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The Clinical Use of Dicumarol
THE CLINICAL USE OF DICUMAROl NELSON
W.
BARKER
IN 1941 Link and his associates 7 ,13 reported the isolation and synthesis of dicumarol [3,3'-methylenebis (4 hydroxycoumarin)]. Since that time a number of reportsl, 2, 5, 6 have been made on the physiologic effects of this drug on animals and human beings. At the Clinic dicumarol has been administered to more than 1,000 surgical patients during the postoperative period for the purpose of preventing postoperative thrombosis and embolism and it has also been administered to more than 100 nonsurgical patients who had various types of arterial and venous thrombosis and embolism for the purpose of preventing or inhibiting the progress of their disease. This report is based on the study of these patients. QUESTIONS AND ANSWERS
What is the physiologic effect of dicumarol on human beings7Dicumarol produces prothrombin deficiency as indicated by the Quick prothrombin time test. 5 , 6 The prothrombin deficiency may be mild or severe depending on the amount of the drug given over a period and by the individual susceptibility of the patient to the drug. As a secondary effect of prothrombin deficiency the coagulation time of the blood (Lee-White) may be, but is not necessarily, prolonged. The degree of prolongation of the coagulation time does not necessarily parallel the degree of prolongation of the prothrombin time. Thus the coagulation time cannot be used as an index of the effect of the drug on an individual patient. Dicumarol usually prolongs the clot retraction time and elevates the sedimentation rate of the erythrocytes. Some recent work l2 indicates that it may inhibit platelet adhesiveness. Otherwise the drug does not appear to have any physiologic or toxic effects on human beings. Even after prothrombin deficiency of moderate to severe degree has been maintained for more than two months by administration of dicumarol, the ordinary tests of hepatic function have been found to give negative results and no untoward effects have been noted. Does dicumarol prevent thrombosis in human beings7-The evidence that the prothrombin deficiency produced by dicumarol prevents thrombosis in human beings has come largely from statistical studies of postoperative patients. At the Clinic it was found that among 678 patients who had a pulmonary embolism and survived and who did not receive dicumarol, 297 (43.8 per cent) had one or more subsequent episodes of thrombophlebitis or pulmonary embolism and 124 (18.3 per cent) had a subsequent fatal pulmonary embolism. 4 Among 180 similar patients who had pulmonary embolism and survived and 929
930
NELSON W. BARKER
did receive dicumarol, only two (1.1 per cent) had subsequent thromut-phlebitis or embolism and only one (0.6 per cent) had a subsequent fatal embolism. Also among 897 patients who had postoperative thrombophlebitis (or phlebothrombosis) and who did not receive dicumarol, ninety-five (10.6 per cent) had one or more subsequent episodes or extensions of the thrombophlebitis and fifty-one (5.7 per cent) had subsequent fatal pulmonary embolism. 4 Among 138 similar patients who received dicumarol four (2.9 per cent) had more thrombophlebitis and none had fatal embolism. Sixty-one patients who have had thrombophlebitis or embolism at some time prior to operation have been given dicumarol prophylactically and none have had thrombosis or embolism after operation. Dicumarol has been given prophylactically to 438 patients on whom abdominal hysterectomy had been performed and who had not had thrombophlebitis or pulmonary embolism. In a previous study it had been found that the risk of thrombophlebitis and embolism in these patients was 4 per cent and the risk of fatal embolism 0.7 per cent. 3 No embolisms developed in the 438 patients who received dicumarol. Two of these patients had minor thrombophlebitis of the veins of the calf but only after they had left the hospital and after the prothrombin had returned to normal. The nonsurgical patients who received dicumarol had various diseases characterized by thrombosis and included patients who had thrombophlebitis or pulmonary embolism, complicating infectious diseases, blood dyscrasias, congestive heart failure and severe injuries, recurrent idiopathic thrombophlebitis, intracardiac thrombosis with arterial embolism, simple arterial thrombosis, thrombo-angiitis obliterans and arteriosclerosis obliterans. In none of these cases was there any evidence that thrombosis or embolism developed during the period in which the prothrombin time was elevated as the result of administration of dicumarol. How important is the Quick prothrombin time test as a guide to the administration of dicumarol?