The Use of Anticoagulants: An Evaluation

The Use of Anticoagulants: An Evaluation

The Use of Anticoagulants An Evaluation WILLIAM T. FOLEY, M.D., F.A.C.P. * IRVING S. WRIGHT, M.D., F.A.C.P.** are now widely employed throughout the ...

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The Use of Anticoagulants An Evaluation WILLIAM T. FOLEY, M.D., F.A.C.P. * IRVING S. WRIGHT, M.D., F.A.C.P.**

are now widely employed throughout the civilized world. They have been accepted for use in many fields of medicine. In some conditions they are of proven value, in others, of questionable worth, and in still others, they are as yet experimental. It seems wise at this time to evaluate these various phases. Clinical work with heparin started in 1936. Among the first diseases to be attacked was subacute bacterial endocarditis. At that time, effective antimicrobial agents were not available. Heparin was given to these patients in an effort to prevent the deposit of fibrin on the bacterial vegetations. Many of them succumbed to cerebral hemorrhage, probably from the weakening of the blood vessel walls due to the toxemia of the disease. The method immediately fell into disrepute. Subacute bacterial endocarditis has been considered a contraindication to anticoagulant therapy ever since. Patients with rheumatic heart disease who have had showers of emboli and who have been maintained on continuous Dicumarol therapy as a prophylactic, some for as long as eight years, have occasionally developed subacute bacterial endocarditis as a natural consequence of their disease. Such patients have been continued on their Dicumarol therapy and at the same time given penicillin. Clinical cure of the subacute bacterial endocarditis has resulted with no untoward effects from the Dicumarol, which in turn continued to afford protection against embolization.

ANTICOAGULANTS

From the Department of Medicine of the New York Hospital and the Cornell University Medical College, New York, N. Y. Aided by grants from the Kress, Hyde, Lasker and Hampil Foundations, the Youngstown Area Heart Association, the Eaton Laboratories, Mrs. Samuel Milbank and Mr. [saac Harter. • Assistant Professor of Clinical Medicine, Cornell University Medical College; Chief of Vascular Clinic, N ew York Hospital. ** Professor of Clinical Medic'ine, Cornell University Medical College; Attending Physician, New York Hospital. 1339

William T. Foley, Irving S. Wright

1340

PHLEBITIS AND PULMONARY EMBOLISM

Phlebitis and pulmonary embolism were the first conditions to be successfully treated with anticoagulants. Simultaneous reports from the Mayo Clinic groupla and Swedish workerslb have since been confirmed by every clinic working in this field. The mortality from subsequent pulmonary emboli can be reduced from 18 per cent to less than 1 per cent. We may consider then that the value of anticoagulants in phlebitis and in pulmonary embolism is well established. Treatment of recurrent or migratory phlebitis presents a slightly different problem. We refer to the patient who has repeated attacks of phlebitis in his legs over a period of months or years, or the patient who has phlebitis which travels from limb to limb and indeed may invade any veins throughout the body. Before the development of anticoagulants they presented an almost hopeless prognosis. We have attempted to treat a group of these patients with continuous Dieumarol administration (Table 1). Table 1

THROMBOEMBOUC EPISODES IN PATIENTS WITH RECURRENT THROMBOPHLEBITIS

NUMBER OF PATIENTS

24

NOT ON ANTICOAGULANT PATIENT NUMBER OF MONTHS EPISODES

2207

x INCLUDES 63 THROMBOPHLEBITIS 20 PULMONARY EMBOU

ON ANTICOAGULANT PATIENT NUMBER OF MONTHS EPISODES

896

o

THROMBOPHLEBITIS (IN 7 PATIENTS)

Twenty-four patients who had had recurrent thrombophlebitis during a period of 2207 patient-months experienced a total of 92 thromboembolic episodes. Sixty-three of these were repeated attacks of thrombophlebitis. There were 20 instances of pulmonary emboli. Of the remaining nine, three were peripheral arterial thrombi or emboli, two cerebral thrombi or emboli and there were four episodes of myocardial infarction. On anticoagulant therapy, over a period lasting 896 months, seven of the 24 patients each had one episode of thrombophlebitis. There were no other complications. The following case report is representative of this group:

