Effect of Metildigoxin (ƒÀ-Methyldigoxin) on Congestive

Heart Failure as Evaluated by Multiclinical

Double Blind Study

Eiichi Kimura,* M.D. and Akira SAKUMA,** Ph.D.

In Collaboration with Mitsuo Miyahara, M.D. (Sapporo Medi-

cal School, Sapporo), Tomohiro Kanazawa, M.D. (Akita Uni-

versity School of Medicine, Akita), Masato Hayashi, M.D. (Hiraga

General Hospital, Akita), Hirokazu Niitani, M.D. (Showa Uni-

versity School of Medicine, Tokyo), Yoshitsugu Nohara, M.D.

(Tokyo Medical College, Tokyo), Satoru Murao, M.D. (Faculty of Medicine, University of Tokyo, Tokyo), Kiyoshi Seki, M.D.

(Toho University School of Medicine, Tokyo), Michita Kishimoto, M.D. (National Medical Center Hospital, Tokyo), Tsuneaki Sugi-

moto, M.D. (Faculty of Medicine, Kanazawa University, Kana-

zawa), Masao Takayasu, M.D. (National Kyoto Hospital, Kyoto),

Hiroshi Saimyoji, M.D. (Faculty of Medicine, Kyoto University,

Kyoto), Yasuharu Nimura, M.D. (Medical School, Osaka Uni-

versity, Osaka), Tatsuya Tomomatsu, M.D. (Kobe University,

School of Medicine, Kobe), and Junichi Mise, M.D. (Yamaguchi

University, School of Medicine, Ube).

SUMMARY

The efficacy on congestive heart failure of metildigoxin (ƒÀ-methyl- digoxin, MD), a derivative of digoxin (DX), which had a good absorp- tion rate from digestive tract, was examined in a double blind study using a group comparison method. After achieving digitalization with oral MD or intravenous deslanoside in the non-blind manner, mainte- nance treatment was initiated and the effects of orally administered MD

and DX were compared. MD was administered in 44 cases , DX in 42. The usefulness of the drug was evaluated after 2 weeks , taking into account the condition of the patient and the ease of administration . No significant difference was observed between the usefulness of MD and that of DX.

The use of digitalis differs according to the preparation involved .

Address for reprint: Eiichi Kimura, M.D., Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113. Received for publication May 22, 1979. *Department of Internal Medicine , Nippon Medical School, Tokyo **Department of Clinical Pharmacology , Medical Research Institute, Tokyo Medical and Dental University, 47 Jap. Heart J. 48 KIMURA AND SAKUMA January, 1980

In the double blind study on MD and DX, the way in which digitalis was used may have inclined towards the way in which DX, which is more familiar to us, is used. Therefore, even if MD were superior to DX in usefulness, it would be difficult to obtain a result which proved this. Taking these points into consideration, it is concluded that MD is practically useful in clinical medicine.

Additional Indexing Words: Digoxin Digitoxin Analog scale Digitalization Maintenance treatment

ETILDIGOXIN (MD) or ƒÀ-methyldigoxin is a digoxin (DX) deriva-

tive which is absorbed almost completely from gastrointestinal tract

and has approximately the same excretion rate as DX. These properties of

MD are thought to be advantageous in the oral treatment of congestive

heart failure. Our previous multiclinical open study on MD1) showed that its effectiveness in the treatment of congestive heart failure was not inferior

to DX either in digitalization or in maintenance therapy. On the basis of

these results a double blind study was undertaken to evaluate the efficacy of

this drug.