-The purpose of administration of dicumarol is to produce a definite but not excessive prothrombin deficiency. If as a result of administration of dicumarol the prothrombin is less than 30 per cent of normal, thrombosis will almost certainly not develop and if the prothrombin is greater than 10 per cent of normal, bleeding will almost certainly not occur. Therefore in any individual case it is necessary to keep the prothrombin between 30 per cent and 10 per cent of normal to achieve the desired effect. Patients vary considerably in their sensitivity to the drug and this variability is usually unpredictable. Furthermore the effect of dicumarol is delayed, developing twenty-four to seventy-two hours after a dose is given, and it may persist for several days after reaching a maximum. For these reasons it is absolutely necessary to do daily prothrombin time tests 10 • 11 (Quick method) on a patient who is receiving dicumarol in order to know each day whether or not; the prothrombin is within
THE CLINICAL USE OF DICUMAROL
931
the desired limits and to determine when another dose of the drug should be given. In doing the Quick prothrombin time test, thromboplastins of different potency, giving different normal prothrombin times and therefore different prothrombin times for certain degrees of prothrombin deficiency, are used in different hospitals and clinics. Also, unfortunately, thromboplastins may vary considerably in their potency even when prepared from similar sources and in the same way.9 For any type of thromboplastin which is used and when any new batch of thromboplastin is prepared, prothrombin times should be determined for 10 per cent, 20 per cent and 30 per cent dilutions of normal plasma. The results will be essentially the same if the dilutions are made with either prothrombin-free plasma or physiologic solution of sodium chloride. It is important that the physician who is supervising dicumarol therapy know each day the values in terms of prothrombin time in seconds for these three dilutions of normal plasma which can be considered as values for 10 per cent, 20 per cent and 30 per cent of normal prothrombin respectively. What is the dose of dicumarol7-Dicumarol is effective when administered orally. A satisfactory preparation for parenteral use has not been developed. The following plan of dosage has been found to be simple and satisfactory and is recommended. All the dicumarol for one day is given in a single dose after the prothrombin time has been determined for that day. Three hundred milligrams are given the first day and 200 mg. are given on each subsequent day that the prothrombin is greater than 20 per cent of normal. No dicumarol is given on days when the prothrombin is less than 20 per cent of normal. For the occasional patient who is found to be resistant to the drug the subsequent doses may be increased to 300 mg. and if the patient is very sensitive to the drug, as indicated by rapidly developing and persistent severe prothrombin deficiency (below 10 per cent) after the usual doses, the dose may be reduced to 100 mg. If dicumarol is given after a surgical operation for prophylaxis against thrombosis, administration is begun on the third postoperative day. When dicumarol is given to surgical patients prothrombin deficiency should be maintained until the patient leaves the hospital and for>at lea~t four days after he has been ambulatory. Daily prothrombin time tests should be done until the administration of the drug is discontinued. When dicumarol is given to nonsurgical patients the desirah.le duration of the prothrombin deficiency may be quite variable. If adequate protection against thrombosis and embolism is desired, the prothrombin deficiency should be maintained until the patient is ambulatory and in some instances for a considerably longer time. However, close observation of the patient and daily prothrombin time tests should be continued for the entire period. Is dicumarol a dangerous drug7-The only untoward effect which has
932
NELSON W. BARKER