The Use of Anticoagulants-an Evaluation

1341

Mr. V.J., a 50 year old postal clerk, developed a right saphenous thrombophlebitis 7 years ago, 3 months after a right herniorrhaphy. After 6 weeks of bed rest he returned to work and wore an elastic stocking until 1948, when he had a recurrence of thrombophlebitis in the same leg. In 1949, he had two episodes involving the same extremity. In 1950, he experienced a fourth attack of thrombophlebitis accompanied by chest pain and hemoptysis and was hospitalized. He was placed on anticoagulants and made a satisfactory recovery. Dicumarol was discontinued and he was discharged. Twenty-three days later, he was readmitted with a further attack of thrombophlebitis and it was decided to keep him on long-term therapy. Three months later, following an episode of rectal bleeding, thought to be related to hemorrhoids, anticoagulants were discontinued. Three days later he developed chest pain associated with hemoptysis and Dicumarol treatment was recommended. Therapy has been continued to date, a total of 44 months. There have been no further episodes of thrombophlebitis or pulmonary embolism, and his prothrombin time is well controlled on 50 mg. of Dicumarol per day. RHEUMATIC HEART DISEASE WITH EMBOLIZATION

Patients with rheumatic heart disease, mitral stenosis and auricular fibrillation frequently extrude emboli to the lungs and to the peripheral circulation. If a patient has had one embolus the chances are very great that he will have more. Anticoagulants have been administered to these patients continuously for periods of years, in an effort to prevent further embolization. We reported our first cases in 1947. 2 Since then confirmation has come from many other clinics including Cosgriff,a Askey 4 and Cherry and Bay 5 in this country and Owren 6 of Norway, Burt 7 of Edinburgh and Beaumont 8 of France. Only those patients who could be relied upon to follow directions carefully were accepted for long-term therapy. Adequate laboratory facilities and a physician well acquainted with the problems involved were always available. In most instances patients were hospitalized at the time anticoagulant treatment was initiated. Where there was a need for immediate anticoagulant effect, heparin was used with Tromexan and/or Dicumarol. As soon as the prothrombin complex time (Link-Shapiro modification 9 of Quick's method 10) reached 25 to 35 seconds, heparin was stopped. Oral anticoagulants were continued, dosage being estimated after the daily prothrombin complex time had been determined. By the time the patient was ready for discharge from the hospital it was usually necessary to determine the prothrombin complex time only once a week. As a result the patient needed to see his physician at weekly intervals, at which times careful note was made of any untoward reactions. On the basis of the prothrombin complex time determined at this visit, the daily dose for the following week was estimated. In some instances the patient's requirements have remained so constant that the intervals between prothrombin complex time determinations could be lengthened to fortnightly. One patient in this series has been tested monthly for six years. However, for ease of administration and safety, we advocate that the

William T. Foley, Irving S. Wright

1342

weekly interval be maintained. A prothrombin complex time between 20 and 35 seconds (with a normal range of 13 to 16 seconds) was regarded as a safe therapeutic level for patients on long-term therapy. An average of 25 seconds appears ideal for most patients. Dosage varies from patient to patient but remains fairly constant for any given patient. However, certain disturbances in physiologic balance may alter the response to the anticoagulant drug. Upper respiratory infections, diarrhea from any cause, the use of gut-sterilizing antibiotics, low food intake and alcoholic excess may at times reduce Dicumarol requirements, as shown by prolongation of the prothrombin time and occasionally by minor hemorrhagic manifestations. Table 2

THROMBOEMBOLIC EPISODES IN PATIENTS WITH RHEUMATIC HEART DISEASE

NUMBER OF PATIENTS

NOT ON ANTICOAGULANT PATIENT NUMBER OF MONTHS EPISODES

ON ANTICOAGULANT PATIENT NUMBER OF MONTHS EPISODES

TWO

OR MORE EPISODES BEFORE

25

765

113

112B

ONE EPISODE BEFORE

4

3

4

21B

THERAPY

THERAPY

o

·IN 1 PATIENTS

Twenty-nine patients had rheumatic heart disease (Table 2). All had mitral valvular disease, and 26 were in persistent auricular fibrillation. Twenty-five patients had had more than one thromboembolic complication before commencement of anticoagulant therapy. During a period of 765 patient-months dating from the first thromboembolic episode to the beginning of long-term therapy, these 25 patients experienced 113 clinically recognizable thromboembolic episodes. Of these, 32 were pulmonary, 44 peripheral, 21 cerebral, 12 visceral, three myocardial, and there was one episode of thrombophlebitis. While on anticoagulant therapy, a period of 1128 patient-months, seven of the 25 patients experienced 18 thromboembolic episodes. Six of these were pulmonary, three peripheral, five cerebral and four visceral in location. The remaining 18 patients had no thromboembolic episodes. Four of the 29 patients had single thromboembolic episodes and were