MATERIALS AND METHODS

1. Materials Needless to say, congestive heart failure is the most common indication for digitalis therapy. Usually, a large dose of digitalis preparation is used at first until a satisfactory effect is obtained (digitalization). Then, a smaller dose is adminis- tered in order to maintain the improved condition (maintenance treatment). Since

patients with severe congestion cannot be used in double blind studies because of the risks involved, we utilized a method whereby the double-blind study was initiated at the time of the changeover from digitalization to maintenance treatment. Since uniformity between the patients was desirable, we selected them ac- cording to the following criteria: (1) in-hospital cases; (2) 18 to 75 years in the age range; and (3) belonging to class III or IV in the old NYHA classification2) at the inception of digitalization (i.e. patients with past history of overt congestive heart failure). Patients in whom digitalis treatment had been discontinued due to intoxica- tion but initiated again after at least 1 week had passed were accepted for this study. In these cases also, a previous history of heart failure of class III or IV was required. Patients having any of the following diseases were excluded: actue myocardial infarction (within the preceding 8 weeks), various myocardial diseases, endocarditis,

pericarditis, cor pulmonale, hyperthyroidism, severe kidney disease, febrile diseases, and hypopotassemia. Patients who were judged by the attending physician to be unsuitable for the trial were also rejected. Vol.21 METILDIGOXIN IN CONGESTIVE HEART FAILURE 49 No.1

Table I. Drug Administration Methods

2. Method of administration of MD and DX DX was chosen as the standard drug in this study because of its similarity to MD in its pharmacological properties. Since the present double blind study was started after digitalization had been achieved, there was a possibility that the patients chosen were those who responded better to one of the cardiac glycosides used in digitalization. Therefore, oral MD or intravenous deslanoside was selected as the standard drugs for digitalization. The design of the trial is shown in Table I. "Variable" means that the digi- talis dosage required for digitalization or maintenance treatment varied among the cases examined. Nevertheless, dosage was roughly estimated on the basis of our earlier open study, which had shown that 75% of the cases were maintained by 0.15 to 0.2mg of MD and that 1mg of MD was equivalent to 1.8mg of DX or 0.6mg of digitoxin. Tablets containing 0.05mg of MD or 0.1mg of DX were used in the present study. The reason that 0.1mg tablets were used instead of the commercially available 0.25mg DX tablets was because it was thought that the smaller dose tablets might facilitate a more accurate determination of the main- tenance dosage. The lowering of the heart rate to less than 90/min was used as the main criterion for the changeover from digitalization to maintenance treatment and also for evalu- ating effective maintenance. However, other criteria such as patient complaints, objective signs of congestion, urine volume and body weight were also used to evaluate the effects. Maintenance therapy was continued for 2 weeks, a period considered to be long enough to detect any aggravation of the symptoms due to insufficient drug effect, or to discover any intoxication. Cardiac glycosides other than DX and MD, ƒÀ-blockers or antiarrhythmics were not used. Administration of diuretics, hypotensives, and antianginal agents were continued, when necessary, without changing the dosage during the course of the study. However, the use of antianginal drugs, which might induce heart failure, was prohibited. Potassium chloride was admitted.

3. Criteria for evaluation

(a) For digitalization Since successful digitalization facilitates the ease with which maintenance treatment can be carried out, we also evaluated the results of digitalization in the Jap. Heart J. J 50 KIMURA AND SAKUMA anuary, 1980

Fig. 1. Analog scale for evaluation of usefulness in digitalization.

Fig. 2. Diagram for evaluation of usefulness of the drugs in maintenance treatment. Ordinate: Comparison of the patient's condition after 2 weeks with that at the start of maintenance treatment Abscissa: Ease of using the drug Areas I, II, III, IV, and V represent the usefulness (see text) Wilcoxon 2 sample test: Comparison of patient condition t0=1.47 p=0.14 Ease of using the drugs t0=0.21 p=0.83 Usefulness of the drug t0=0.86 p=0.39