been observed in human beings after dicumarol has been administered has been bleeding. If the contraindications to administration of dicumarol are observed and if the drug is administered according to the plan mentioned in the previous section the danger of bleeding is minimal. Minor epistaxis and microscopic hematuria may occur during administration of dicumarol but they may be disregarded. More serious bleeding may occur from recent operative wounds or ulcerative lesions, particularly of the gastro-intestinal tract. Usually such bleeding is not primarily caused by the prothrombin deficiency but what might have been minor transient bleeding becomes prolonged bleeding because of the prothrombin deficiency. Multiple widespread ecchymoses and hemorrhages are extremely rare. Definite bleeding is rare if the prothrombin does not fall below 10 per cent of normal and only occurs in about 4 per cent of cases when the prothrombin does fall below 10 per cent of normal. Among the first 1,000 patients who received dicumarol during the immediate postoperative period the incidence of serious bleeding was 2.5 per cent. Among the 318 patients who had had thrombophlebitis or pulmonary embolism it was only 1 per cent. Only one fatality from hemorrhage occurred among the 1,000 patients who received dicumarol during the postoperative period and in this case it is doubtful that the dicumarol was a factor, since there was relatively little prothrombin deficiency when bleeding occurred. The experience at the Clinic has been that, when properly used, dicumarol is no more dangerous than many other potent drugs. How can excessive prothrombin deficiency or bleeding be controlled? -In using the plan of dosage recommended in this paper, patients may be encountered who have excessive prothrombin deficiency (below 10 per cent of normal) after the first one or two doses of the drug. Such patients usually are among the group who have recent or prolonged dietary deficiency or lesions of the gastro-intestinal tract and are usually those who have not had previous thrombosis or embolism. This excessive prothrombin deficiency can be restored to within safe limits in about 90 per cent of cases by a single intravenous injection of a large dose (60 mg.) of menadione bisulfite (2-methyl-naphthoquinone monosodium bisulfite).8 Thereafter dicumarol should be given more cautiously or in 100 mg. doses to that patient. If bleeding occurs during administration of dicumarol 60 mg. of menadione bisulfite should be given intravenously and the patient should be transfused with 500 c.c. of freshly drawn citrated blood, which will usually cause the bleeding to stop within a few hours. Rarely, subsequent transfusions and injections of menadione bisulfite may be necessary. What are the deficiencies of dicumarol therapy?-As far as is known, dicumarol has no effect on a thrombus or embolus that is already present. It is used for the prevention of new thrombosis or extension of existing thrombosis and since emboli arise from fresh thrombi only, the prevention of fresh thrombosis will prevent embolism. The effect
THE CLINICAL USE OF DICUMAROL
933
of dicumarol is delayed for a day or more after it is administered and during this period the patient is not protected against thrombosis. The zone of effective and safe prothrombin deficiency produced by dicumarol is rather narrow (10 per cent to 30 per cent prothrombin) and the administration of dicumarol requires close observation of the patients and daily prothrombin time tests; therefore it is a rather unpractical method of preventing thrombosis for long periods (more than three months). Protection against thrombosis and therefore embolism ceases after the prothrombin deficiency induced by dicumarol ceases. There is the small risk of bleeding during the period of activity of the drug. What is the best and simplest way to obtain a rapid anticoagulant antithrombotic effect and maintain it during a prolonged period7-Heparin injected intravenously will produce a rapid anticoagulant effect but it is impractical to use heparin for long periods because of its cost and the necessity for continuous or repeated intravenous administration. However, heparin can be administered during the few days between the time of administration of the first dose of dicumarol and the development of adequate prothrombin deficiency. The simplest method, is to start the administration of heparin and dicumarol simultaneously, giving 50 mg. of heparin intravenously every four hours and giving the dicumarol according to the plan noted previously. As soon as the prothrombin is less than 20 per cent of normal the heparin may be discontinued. Prothrombin time tests to determine when this point is reached should be done at the end of the four-hour period after an injection of heparin and before the next dose of heparin is administered. What are contraindications to the use of dicumarol7-Dicumarol is contraindicated in (1) the presence of definite renal insufficiency, because renal insufficiency greatly prolongs and increases its effect; (2) the presence of