The Use of Anticoagulants~an Evaluation maintained on long-term anticoagulant therapy. During the period of 218 patient-months on treatment no episodes of thromboembolism were experienced. The following is a typical case history: Mrs. A.J. is a 43 year old housewife who has rheumatic heart disease with mitral stenosis and insufficiency, aortic insufficiency and auricular fibrillation. At the age of 6 years she had chorea. A heart murmur was discovered when she was 13; and at 21, in her first pregnancy, she developed cardiac failure. During the next 20 years she had recurrent episodes of failure and at 41, developed a left hemiparesis and a diagnosis of cerebral embolism was made. The neurological condition improved rapidly and she was given Dicumarol for 3 weeks. Seven months after this incident, evidence of gross renal infarction occurred and because of these two serious episodes and her persistent signs of failure, she was placed on long-term anticoagulant therapy. She has now had 50 mg. of Dicumarol daily for 18 months, is seen at one or two weekly intervals and is well controlled. There have been no further incidents. MYOCARDIAL INFARCTION

Thromboembolic phenomena after myocardial infarction are a major complication of this condition. The cooperative clinic study of the American Heart Association ll showed conclusively that mortality and morbidity could be greatly reduced by the proper use of these drugs. Recently, it has been suggested that anticoagulants be reserved for the "severe" cases of this disease. Myocardial infarction is notorious for masking its clinical signs and symptoms. Indeed the diagnosis is often hidden until a major thromboembolic complication focuses attention on it. We have held that it is impossible to predict the severity of such a case during the early stages and therefore advise anticoagulants for all cases unless there are contraindications. Many other investigators have now confirmed this position. Attempts have been made to forestall an impending coronary thrombosis. NichoP2 was one of the first to report on this phase of therapy. Keyes13 and his co-workers have recently reported that a group of patients given long-term therapy had a recurrence rate of 5 per cent compared to 25 per cent in a control group. Suzman14 of South Africa at the Second World Cardiac Congress (September 1955), reported a mortality of 10 per cent in treated cases compared to 33 per cent in control cases. We have had similar experiences in patients treated from one to eight years. Two groups of patients with myocardial infarction were studied (Table 3). In the first group 11 patients who had had two or more episodes of infarction were observed for 587 patient-months without anticoagulant therapy. During this time they had 49 thromboembolic episodes, 30 of which were myocardial infarctions, ten were pulmonary emboli, two peripheral, two cerebral, four visceral emboli, and there was one episode of thrombophlebitis. Under anticoagulant therapy there were but three thromboembolic episodes in the subsequent period of 393 patient-months.

1344

William T. Foley, Irving S. Wright

In the second group, 12 patients who had experienced single myocardial infarctions were treated by anticoagulants for 554 months during which period there was one questionable thromboembolic episode. An illustrative case follows: R.M., a business executive, had a myocardial infarction 8 years ago. He survived this attack and two further infarctions during the next 4 years. After this third episode it was considered advisable by Dr. E. S. Nichol of Miami to commence long-term anticoagulant therapy. The patient continued satisfactorily on Dicumarol, 100 mg. per day, and saw his physician every 2 weeks. He was able to live a normal life and to travel about the country in pursuit of his occupation. Five years ago hematuria occurred although the prothrombin time was within Table 3

THROMBOEMBOLIC EPISODES IN PATIENTS WITH MYOCARDIAL INFARCTION

NUMBER OF PATIENTS

NOT ON ANTICOAGULANT PATIENT NUMBER OF MONTHS EPISODES

TWO OR MORE EPISODES BEFORE

II

587

ONE fPlSODE BEFORE

12

41

ON ANTICOAGULANT PATIENT NUMBER OF MONTHS EPISODES

393

3

554

1('1)

THERAPY

12

THERAPY )( INCLUDES 30 MYOCARDIAL INFARCTS 10 PULMONARY EMBOU

therapeutic range. Investigation revealed a renal calculus which he later pass:)d spontaneously, whilst the prothrombin time was kept at a lower therapeutic level. On a second occasion, hematuria occurred when the prothrombin time was unduly elevated. Investigation revealed that a pharmacist had refilled his prescription giving him 100 mg. tablets of Dicumarol instead of 50 mg. tablets. His dosage was thus unwittingly doubled. A blood transfusion and intravenous vitamin K, however, quickly restored the prothrombin time to a safe level. Three months ago while in a distant city, because of a genitourinary complaint he discontinued Dicumarol and the prothrombin time became normal. A few days later he developed severe substernal pain and died a few hours later. ACUTE ARTERIAL OCCLUSION

