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Eiichi Kimura, MD, Department of Internal Medicine, Nippon Medical

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Eiichi Kimura, MD, Department of Internal Medicine, Nippon Medical 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.
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