definite hepatic insufficiency for the same reason; (3) purpura of any type because of the danger of bleeding when capillary weakness and impaired coagulation are both present; (4) subacute bacterial endocarditis because of the vascular weakness caused by the disease and therefore increased liability to hemorrhage; (5) blood dyscrasia with tendency to bleed and (6) recent operation on the brain or spinal cord because of the grave consequence of even slight bleeding at the operative site. Dicumarol should be given cautiously to patients who have (1) ulcerative lesions, open wounds or potentially ble~ding surfaces, (2) vomiting due to gastric or intestinal obstruction, (3) continuous or repeated gastric or intestinal drainage or (4) known dietary or nutritional deficiency. If patients are vomiting or have continuous or intermittent gastric or intestinal drainage by tube it may be futile to give dicumarol because the drug is absorbed poorly if at all. What are the indications for the use of dicumarol7-Experience at the Clinic has indicated that the anticoagulant action of dicumarol is of
934
NELSON W. BARKER
value in the following conditions: (1) nonfatal postoperative, postinfectious or posttraumatic pulmonary embolism, because of the great risk of subsequent venous thrombosis and embolism during the subsequent few days or few weeks; (2) postoperative, postinfectious or posttraumatic thrombophlebitis because of the danger of extending or remote venous thrombosis and therefore of pulmonary embolism both fatal and nonfatal during the subsequent few days or few weeks; ( 3) after operations on patients who have previously had thrombophlebitis or pulmonary embolism because of the danger of recurrence of these complications; (4) after peripheral arterial embolism because of the danger of further intracardiac thrombosis and of propagating thrombosis from the embolus when the arterial spasm relaxes and (5) after acute peripheral arterial thrombosis from any cause because of the imminent danger of extending arterial thrombosis. Dicumarol may also be of value for patients who have thrombophlebitis or pulmonary embolism complicating blood dyscrasias or congestive heart failure, although there is a limit to the time that the anticoagulant effect can be maintained in these conditions and the thrombosing tendency may be prolonged. For the same reason dicumarol is of less value in recurrent idiopathic thrombophlebitis but during periods when the episodes recur with great frequency and may be interspersed with pulmonary infarcts, it may be advisable to use dicumarol. In postpartum thrombophlebitis or pulmonary embolism dicumarol should be used with caution although there is minimal risk of uterine bleeding if the uterus is normally involuted and if administration of the drug is not begun until the first postpartum week has elapsed. In patients who have a large pulmonary embolism or acute peripheral arterial occlusion it is advisable to secure a rapid anticoagulant effect and to use preliminary heparinization as well as dicumarol. In cases of thrombophlebitis or in cases in which the drug is used for prophylactic purposes, preliminary heparinization is not necessary. REFERENCES
1. Allen, E. V., Barker, N. W. and Waugh, J. M.: A preparation from spoiled sweet clover [3,3'-methylene-bis- (4-hydroxycoumarin)] which prolongs
coagulation and prothrombin time of the blood: a clinical study. }.A.M.A.
120:1009-1015 (Nov. 28) 1942.
2. Barker, N. W.: The use of dicumarol in surgery. Minnesota Med. 27:102-106 (Feb.) 1944.
3. Barker, N. W., Nygaard, K K., Waiters, Waltman and Priestley, }. T.: A statistical study of postoperative venous thrombosis and pulmonary embolism. I. Incidence in various types of operations. Proc. Staff Meet., Mayo Clin. JS:769-773 (Dec. 4) 1940. 4. Barker, N. W., Nygaard, K K, Waiters, Waltman and Priestley, }. T.: A statistical study of postoperative venous thrombosis and pulmonary embolism. Ill. Time of occurrence during the postoperative period. Proc. Staff Meet., Mayo Clin. 16:17-21 (jan. 8) 1941.
935
THE CLINICAL USE OF DICUMAROL
;. Bingham, J. B., Meyer, O. O. and Pohle, F. J.: Studies on the hcmorrhagic agent 3,3'-methylencbis (4-hydroxycoumarin). l. Its effect on the prothrombin and coagulation time of the blood of dogs and humans. Am. ]. M. Sc. 202:563-578 (Oct.) 1941. 6. Butt, H. K, Allen, E. V. and BolIman, ]. L.: A preparation from spoiled sweet clover [3,3'-methylene-bis-(4-hydroxycoumarin)] which prolongs coagulation and prothrombin time of the blood: preliminary report of experimental and clinical studies. Proc. Staff Meet., Mayo Clin. 16:388-395
"'1.