Following embolism or other form of acute occlusion of an artery to a limb, the blood flow in the affected capillary bed is very sluggish. While awaiting collateral blood flow to be established there is great danger of thrombosis in situ in the capillaries and veins of this area. This danger

The Use of Anticoagulants~an Evaluation

1345

can often be successfully combated by the prompt use of anticoagulants. Propagation of the embolus or thrombus can also be stopped. CEREBRAL VASCULAR DISEASE

Tlhis is a neglected field of medicine. The problem is enormous. It is estimated that there are 1,800,000 victims of strokes alive today. Cerebral arteriosclerosis is second only to schizophrenia as the leading cause for oomission to state mental hospitals. This ~es a grea;t challenge and the use of any means to combat it is worthy of trial. Lyager l9 has re"Cently reported on 100 cases of apoplexy in Sweden and suggests the use of an ticoagulan ts. In 1945 Wright reported the first experiences with anticoagulants in a patient with a cerebral embolus. In 195015 a small series of cases was described in these pages by us. Since then many more patients have been treated. 16 The use of these drugs is based on the following argument: (1) to prevent new emboli from forming in the heart or aorta; (2) to prevent propagation of the original thrombus or lodged embolus which might occlude additional branches of the involved artery, thus increasing the size of the infarcted area; (3) to prevent the development of additional thrombi in other vessels, a common occurrence in the brain, and (4) to encourage the more rapid disintegration of the original thrombus by the enzyme systems in the blood, which may have a freer action in the presence of adequate anticoagulant therapy. There is also another good argument for giving anticoagulant drugs to these patients. Most of them are severely ill and confined to bed. Many have an increased tendency to thrombosis; phlebitis, pulmonary embolism and other thromboembolic episodes are quite common. In the Cornell Division of Bellevue Hospital, in a ten year period, 98 patients with cerebral vascular diseases were autopsied. More than half of them had major thrombi elsewhere in addition to their cerebral disease (Table 4). The differentiation between cerebral hemorrhage and cerebral thrombosis is discussed elsewhere in this issue (page 1360). It is extremely important to make a proper diagnosis, since one would not wish to give anticoagulants to a patient with a fresh hemorrhage. Fifty-seven patients have been studied (Table 5). They were observed for 795 months after their first thromboembolic episode. During this time they had a total of 205 subsequent intravascular clots, including 81 in the brain. Then therapy was commenced and continued for a total of 1162 months. During this time 2.3 clotting complications took place, including six in the brain. Many of these occurred during interruptions in treatment. Millikan, Siekert and Shick2Q recently reported the successful use of anticoagulants in the basal artery syndrome.

William T. Foley, Irving S. Wright

1346

Table 4.

MAJOR THROMBOEMBOLIC EPISODES IN 98 PATIENTS WITH CEREBRAL VASCULAR DISEASES AUTOPSIED AT BELLEVUE HOSPITAL. 1942 - 1952

TOTAL NUMBER OF PATIENTS

46

52

DIAGNOSIS

CEREBRAL THROMBOSIS OR EMBOLISM

CEREBRAL HEMORRHAGE

PATIENTS WITH COMPLICATIONS

NUMBER OF MAJOR THROMBOEMBOLIC COMPLICATIONS

23

50

17

23

Table 5

SUMMARY

NUMBER OF PATIENTS

PATIENT MONTHS

TOTAL THROMBOEMBOLIC EPISODES

CEREBRAL VASCULAR

BEFORE ANTICOAGULANT THERAPY 57

795

205

81

DURING ANTICOAGULANT THERAPY 57

1162

23

6

CEREBRAL EMBOLISM IN RHEUMATIC HEART DISEASE

The most definitive results have been in the group of patients who have had emboli to the brain from fibrillating rheumatic hearts. Thirtyone patients have been studied 16 (Table 6). In the period of 463 months after their first thromboembolic episode, they experienced 137 clotting

