The clinical usage of heparin

Panel Discussion II The Clinical Usage of Heparin Moderator:

E. GREY DIMOND, M.D., F.A.c.c.,

WILLARD J. ZINN, M.D., F.A.c.c.,

Los Angeles

that tobacco-smoking affected the heart adversely and suggested that, if coronary artery disease is present, tobacco be eliminated or avoided. Why was this statement made? There appear to be several reasons. We know that nicotine increases the heart rate and may increase the blood pressure by the mechanism of peripheral vasoconstriction. I was very pleased a few weeks ago to note that the work of Dr. H. J. White and his co-workers of the Veterans Administration Hospital in West Roxbury, Massachusetts, had been reported in an interview. These investigators demonstrated that nicotine increased elastolysis of bovine aorta slices treated with elastase, and that heparin tended to provide a protection against elastolysis; this protection was decreased when nicotine was added to the heparin. This study has implications concerning the relationship of tobacco-smoking to atherosclerosis and coronary disease. For example, it was shown that nicotine inhibited the lipid-clearing and anticoagulant actions of heparin in rats. If this work can be confirmed in man, we may at last know or believe that we know, that there is a biochemical reason to say that nicotine is harmful. DR. DIMOND: Are you using heparin for long term therapy? If so, what is the range of dosage and the frequency of administration? Are you using Depoheparin@? DR. GRIFFITH : It is my opinion that Depo-heparin is archaic and should not be used. It is in a gelatinlike substance, and the gel itself is harmful. The volume of the injection is too great, and the tendency to create a hemorrhage is prohibitory. Aqueous heparin is the preparation of choice. It should be used in as concentrated solution as possible, specifically 40,000 units/cc. Using this concentration, 0.25 cc. may be placed into the subcutaneous fat, and this results in slow absorption, which is desirable. DR. DIMOND: Dr. Lyons, does heparin aid in the treatment of the complications of diabetes? Since heparin is a polysaccharide, does it act as a sugar and require more insulin, or does heparin actually

DR. DIMOND: Dr. Bauer, what problems are encountered in the use of heparin in the menstruating female patient? Assuming she is normal insofar as her reproductive organs are concerned, is there any endometrial problem involved if the use of heparin Is it safe to do a dilatation and is to be considered? curretage in a woman who is on heparin? DR. BAUER: In my experience, bleeding from the female organs is not a contraindication for the use of heparin. DR. LYONS: One should never perform a transurethral prostatectomy unless the Lee-White clotting time is normal. DR. DIMOND : Extending the question which is in most of our minds, let me ask if a surgeon generally hesitates to take a heparinized patient into the operating room? DR. BAUER: This issue seldom arises, since it is so infrequent that surgery is necessary within two or three hours after an intravenous dose of heparin. After three hours the concentration is so low that one can operate without fear of excessive bleeding. Of course, one can use protamine sulfate if necessary. DR. LYONS: I am maintaining four or five female patients on heparin, which they take at home in doses of 200 mg. twice weekly. One has peripheral vascular disease, is 35 years old and menstruates regularly. We have not thought it necessary to alter her heparin dosage in accordance with her menstrual cycle. We have other female patients who have reacted in a similar manner. We have had no complications. DR. DIMOND: There is a distinct group of women with mitral valve stenosis who have had peripheral emboli. These women, still menstruating, are taking various anticoagulants without difficulty. Dr. Griffith, would you please comment on the subject of nicotine as a heparin-inhibitory agent, and then on the possible relationship of smoking, (if nicotine is indeed a heparin-inhibitory agent) to the increased incidence of cardiovascular disease among heavy smokers? DR. GRIFFITH : Two years ago, after many years of deliberation, the American Heart Association stated

JULY 1964

La Jolla, California

WILLIAM J. DONALDY, M.D., Cleveland, Ohio THOMAS P. LYONS, M.D., San Jose’ SAMUEL I. RAPAPORT, M.D., Los Angh

GUNNAR BAUER, M.D., Mariestad, Sweden HYMAN ENGELBERG, M.D., F.A.c.c., Los Angeles GEORGE C. GRIFFITH, M.D., F.A.c.c., Los Angeles

49

polentiatc insulill? Is there any predictable change in the required dose of insulin in a diabetic to whom heparin is administered? DR. LYONS: It is our impression that heparin is of great benefit in diabetic patients. In our work in 1950 on lipoproteins we showed that diabetics had certain patterns which developed earlier in arterioIn our now. sclerosis ; this is common knowledge office all of our intelligent diabetics arc placed on heparin, and we have found that we have been able either to reduce their insulin dosage or to maintain them entirely on oral antidiabetic therapy. DR. DIMOND: Have you seen, or do you know of patients who have been getting a consistent dose of insulin, and then who have had a definite change in their dosage requirement coincident with the administration of heparin? DR. LYONS: I know of 2 patients on heparin for two years, one taking 80 units of insulin and the other 60 units. After about the eighteenth or twentieth month of heparin therapy, both went into insulin shock and were thereafter controlled on oral medication. More recently. all medications have been discontinued, and these two patients have required no treatment other than dietary restriction. DR. DIMOND: I have been asked if I ever use the coumarin products? My comment is that I have not for the past eight years, primarily because the patients I see in my practice are referred patients. When the patient returns to his own physician, I lose control of him. Many of the referring physicians convince the patients that they should be on Coumadin@. I have accepted this as one of the hazards of giving an opinion and therefore assume that many of the patients I have placed on heparin are now taking Coumadin. Dr. Griffith, do you feel that prompt administration of intravenous heparin diminishes the possibility of an extension of an acute myocardial infarction? Is intravenous heparin indicated or effective in impending infarction? DR. GRIFFITH: I have no way of knowing whether intravenous heparin lessens the possibility of extension of a myocardial infarct. I believe, however, that collateral circulation develops better in my In regard to impending inheparinized patients. farction, my answer is, yes, I believe that heparin in adequate dosage is the most effective drug therapy we have available. I have reason to believe that intravenous heparin reduce the incidence of impending infarction advancing to actual myocardial infarction by about 10 per cent. DR. DIMOND: One of the good papers relating to this was given by Dr. Paul Wood in about 1959. He had treated people in that immediate state before infarction

known

not treating He found siderably period.