W.
BARKER
IN 1941 Link and his associates 7 ,13 reported the isolation and synthesis of dicumarol [3,3'-methylenebis (4 hydroxycoumarin)]. Since that time a number of reportsl, 2, 5, 6 have been made on the physiologic effects of this drug on animals and human beings. At the Clinic dicumarol has been administered to more than 1,000 surgical patients during the postoperative period for the purpose of preventing postoperative thrombosis and embolism and it has also been administered to more than 100 nonsurgical patients who had various types of arterial and venous thrombosis and embolism for the purpose of preventing or inhibiting the progress of their disease. This report is based on the study of these patients. QUESTIONS AND ANSWERS
What is the physiologic effect of dicumarol on human beings7Dicumarol produces prothrombin deficiency as indicated by the Quick prothrombin time test. 5 , 6 The prothrombin deficiency may be mild or severe depending on the amount of the drug given over a period and by the individual susceptibility of the patient to the drug. As a secondary effect of prothrombin deficiency the coagulation time of the blood (Lee-White) may be, but is not necessarily, prolonged. The degree of prolongation of the coagulation time does not necessarily parallel the degree of prolongation of the prothrombin time. Thus the coagulation time cannot be used as an index of the effect of the drug on an individual patient. Dicumarol usually prolongs the clot retraction time and elevates the sedimentation rate of the erythrocytes. Some recent work l2 indicates that it may inhibit platelet adhesiveness. Otherwise the drug does not appear to have any physiologic or toxic effects on human beings. Even after prothrombin deficiency of moderate to severe degree has been maintained for more than two months by administration of dicumarol, the ordinary tests of hepatic function have been found to give negative results and no untoward effects have been noted. Does dicumarol prevent thrombosis in human beings7-The evidence that the prothrombin deficiency produced by dicumarol prevents thrombosis in human beings has come largely from statistical studies of postoperative patients. At the Clinic it was found that among 678 patients who had a pulmonary embolism and survived and who did not receive dicumarol, 297 (43.8 per cent) had one or more subsequent episodes of thrombophlebitis or pulmonary embolism and 124 (18.3 per cent) had a subsequent fatal pulmonary embolism. 4 Among 180 similar patients who had pulmonary embolism and survived and 929
930
NELSON W. BARKER
did receive dicumarol, only two (1.1 per cent) had subsequent thromut-phlebitis or embolism and only one (0.6 per cent) had a subsequent fatal embolism. Also among 897 patients who had postoperative thrombophlebitis (or phlebothrombosis) and who did not receive dicumarol, ninety-five (10.6 per cent) had one or more subsequent episodes or extensions of the thrombophlebitis and fifty-one (5.7 per cent) had subsequent fatal pulmonary embolism. 4 Among 138 similar patients who received dicumarol four (2.9 per cent) had more thrombophlebitis and none had fatal embolism. Sixty-one patients who have had thrombophlebitis or embolism at some time prior to operation have been given dicumarol prophylactically and none have had thrombosis or embolism after operation. Dicumarol has been given prophylactically to 438 patients on whom abdominal hysterectomy had been performed and who had not had thrombophlebitis or pulmonary embolism. In a previous study it had been found that the risk of thrombophlebitis and embolism in these patients was 4 per cent and the risk of fatal embolism 0.7 per cent. 3 No embolisms developed in the 438 patients who received dicumarol. Two of these patients had minor thrombophlebitis of the veins of the calf but only after they had left the hospital and after the prothrombin had returned to normal. The nonsurgical patients who received dicumarol had various diseases characterized by thrombosis and included patients who had thrombophlebitis or pulmonary embolism, complicating infectious diseases, blood dyscrasias, congestive heart failure and severe injuries, recurrent idiopathic thrombophlebitis, intracardiac thrombosis with arterial embolism, simple arterial thrombosis, thrombo-angiitis obliterans and arteriosclerosis obliterans. In none of these cases was there any evidence that thrombosis or embolism developed during the period in which the prothrombin time was elevated as the result of administration of dicumarol. How important is the Quick prothrombin time test as a guide to the administration of dicumarol?