The Use of A nticoagulants ~an Evaluation

1347

episodes of which 46 were cerebral. In the 709 months of treatment this was reduced to 11 episodes, four of which were cerebral. An illustrative case report follows: L.B., a woman 38 years of age, developed rheumatic fever at 4 years of age. From then until she was 12 she had multiple attacks of rheumatic fever with the development of a heart lesion. In 1941, she developed auricular fibrillation, was found to have mitral stenosis with cardiac decompensation. In February 1946, she had a severe saddle embolus. She was then given heparin for 2 weeks. The embolus apparently divided, descending into both legs, and leaving her with occlusion of the major arteries above the knees bilaterally. In 1946, between February and June, she suffered six embolic episodes again involving her legs Tahle 6 THROMBOEMBOLIC WITH

EPISODES

RHEUMATIC

BEFORE

IN

HEART

ANTICOAGULANT

31

PATIENTS

DISEASE

THERAPY

NUMBER OF PATIENTS

TOTAL PATIENT MONTHS

TOTAL THROMBOEMBOLIC EPISODES

CEREBRAL VASCULAR

31

463 MONTHS 19 DAYS

137

46

DURING ANTICOAGULANT 31

709MONTHS 22 DAYS

THERAPY 11

4

and also her abdomen and brain. In September 1946, she had another embolus to her right foot, and again one to both legs. On November 2,1946, she developed a cerebral embolus which produced dizziness, diplopia, slurring of speech, involuntary twitching of the right arm, occipital headaches and loss of convergence of the left eye. She was admitted to the New York Hospital on November 3 and Dicumarol was started at that time. She remained in the hospital for 1 month. She was then ambulatory. Her average weekly requirement of Dicumarol was slightly above average. She needed approximately 900 mg. per week to maintain a level between 28 and 35 seconds. She had no further emboli and led a rather active life for the next 3 years. She neglected her prothrombin schedule. She would come in for tests only at infrequent intervals and after much urging. Suddenly she had a massive embolus and died. Her prothrombin time on that day was 19 seconds, far too low to give her protection. CEREBRAL ARTERIOSCLEROTIC DISEASE

Nineteen patients (Table 7) who suffered from cerebral vascular accidents believed to be on the basis of embolization arising from a mural

William T. Foley, Irving S. Wright

1348

thrombus secondary to myocardial infaretion/ or to thrombo:;is of cerebral arteries, were treated with antieoagulant:;. Eighteen of these patients suffered 13 myocardial infarctions preeeding other thromboembolic episodes; some thromboembolic episodes did oeeur at therapeutic levels. Thirteen of the 19 patients were hypertensive. In 248 months and 1:3 days before anticoagulant therapy 48 thromboembolic episodes occurred, 25 of which were cerebral. During 287 patient-months (a longer period of anticoagulant therapy) the same patients suffered only eight thromboembolic episodm!, of which two were cerebral, as in the cases of old rheumatic heart diseas()~a striking reduction. Table 7

THROMBOEMBOLIC WITH

NUMBER OF

PATIENTS

GENERALIZED

PATIENT MONTHS

BEFORE 19

EPISODES

IN

PATIENTS

ARTERIOSCLEROSIS

TOTAL THROMBOEMBOLIC EPISODES

CEREBRAL VASCULAR

ANTICOAGULANT . THERAPY

248 MONTHS 13 DAYS

287 MONTHS 10 DAYS

25

48

DURING ANTICOAGULANT 19

19

8

THERAPY

2

As in patients with rheumatic heart disease, there i:; a striking relationship between the recurrence of thromboembolic incidents and the intermittent use of anticoagulants. There were seven patients in this group in whom anticoagulants were used intermittently, and in each instanee interruption of therapy was followed by recurrence of thromboembolic complications. The following case illustrates graphically these relationships: M.A. (Fig. 166), a 53 year old white man, at the age of 50 experienced his first myocardial infarction, which was mixed in type. He was admitted to New York Hospital and anticoagulants were begun July 20, 1950, effective levels being reached within 72 hours, but dropping below therapeutic levels on six occasions. The patient made a satisfactory recovery and was discharged after 30 days. Anticoagulants were discontinued at that time. Seven months later the patient suddenly developed pain and coldness in the left lower extremity from the knee down; anticoagulants were not given. Eleven months after this episode he de·

The Use of Anticoagulants-an Evaluation MYOGA~DIAL

PE.hIPil:..R.AL

l£.H£Bh'AL

INrARCilQN

[filBOlUS

( /,1BOLUS

o

4

I

8

12

I

16

20

134B AGE 5)