examined cases in a non-blind manner. For this evaluation, we used such criteria as the lowering of the heart rate to less than 90/min, the period required for digitali- zation, and the appearance of intoxication or side effects. The results obtained were compared with the experiences of the attending physicians using glycosides and expressed on the analog scale shown in Fig. 1. (b) For maintenance therapy To evaluate the usefulness of cardiac glycosides in maintenance therapy, the ease of drug administration and the maintenance of the patient's improved condition were used as criteria. The ordinate in Fig. 2 serves to compare the patient's condition at the start of maintenance therapy and 2 weeks later. The results are expressed by analog scores; for example, 100 means vastly improved, 50 no change, and 0 greatly wors- ened. Simultaneously, the ease of drug administration was evaluated analogously, taking into account the ease with which the optimal maintenance dose can be determined, the number of times the dose has to be changed before the optimal Vol.21 No.1 METILDIGOXIN IN CONGESTIVE HEART FAILURE 51 dose is determined, and the side effects, and plotted on abscissa. The evaluation was based on a comparison of the ease of use of the drug to be tested with the ease of use of other cardiac glycosides as experienced by the physicians. The scales 100, 50, and 0 correspond to easy, equal to and difficult, respectively. (c) Evaluation of usefulness The usefulnessof the drugs was evaluated according to the improvement in the patient's condition and the ease of drug administration. In Fig. 2 the area is divided into 5 parts based on the consensusof all members of the study group. The cases in which the drug could be used easily and the patient's condition was main- tained extremely well are plotted in Area I, while the cases in which the drug was difficult to use and the patient's condition was not satisfactorily maintained are plotted in Area V. The area at lower right would represents the cases in which the drug was easily used but in which the patient's condition could not be main- tained satisfactorily,if such a situation was possible. Actually, no caseswere plotted in this contradictory area. The average daily dose administered to the patients was 2.98 MD tablets (approximately 0.15mg) and 3.02 DX tablets (approximately 0.30mg), coinciding with the dosages estimated from our preliminary study. (d) Other items to be checked Subjective complaints, heart rate, pulse rate, blood pressure, edema, urine volume, body weight, physical chest findings, swelling of the liver, electrocardio- gram, side effects,and so on were examined before digitalization, at the time of the changeover to maintenance therapy, and 1 and 2 weeks later. Venous pressure and chest X-ray examinations were carried out before digitalization, at the time of changing to maintenance therapy and 2 weeks thereafter. Drug effects were evalu- ated at the time of the changeover to maintenance therapy and 2 weeks there- after. (e) Criteria for exclusion, drop out, and discontinuation of the treatment Cases which did not meet the above selection criteria, cases in which drugs other than those mentioned above were administered, and cases which were not suitable for the analyses were excluded. Cases in which the test was discontinued for reasons unrelated to the effects of the drug or side effects, e.g. cases which de- veloped complications due to other diseases, were dropped from the present study. The test was discontinued at the decision of the attending phycisian when symptoms became aggravated, when serious side effects appeared, or when the patient was discharged from the hospital as a result of rapid improvement. How- ever, these cases are included in the discussion of the effects of the drug.

RESULTS 1. Subjects employed for analyses The test was carried out in a total of 104 cases. Fourteen of these were excluded and 4 were dropped from the present study. The remaining 86 cases were subjected to evaluations of the efficacy of the drugs. In main- tenance therapy, MD was used in 44 and DX in 42 cases. There was no statistically significant difference between the MD and DX groups in respect Jap. Heart J. J 52 KIMURA AND SAKUMA anuary, 1980 Table II. Relationships between the Results of Global Judgement and the Background Factors

ƒÏs=Spearman's rank correlation coefficient.

of the patients' characteristics such as sex, age, underlying diseases (valvular diseases, congenital heart diseases, hypertension, myocarditis, etc), the pre- sence of atrial fibrillation, the use of diuretics, the drugs used for digitalization (MD or deslanoside) and their effects, the initial values of the heart rate, the pulse rate and venous pressure, and the stage of heart failure at the start of maintenance therapy according to the NYHA classification.

2. Comparison of drug efficacy in maintenance therapy (a) Evaluation according to patient condition The ordinate in Fig. 2 represents the comparison of patient condition just prior to the start of maintenance therapy and 2 weeks later. Although there were slightly more patients with a score below 50 (no change) in the MD group than in the DX group, the majority of cases in both groups showed score 50 or more. There was no significant difference between the 2 groups. (b) Evaluation according to ease of drug administration Most cases showed a score of nearly 50 (equal), as shown by the abscissa in Fig. 2, and there was no significant difference between the 2 groups. (c) Evaluation of usefulness-global judgement Global judgement was made using the diagram shown in Fig. 2. Cases plotted in Areas 4 and 5 occurred slightly more frequently in the MD group, Vol.21 No.1 METILDIGOXIN IN CONGESTIVE HEART FAILURE 53