-The purpose of administration of dicumarol is to produce a definite but not excessive prothrombin deficiency. If as a result of administration of dicumarol the prothrombin is less than 30 per cent of normal, thrombosis will almost certainly not develop and if the prothrombin is greater than 10 per cent of normal, bleeding will almost certainly not occur. Therefore in any individual case it is necessary to keep the prothrombin between 30 per cent and 10 per cent of normal to achieve the desired effect. Patients vary considerably in their sensitivity to the drug and this variability is usually unpredictable. Furthermore the effect of dicumarol is delayed, developing twenty-four to seventy-two hours after a dose is given, and it may persist for several days after reaching a maximum. For these reasons it is absolutely necessary to do daily prothrombin time tests 10 • 11 (Quick method) on a patient who is receiving dicumarol in order to know each day whether or not; the prothrombin is within
THE CLINICAL USE OF DICUMAROL
931
the desired limits and to determine when another dose of the drug should be given. In doing the Quick prothrombin time test, thromboplastins of different potency, giving different normal prothrombin times and therefore different prothrombin times for certain degrees of prothrombin deficiency, are used in different hospitals and clinics. Also, unfortunately, thromboplastins may vary considerably in their potency even when prepared from similar sources and in the same way.9 For any type of thromboplastin which is used and when any new batch of thromboplastin is prepared, prothrombin times should be determined for 10 per cent, 20 per cent and 30 per cent dilutions of normal plasma. The results will be essentially the same if the dilutions are made with either prothrombin-free plasma or physiologic solution of sodium chloride. It is important that the physician who is supervising dicumarol therapy know each day the values in terms of prothrombin time in seconds for these three dilutions of normal plasma which can be considered as values for 10 per cent, 20 per cent and 30 per cent of normal prothrombin respectively. What is the dose of dicumarol7-Dicumarol is effective when administered orally. A satisfactory preparation for parenteral use has not been developed. The following plan of dosage has been found to be simple and satisfactory and is recommended. All the dicumarol for one day is given in a single dose after the prothrombin time has been determined for that day. Three hundred milligrams are given the first day and 200 mg. are given on each subsequent day that the prothrombin is greater than 20 per cent of normal. No dicumarol is given on days when the prothrombin is less than 20 per cent of normal. For the occasional patient who is found to be resistant to the drug the subsequent doses may be increased to 300 mg. and if the patient is very sensitive to the drug, as indicated by rapidly developing and persistent severe prothrombin deficiency (below 10 per cent) after the usual doses, the dose may be reduced to 100 mg. If dicumarol is given after a surgical operation for prophylaxis against thrombosis, administration is begun on the third postoperative day. When dicumarol is given to surgical patients prothrombin deficiency should be maintained until the patient leaves the hospital and for>at lea~t four days after he has been ambulatory. Daily prothrombin time tests should be done until the administration of the drug is discontinued. When dicumarol is given to nonsurgical patients the desirah.le duration of the prothrombin deficiency may be quite variable. If adequate protection against thrombosis and embolism is desired, the prothrombin deficiency should be maintained until the patient is ambulatory and in some instances for a considerably longer time. However, close observation of the patient and daily prothrombin time tests should be continued for the entire period. Is dicumarol a dangerous drug7-The only untoward effect which has
932
NELSON W. BARKER