I

24

I

28

I

32

36

40

44

PATIENT MONTHS

~=

D

ANTICOAGULANT THERAPY

= NO

ANTICOAGULANT

THERAPY

Fig. 166. Relationship of intermittent use of anticoagulants to recurrent thromboembolic episodes as shown by patient M.A.

veloped evidence of a left hemiparesis, which was transient, the only residual being a left facial weakness. Eight months later the second myocardial infarction occurred in the posterior base, and the patient was again placed on anticoagulants, thil! time for 40 days. On discharge, anticoagulants were again discontinued and 3 months later he developed sudden coldness and pain in the entire right lower extremity; an embolus was removed from the right femoral artery and anticoagUlants were reinstituted. The patient has remained under this therapy since that time (11 months 20 days) without further incident. IMPENDING CEREBRAL INFARCTION

There is increasingly strong evidence that vasospasm can occur in the cerebral vessels just as it does elsewhere in the vascular tree. We see many patients who have a series of transient or "little" strokes which may range in severity from slight numbness or weakness of the side of the face, or slight difficulty with speech, to hemiplegia, and which may last for from a few minutes to several days, with complete recovery. They may recur repeatedly in the same day. Some of these may be due to minute thrombi, but many, probably a majority, are based on temporary spasm of the arteries involved. These phenomena have been too caSltally regarded in the past. They frequently presage a major paralysis, with all of its potential tragedy. The frequency with which such reactions are immediately preceded by intense emotional strain or disturbance suggests that in some instances there is a direct relationship, but in other instances no such relationship can be established. Treatment has the best chance of being effective if undertaken promptly, as in the following case: L.S.; an 82 year old woman, vigorous and active for her years, suffered an acut2 myocardial infarct in February 1947 (Fig. 167). She was hospitalized for 3 months and maintained on anticoagulants during that period. She returned home and Was able to carry on her usual mild social activity without symptoms of

Williarn T. Folcy, Irving S. Wright

1350 MYOCAROIAL IfilFARCTION

AGE 84 CEREBRAL VASCULAR

o

14

21

ACCIDENT

28

35

42

49

PATIENT

~ (

::::: ANTICOAGULANT

] ':" NO

56

63

70

77

MONTHS

TH(RAPY

I\.NTIC0~GUtANT

THERAPY

Fig. 167. Relationship of intermittent use of anticoagulantR to recurrent thromboembolic episodes as shown by patient L.S. cardiac disease. She continued well until November 1948, when three times in the course of one day she experienced a sensation of numbness with loss of light touch involving the left side, including her face, arm, trunk and leg. Each attack was progressively longer and more pronounced. Sensory perception was otherwise normal. Her muscular strength and reflexes remained normal. It appeared probable that she was threatened with impending cerebral thrombosis associated with an underlying condition of arteriosclerosis. A sludge formation may have developed repeatedly, only to break up and pass through a narrowed lumen, such as Knisely has demonstrated in dogs, or a spasm of the vessel may have occurred repeatedly. She was placed on heparin and Dicumarol. All numbness and sensory changes disappeared within 48 hours. The patient remained in the hospital until February 19. She then returned home and has remained on Dicumarol therapy (6 years). Her blood prothrombin clotting time is tested weekly. Her average daily dose is 25 to 50 mg. There has been no return of cerebral symptoms or signs of thromboses elsewhere.

It is difficult to evaluate a new mode of therapy. After nine years of clinical experience it appears possible to prevent repeated embolizations from rheumatic hearts and to prevent thromboembolic phenomena in other parts of the body in patients ill with cerebrovascular accidents. Serious clots have apparently been avoided in patients with impending infarction. It is impossible to state conclusively whether the propagation of thrombi has been intercepted. To accumulate additional evidence on this point a comparative group of control and treated patients is under study.

IMPROVEMENTS IN TECHNIQUE

The technique of administering these drugs has undergone considerable change. Heparin is now available in highly concentrated form. As much as 20,000 units in 1 cc. of solution may be given by deep subcutaneous injection (Figs. 168 and 169). Excellent anticoagulant activity

The Use of A nticoagulants-an Evaluation

1351

Fig. 168

.

~

\

I::

o

\

"

\

'" .. a.o ou'" "

.~

~

...... ;::I

..... o

Il)

E

~

"

1\ \

-...........

10

~

Hours after injection 10

I::

o

"

.~

" '3'a.o ~

"

~u "

.....

o Il)

20

E

.~

E-< ..