Table III. Differences in Cardiovascular Measurements before and after Maintenance Therapy (Average Values)

* NYHAclassification was treated quantitatively. ** There were no significantdifferences between the valuesat the start of the maintenance therapyand 1week after, and betweenthe valuesat the start and 2 weeksafter (Student t test). but no significant difference was demonstrated between the 2 drugs. (d) Relationship between the results of global judgement and back- ground factors As shown in Table II, no particular relationships were found in either group. In addition, there were no specific relationships between the results of global judgement and underlying diseases. (e) Differences in hemodynamic measurements before and after main- tenance therapy Table III shows the differences in hemodynamic measurements prior to maintenance therapy and after 1 or 2 weeks in maintenance therapy. While the heart and pulse rates decreased with the lapse of treatment, the changes were not statistically significant. There were no differences between the 2 drugs. On the other hand, the cardiothoracic ratio and the degree of severity of heart failure determined according to the old NYHA classification were clearly improved after 2 weeks of maintenance thereapy, but there were no differences between the 2 drugs. The venous pressure decreased significantly in the DX group, while no such significant changes were observed in the MD group. The differences between the drugs, however, were not significant. (f) Comparison of other symptoms Although no statistically significant differences were observed between the 2 groups in shortness of breath, cough, sputum, and lung rales, the MD group showed a significantly higher incidence of palpitation at 1 week after the start of maintenance therapy. On the other hand , the DX group evi- 54 KIMURA AND SAKUMA Jap. Heart J. January, 1980

Table IV. Comparison of the Effects of MD and Deslanoside in Digitalization

(The analogscale in Fig. 1 wasused) 100: far superior 50: equal 0: far inferior Wilcoxon2 sampletest t0=1.9243,p=0.0543

denced edema more frequently than the MD group at 1 and 2 weeks after the start of maintenance therapy.

3. Comparison of drug efficacy in digitalization As seen in Table IV, MD seems slightly superior to deslanoside in digi- talization, but the difference was not statistically significant at p=0.05.

4. Side effects Side effects were analyzed in 96 (49 MD and 47 DX cases) out of the total of 104 cases. The cases in which description was incomplete, and the cases in which digitalis intoxication was difficult to confirm because of pre- existing bradycardia were excluded. However, among the patients excluded or dropped from the study on the maintenance treatment, those cases which were available for the investigation of side effects are included in the dis- cussion. Side effects were observed in 10 cases in each group. In the MD group, bradycardia was noted in 3 cases, extrasystole in 3, bradycardia complicated with extrasystole in 1, prolongation of PR interval in 1, diarrhea in 1, and nausea accompanied with soft stool in 1. In the DX group, extrasystole was noted in 3 cases, bradycardia in 1, bradycardia associated with nausea and anorexia in 1, prolongation of PR interval in 1, palpitation in 1, nausea ac- companied with anorexia in 1, skin itching in 1, and liver function disorder in 1. Vol.21 No.1 METILDIGOXIN IN CONGESTIVE HEART FAILURE 55

DISCUSSION 1. MD and other digitalis preparations The use of digitalis has been considered to be extremely difficult because its effective dose varies from case to case. In cases where gastrointestinal tract absorption is poor or unstable, it is difficult to determine the effective dose because the absorbed amount cannot be estimated. Therefore a preparation which is absorbed easily and at a constant rate and then rapidly excreted is highly desirable for clinical use. MD was found to be a drug which meets these requirements well. In our preliminary study, in which MD, DX, digitoxin, lanatoside C, and proscillaridin were compared in the non-blind manner, we obtained results which showed that MD was an excellent drug. Generally speaking, a double blind trial is not necessary for the evalua- tion of drugs, such as digitalis preparations, which are obviously effective in the treatment of congestive heart failure. Furthermore, from a medical point of view, serious problems are posed in conducting a double blind study on digitalization because patients with overt congestive heart failure must be used for the trial. In respect of maintenance therapy, on the other hand, the conducting of a double blind study is of significance because the dose administered is changed in response to subjective symptoms such as palpitations and short breath, and toxic symptoms such as nausea and anorexia. Therefore, a majority of the researcher, who participated in the prelimi- nary study decided to carry out a double blind trial. However, it should be noted that some of the researchers did not participate in this trial because they felt that a double blind study was not necessary for the evaluation of digitalis preparations. There have been very few double blind studies reporting on the effects of digitalis preparations. The report of Starr and Luchi3) on maintenance therapy with digitoxin in 11 patients is a rather specific research because the findings in the ballistocardiogram were used for evaluation. The report of Yoshimura et al4) using peruvoside is also specific because patients with latent heart failure were included among the subjects. A double blind trial on MD similar to the one reported here was conducted by Toi et al,5) but because most of their patients belonged to class I in the old NYHA classification, it is diffi- cult to determine whether in fact the real effects of MD were examined.