been observed in human beings after dicumarol has been administered has been bleeding. If the contraindications to administration of dicumarol are observed and if the drug is administered according to the plan mentioned in the previous section the danger of bleeding is minimal. Minor epistaxis and microscopic hematuria may occur during administration of dicumarol but they may be disregarded. More serious bleeding may occur from recent operative wounds or ulcerative lesions, particularly of the gastro-intestinal tract. Usually such bleeding is not primarily caused by the prothrombin deficiency but what might have been minor transient bleeding becomes prolonged bleeding because of the prothrombin deficiency. Multiple widespread ecchymoses and hemorrhages are extremely rare. Definite bleeding is rare if the prothrombin does not fall below 10 per cent of normal and only occurs in about 4 per cent of cases when the prothrombin does fall below 10 per cent of normal. Among the first 1,000 patients who received dicumarol during the immediate postoperative period the incidence of serious bleeding was 2.5 per cent. Among the 318 patients who had had thrombophlebitis or pulmonary embolism it was only 1 per cent. Only one fatality from hemorrhage occurred among the 1,000 patients who received dicumarol during the postoperative period and in this case it is doubtful that the dicumarol was a factor, since there was relatively little prothrombin deficiency when bleeding occurred. The experience at the Clinic has been that, when properly used, dicumarol is no more dangerous than many other potent drugs. How can excessive prothrombin deficiency or bleeding be controlled? -In using the plan of dosage recommended in this paper, patients may be encountered who have excessive prothrombin deficiency (below 10 per cent of normal) after the first one or two doses of the drug. Such patients usually are among the group who have recent or prolonged dietary deficiency or lesions of the gastro-intestinal tract and are usually those who have not had previous thrombosis or embolism. This excessive prothrombin deficiency can be restored to within safe limits in about 90 per cent of cases by a single intravenous injection of a large dose (60 mg.) of menadione bisulfite (2-methyl-naphthoquinone monosodium bisulfite).8 Thereafter dicumarol should be given more cautiously or in 100 mg. doses to that patient. If bleeding occurs during administration of dicumarol 60 mg. of menadione bisulfite should be given intravenously and the patient should be transfused with 500 c.c. of freshly drawn citrated blood, which will usually cause the bleeding to stop within a few hours. Rarely, subsequent transfusions and injections of menadione bisulfite may be necessary. What are the deficiencies of dicumarol therapy?-As far as is known, dicumarol has no effect on a thrombus or embolus that is already present. It is used for the prevention of new thrombosis or extension of existing thrombosis and since emboli arise from fresh thrombi only, the prevention of fresh thrombosis will prevent embolism. The effect
THE CLINICAL USE OF DICUMAROL
933
of dicumarol is delayed for a day or more after it is administered and during this period the patient is not protected against thrombosis. The zone of effective and safe prothrombin deficiency produced by dicumarol is rather narrow (10 per cent to 30 per cent prothrombin) and the administration of dicumarol requires close observation of the patients and daily prothrombin time tests; therefore it is a rather unpractical method of preventing thrombosis for long periods (more than three months). Protection against thrombosis and therefore embolism ceases after the prothrombin deficiency induced by dicumarol ceases. There is the small risk of bleeding during the period of activity of the drug. What is the best and simplest way to obtain a rapid anticoagulant antithrombotic effect and maintain it during a prolonged period7-Heparin injected intravenously will produce a rapid anticoagulant effect but it is impractical to use heparin for long periods because of its cost and the necessity for continuous or repeated intravenous administration. However, heparin can be administered during the few days between the time of administration of the first dose of dicumarol and the development of adequate prothrombin deficiency. The simplest method, is to start the administration of heparin and dicumarol simultaneously, giving 50 mg. of heparin intravenously every four hours and giving the dicumarol according to the plan noted previously. As soon as the prothrombin is less than 20 per cent of normal the heparin may be discontinued. Prothrombin time tests to determine when this point is reached should be done at the end of the four-hour period after an injection of heparin and before the next dose of heparin is administered. What are contraindications to the use of dicumarol7-Dicumarol is contraindicated in (1) the presence of definite renal insufficiency, because renal insufficiency greatly prolongs and increases its effect; (2) the presence of definite hepatic insufficiency