I1

/

/

/

/

/

/

/

/

1\

\

\

\\

10

\

11

\

\

U

"", Il

14

Hours after injection

Fig. 169

Fig. 168. Intravenous administration of heparin 7500 units in a 150 pound man. Fig. 169. Subcutaneous administration of 20,000 units of concentrated heparin to each of a group of patients.

1352

William T. Foley, Irving S. Wright

may be expected starting one hour after giving the injection and lasting for 14 to 20 hours. It is not as painful and its effects are more reliable than the older forms of heparin mixed with gelatin and glucose, given intramuscularly. Unfortunately, the report of heparin activity by the sublingual route could not be substantiated. Heparin-like products, such as paritol, have proved to be too toxic for clinical use. The number of oral anticoagulants has greatly increased. In addition to Dicumarol many other coumarin derivatives are now available. Of these Tromexan is quicker acting and more rapidly ex~reted. Marcumar acts about as quickly as Tromexan but is slowly excreted. The phenylindanedione derivatives act rapidly and are excreted quickly. They give urine an orange tint that may he confused with hematuria. It is advisable for the physician to become thoroughly familiar with the actions of any drugs he may wish to use. For long-term therapy, Dicumarol has thus far been the drug most widely employed. Antidotes have improved. Vitamin KI given orally in a dose of 20 mg. will usually reduce unduly elevated prothrombin times to a therapeutic level in a period of six hours. Slightly quicker action can be obtained by intravenous injection, but this is rarely necessary. The preparation is an oil and has to be given in an emulsion over a period of hours. This method, therefore, has little advantage over the oral route. The antidote to heparin is protamine. One hundred milligrams will counteract the effect of apprmcimately 10,000 units of heparin. It is very rarely needed because the action of heparin is usually so brief. Whole fresh blood may be used to counteract bleeding from heparin or coumarin derivatives. Stored blood is less satisfactory. ENZYMES

The use of parenteral trypsin has been advocated as a means of treating intravascular thromboses. Certain pharmaceutical companies have widely propagandized its use and many physicians are employing it, even though it has not been sanctioned by the Council on Pharmacy and Chemistry. In our laboratory (Table 8),17 and in that of Tagnon 18 and others, it has been found that intravenous trypsin is a very strong thromboplastic agent. Only when a high concentration has been reached in the body does it become an anticoagulant and then it makes the blood incoagulable. Most of our experimental animals died when given trypsin, from pulmonary emboli or from hemorrhagic effects. In the small doses now recommended for subcutaneous or intramuscular use no measurable effect can be noted in our experience. Numerous inflammatory reactions have occurred. We do not advocate its use. CAUTION

A word of caution should be given. Anticoagulant therapy should be undertaken only by physicians who have mastered the technique. They

The Uge of Anticoagulants-an Emluation

1353

must be willing to devote the time and effort needed to follow each case in minute detail. A reliable laboratory must be available. Only intelligent, {'ooperative patients should be given long-term therapy. The patient must be tested frequently. Antidotes must always be on hand. The physician cannot take a day off or a vacation unless he is covered by another physician equally skilled in the technique of this therapy. As a Table 8

Effect of small and large amounts o'f intravenous trypsin Gn the blood coagulation mechGn;sm J

Trypsin

AntiPro- Calcium thrombin PrO GJ!loride thrombin Glofl/ng Clotting convertln Time time Time Time Time (QUICK'S (OWREN'S Method i Method)

-

-.

..

Control 4.§mins. 85secs. 45 sees. 27sees. 58secs. 15mg. 120mo.

5mlns. .82 secs. 48 sees. 28 secs. CD

CID

CD

11

Fi~riri-

ogen II1'g. "/.

Total Protein

,m.-I_

-.

-. 270 11

/6 sees. 57 secs. Absent'

- .5.1

'''

.-

4.8

-.

reward for thtis painstaking effort, many patients not amenable to any other form of treatment can be maintained as useful citizens. SUMMARY The use of anticoagulants is of established value in pulmotiary' embolism, vhlebitis, my~cardial infarction, and embolization in rheumatic heart disease. It is of value in the prevention of thromboembolic complications sHer cerebral thrombosis. It is of probable value in the prevention of impending myocardial infarction. It is uRder experimental study in the treatment of acute cerebral thrombosis and in impending cases of this disorder. There have been improvements in heparin administration. New, effective oral anticoagulants are available. Vitamin KI is of value as an oral antidote. The use of trypsin given parenterally is not recommended. REFERENCES 1. (a) Barker, N. W. and others: Use of Dicumarol in Prevention of Postoperative Thrombosis and Embolism. Surgery 17: 207, 1945. (b) Zilliacus, H.: On the Specific Treatment of Thrombosis. Acta med. Scandinav. (Suppl.) 1946. 2. (a) Wright, I. S. and Foky, W. T.: Use of Anticoagulants in Treatment of Heart Disease. Am. J. Med. 3: 718, 1947.

