption of orally given digoxin preparations, J. A. M. A. 222:957, 1972. 21. Smith, T. W., Butler, V. P., Jr., and Haber, E.: Characterization of antibodies of high affinity and specificity for the digitalis glycoside digoxin, Biochemistry 9:331, 1970. 22. Stoll, R. G., Christenson, M. S., Sakmar, E., and Wagner, J. G.: The specificity of the digoxin radioimmunoassay procedure, Res. Comm. Chem. Pathol. Pharmacol. 4:503, 1973. 23. Duncan, D. B.: Multiple range and multiple F tests, Biometrics 1 1:1, 1955. 24. Kramer, C. Y.: Extension of multiple range tests to group means with unequal numbers of replications, Biometrics 12:307, 1956. 25. Siersbaek-Nielsen, K., Molholm Hansen, J., Kampmann, J., and Kristensen, M.: Rapid evaluation of creatinine clearance. Lancet 1:1133, 1971. 26. Dixon, W. J., editor: Biomedical Computer Program BMD02R, Berkeley and Los Angeles, 1968, University of California Press. 27. Duhme, D. W., Greenblatt, D. J., and Koch-Weser, J.: Reduction of digoxin toxicity associated with measurement of serum levels, Ann. Intern. Med. 80:516, 1974. 28. Koch-Weser, J., Duhme, D. W., and Greenblatt, D. J.: Influence of serum digoxin concentration measurements on frequency of digitoxicity, Clin. Pharmacol. Ther. 16:284, 1974. 29. Ogilvie, R. I., and Ruedy, J.: Adverse drug reactions during hospitalizations, Can. Med. Assoc. J. 97:1450, 1967. 30. Shapiro, S., Slone, D., Lewis, G. P., and Jick, H.: Fatal drug reactions among medical inpatients, J. A. M. A. 216:467, 1971. 31. Miller, R. R.: Hospital admissions due to adverse drug reactions: A report from the Boston Collaborative Drug
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Huffman et aL
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34
Surveillance Program, Arch. Intern. Med. 134:219, 1974. Weintraub, M., Au, W. Y. W., and Lasagna, L.: Compliance as a determinant of serum digoxin concentration, J. A. M. A. 224:481, 1973. Koch-Weser, J.: Serum drug concentrations as therapeutic guides, N. Engl. J. Med. 287:227, 1972. Jelliffe, R. W.: An improved method of digoxin therapy, Ann. Intern. Med. 69:703, 1968. Jelliffe, R. W., Buell, J., and Kalaba, R.: Reduction of digitalis toxicity by computer-assisted glycoside dosage regimens, Ann. Intern. Med. 77:891, 1972. Peck, C. C., Sheiner, L. B., Martin C. M., Combs, D. T.,
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January, 1976, Vol. 91, No. 1