for the same reason; (3) purpura of any type because of the danger of bleeding when capillary weakness and impaired coagulation are both present; (4) subacute bacterial endocarditis because of the vascular weakness caused by the disease and therefore increased liability to hemorrhage; (5) blood dyscrasia with tendency to bleed and (6) recent operation on the brain or spinal cord because of the grave consequence of even slight bleeding at the operative site. Dicumarol should be given cautiously to patients who have (1) ulcerative lesions, open wounds or potentially ble~ding surfaces, (2) vomiting due to gastric or intestinal obstruction, (3) continuous or repeated gastric or intestinal drainage or (4) known dietary or nutritional deficiency. If patients are vomiting or have continuous or intermittent gastric or intestinal drainage by tube it may be futile to give dicumarol because the drug is absorbed poorly if at all. What are the indications for the use of dicumarol7-Experience at the Clinic has indicated that the anticoagulant action of dicumarol is of
934
NELSON W. BARKER
value in the following conditions: (1) nonfatal postoperative, postinfectious or posttraumatic pulmonary embolism, because of the great risk of subsequent venous thrombosis and embolism during the subsequent few days or few weeks; (2) postoperative, postinfectious or posttraumatic thrombophlebitis because of the danger of extending or remote venous thrombosis and therefore of pulmonary embolism both fatal and nonfatal during the subsequent few days or few weeks; ( 3) after operations on patients who have previously had thrombophlebitis or pulmonary embolism because of the danger of recurrence of these complications; (4) after peripheral arterial embolism because of the danger of further intracardiac thrombosis and of propagating thrombosis from the embolus when the arterial spasm relaxes and (5) after acute peripheral arterial thrombosis from any cause because of the imminent danger of extending arterial thrombosis. Dicumarol may also be of value for patients who have thrombophlebitis or pulmonary embolism complicating blood dyscrasias or congestive heart failure, although there is a limit to the time that the anticoagulant effect can be maintained in these conditions and the thrombosing tendency may be prolonged. For the same reason dicumarol is of less value in recurrent idiopathic thrombophlebitis but during periods when the episodes recur with great frequency and may be interspersed with pulmonary infarcts, it may be advisable to use dicumarol. In postpartum thrombophlebitis or pulmonary embolism dicumarol should be used with caution although there is minimal risk of uterine bleeding if the uterus is normally involuted and if administration of the drug is not begun until the first postpartum week has elapsed. In patients who have a large pulmonary embolism or acute peripheral arterial occlusion it is advisable to secure a rapid anticoagulant effect and to use preliminary heparinization as well as dicumarol. In cases of thrombophlebitis or in cases in which the drug is used for prophylactic purposes, preliminary heparinization is not necessary. REFERENCES
1. Allen, E. V., Barker, N. W. and Waugh, J. M.: A preparation from spoiled sweet clover [3,3'-methylene-bis- (4-hydroxycoumarin)] which prolongs
coagulation and prothrombin time of the blood: a clinical study. }.A.M.A.
120:1009-1015 (Nov. 28) 1942.
2. Barker, N. W.: The use of dicumarol in surgery. Minnesota Med. 27:102-106 (Feb.) 1944.
3. Barker, N. W., Nygaard, K K., Waiters, Waltman and Priestley, }. T.: A statistical study of postoperative venous thrombosis and pulmonary embolism. I. Incidence in various types of operations. Proc. Staff Meet., Mayo Clin. JS:769-773 (Dec. 4) 1940. 4. Barker, N. W., Nygaard, K K, Waiters, Waltman and Priestley, }. T.: A statistical study of postoperative venous thrombosis and pulmonary embolism. Ill. Time of occurrence during the postoperative period. Proc. Staff Meet., Mayo Clin. 16:17-21 (jan. 8) 1941.
935
THE CLINICAL USE OF DICUMAROL
;. Bingham, J. B., Meyer, O. O. and Pohle, F. J.: Studies on the hcmorrhagic agent 3,3'-methylencbis (4-hydroxycoumarin). l. Its effect on the prothrombin and coagulation time of the blood of dogs and humans. Am. ]. M. Sc. 202:563-578 (Oct.) 1941. 6. Butt, H. K, Allen, E. V. and BolIman, ]. L.: A preparation from spoiled sweet clover [3,3'-methylene-bis-(4-hydroxycoumarin)] which prolongs coagulation and prothrombin time of the blood: preliminary report of experimental and clinical studies. Proc. Staff Meet., Mayo Clin. 16:388-395
"'1.