1354

r. S.: Long-Term Anticoagulant Therapy for Cardiovascular Diseases. Am. J. M. Sc. 217: 136, 1949. (c) Foley, W. T. and Wright, I. S.: Use of Dicumarol in Office Practice. New York Med. 6: 16, 1950. (d) Wright, 1. S.: Experienccs with Dicumarol in Treatment of Coronary Thrombosis. Proc. Am. Fed. Clin. Res. 2: Dec. 29, 1945. Cosgriff, S. W.: Prophylaxis of Recurrent Embolism of Intracardiac Origin. J.A.M.A. 143: 870, 1950. Askey, J. M. and Cherry, C. B.: Thromboembolism Associatcd with Auricular Fibrillation. J.A.M.A. 144: 97, 1950. Bay, E. M. and others: Use of Anticoagulant Drugs in Ambulatory Patients. Circulation 2: 741, 1954. Owren, P. A.: International Congress of Thrombosis and Embolism. Basel, July, 1954. Published by Schwabe & Co., Basel, Switzerland, 1955. Burt, C.: Ibid. Beaumont, J. L.: Ibid. (a) Shapiro, S.: Hyperprothrombinemia. Exper. Med. & Surg. 2: 103, 1944. (b) Brambel, C. E.: Thromboplastic Reagent. Arch. Surg. 50: 137, 1945. Quick, A. J.: Hemorrhagic Diseases and Physiology of Hemostasis. Springfield, Ill., Charles C Thomas, 19.14, p. 312. Wright, 1. S., Marple, C. D. and Beck, D. F.: Myocardial Infarction. New York, Grune & Stratton, 1954. Nichol, E. S. and Page, S. W.: Dieumarol Therapy in Acute Coronary Thrombosis. J. Florida M. A. 32: 365, 1946. Keyes, J. W., Drake, E. H., Jones, T. N. and Smith, F. J.: Survival Rates after Myocardial Infarctions with and without Long-Term Anticoagulant Therapy. Am. J. M. Sc. 226: 607, 1954. Suzman, M. M., Ruskin, H. D. and Goldberg, B.: Evaluation of Continuous Long-Term Anticoagulant Therapy on Progress of Myocardial Infarction. Second World Congress of Cardiology, Washington, D. C., 1954. Foley, W. T. and Wright, 1. S.: Treatment of Cerebral Thrombosis and Embolism with Anticoagulant Drugs. M. CLIN. NORTH AMERICA 3: 909, 1950. (a) McDevitt, E., Foley, W. T. and Wright, I. S.: Gerinnungshemmende Substanzen in der Behandlung der Zerebral-Thrombose und Embolie. Med. Klin. July 24, 1954, Nos. 29 and 30. (b) Wright, I. S. and McDevitt, E.: Cerebral Vascular Diseases. Ann. Int. Med. 41: 682, 1954. (a) Taylor, A. and Wright, 1. S.: Intravenous Trypsin. Circulation 10: 331,1954. (b) Taylor, A., Overman, R. S. and Wright, 1. S.: Studies with Intravenous Trypsin. J.A.M.A. 155: 347, 1954. Tagnon, H. J.: Nature of Mechanism of Shock Produced by Injection of Trypsin and Thrombin. J. Clin. Invest. 24: 1, 1954. Lyager, T.: Causes of Death in Cerebral Apoplexy. Nord. Med. 54: 1315, 1955. Millikan, C. H., Siekert, R. G. and Shick, R. M.: Use of Anticoagulant Drugs in Treatment of Insufficiency or Thrombosis within Basilar Arterial System. Proc. Staff Meet., Mayo Clin. 30: 116, 1955. (b) Foley, W. T. and Wright,

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Williarn T. Foley, Irving S. Wright

2 E. Fifty-fourth Street New York 22, N. Y. (Dr. Foley)