2. The evaluation of MD by the double blind method As shown in Fig. 2, no significant difference was demonstrated between Jap. Heart J. J 56 KIMURA AND SAKUMA anuary, 1980

MD and DX in maintenance therapy for congestive heart failure. Although we had expected before the trial that MD would be found to be superior to DX, such a result was not obtained. Digitalis preparations such as digitoxin, DX and deslanoside require different methods of administration in individual cases. Because the attend- ing physiciansparticipating in this study did not know which drugs were used in the double blind test, the way in which they used the drugs inclined naturally to the one appropriate for DX, with which they were more familiar. Therefore, if optimal MD usage differs from optimal DX usage, the true value of MD cannot be demonstrated and we may obtain results that indicate that DX is superior to MD. Despite the 18-month experience we obtained in the preliminary test, it did not seem that we had become accustomed to using MD. Since the cases in which digitalization is complete should be free from heart failure, no further improvement can be expected from maintenance therapy. However, further improvement in the grade of NYHA classifica- tion was obtained both by MD and DX, indicating that some cases still had heart failure at the start of maintenance therapy. The fact that no significant lowering of venous pressure was noted in the MD group may indicate that venous pressure had been lowered completely by digitalization in more cases in this group than in the DX group. That the cardiothoracic ratio was im- proved by maintenance therapy is to be expected because a relatively long time is needed to obtain a reduction in cardiac size. As for side effects, we obtained similar results in both the MD and the DX group. Although the higher absorption rate of MD by the gastroin- testinal tract was expected to make estimation of the effective dose easier and thereby reduce the incidence of intoxication, no results were obtained to substantiate this expectation. One of the reasons must be the fact that all the members of the group participating in this study were accustomed to using DX. The same results may not have been obtained if the drugs had been used by non-specialists. Recently, it has become possible to use radioimmunoassays of the blood level of DX to make the use of digitalis preparations more efficient and the prevention of intoxication easier. The blood level of MD can also be de- termined by this method. Investigations along this line should be carried out in the future.

3. The usefulness of MD Digitalis preparations are even now the first choice in the treatment of congestive heart failure. Depending on the case, digitoxin, digoxin, deslano- Vol.21 No.1 METILDIGOXIN IN CONGESTIVE HEART FAILURE 57 side, or lanatoside C are chosen on the basis of their pharmacological charac- teristics. Any newly developed digitalis preparation must possess unique properties that are not found in the existing preparations. Although MD is a preparation which is absorbed almost completely through the gastrointestinal tract, the present double blind study did not obtain any results that indicated that MD is more advantageous than DX. Because digitalis is one of the most effective drugs used clinically, it may be difficult to obtain results from a double blind study which indicate that a newly developed digitalis preparation is superior to preparations that already exist, even if the effectiveness of the new drug exceeds that of the existing preparations. The usefulness of MD may therefore be judged more appropriately from its pharmacological or its pharmacokinetic properties and from the results obtained by a non-blind rather than a double blind study. Taking these points into account, it can be concluded that MD is a digitalis preparation which is useful in practical medicine.

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3. Starr I, Luchi RJ: Blind study of the action of digitoxin on elderly women. Am Heart J

78: 740, 1969

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