as coronary

angina that

fewer

or actual

patients

myocardial

on anticoagulants

infarctions

He based

insufficiency.

for a four

He was infarction. had con-

or five year

his data on the use of dicumarol

and hcparin and did 11ot separate the t\vo drugs; \ve can only say that anticoagulant therapy did appear to prevent the development of real myocardial infarctions. Dr. Lyons, at what level of high blood pressure do you hesrtatc to use heparin? DR. LYONS: We do use heparin in patients with hypertension. Fortunateiy, we nave some excellent drugs to control this disease, so as a general rule, if the systolic blood pressure is 200 mm. Hg or more when the patient is first seen, the hypertension is treated first. I like the pressure to remain below 200 mm. Hg systolic before beginning long term heparin therapy. DR. GRIFFITH: I agree with Dr. Lyons. I do, however. take the diastolic pressure; and if we have a persistent diastolic pressure of 110 or above, then we must be hesitant. If, however, we have a patient with hypertension and that patient has evidence of cerebral arterial insufficiency, I believe he should be given a trial with heparinization. Recently an ophthalmologic group in Philadelphia has studied a series of patients with hypertension and retinopathies. They placed these patients on heparin and expressed the belief that the retinopathies of the treated patients cleared more rapidly than in the nonheparinized individuals. Ophthalmologists use heparin in retinal artery thrombosis in patients with hypertension. They do this almost without any restriction insofar as the high blood pressure is concerned. DR. LYONS: I would use heparin on any hypertensive person, but not necessarily in full anticoagulating doses. It is my opinion that the clearing factor is of more importance than the anticoagulation. I maintain my opinion that giving a hypertensive person a full dose of any anticoagulant is potentially fraught with disaster. DR. DIMOND : One indication for the use of heparin may have been mentioned earlier. Today frequent consideration is given to the need for a right ventricular catheter pacemaker in the treatment of acute myocardial infarction with heart block, and in such situations we have no hesitation in doing a venous cutdown for insertion of the catheter. We feel the heparin effect is desirable. Another such example is the vast number of patients having arteriotomies and venous cutdowns during cardiac catheterization, when heparin is given deliberately. During these procedures we make incisions into arterial pressure chambers with no hesitation. Dr. Griffith, has heparin ever been prepared as an aerosol or an unction? DR. GRIFFITH: Dr. Dolowitz has spoken of its use in certain dermatologic lesions. I know of a group in this community where certain skin diseases are treated by an unction of heparin. DR. DIMOND : This is intended effect.

Is there

DR. GRIFFITH:

any effect

for a local cutaneous

on the Lee-White

time?

No, none whatever.

DR. DIMOND: Do you all know that the White of the Lee-White

time is the great Paul Dudley

White

in his

I’HE AMERICANJOURNAL OF CARDIOLOGY

Panel

Discussion

II

days as a house officer at the Massachusetts General Hospital? This is one of his first papers. Dr. Zinn, is there any rebound clotting tendency when long term, intermittent heparin is administered? DR. ZINN : No. The patient that I am speaking of is that patient who is on prolonged therapy, consisting of one injection daily or three injections a week. I am not concerned about the patient who is receiving heparin three times a day. We have not seen rebound in prolonged therapy. In long term heparin therapy we are concerned more with the antilipemic effect than the anticoagulant effect. When a patient is given an injection of heparin at 8 or 9 A.M., his clotting is normal by late afternoon; so I don’t see any rebound. DR. DIMOND: Dr. Bauer, at your institution, is venous ligation, either of the superficial femorals or the inferior vena cava, performed for venous thrombotic disease with embolization? DR. BAUER: No. Those operations have not been used in my clinic. We believe that with heparin we can achieve the same effect. DR. DIMOND : In 19 instances, we have used inferior vena cava ligation for persons with panvalvular disease secondary to rheumatic heart disease and who have reached that stage of tricuspid insufficiency with On 7 of such patients liver engorgement and ascites. we have catheter data which indicate a decrease in the pulmonary resistance following vena cava ligation, and we have noticed an increased sodium excretion and a return of responsiveness to mercurials for a period of 12 to 18 months. This form of therapy was first advanced by Cossio in Argentina. We have found in this group of individuals with heart failure and probably emboli, a number in whom inferior vena cava ligation was effective therapy. Dr. Griffith, if QUESTION FROM THE AUDIENCE: the majority of physicians used anticoagulants for myocardial infarction, and I am too lazy to do so, am I liable legally if the patient dies and his wife sues? DR. GRIFFITH: Several people have been sued, and it has been settled by the insurance company on the basis of the usual practice of the physicians in that community. This I think is wrong. If you believe that you do not know how, do not want to take the responsibility, and believe that your patient really needs it, then you are in a dilemma. If you think he doesn’t need the anticoagulant and you don’t want to use these drugs, then it’s your good judgment. If you can substantiate that, then you can beat any suit. If, however, you believe that the patient needs an anticoagulant and if he has indications for which four out of five doctors in your area would give it, then I think you would be open to

tamine zinc insulin? Does this act in some manner with heparin to bring about an adverse result? DR. ZINN: A man I took care of for ten years always mixed his insulin with heparin and had no trouble. DR. DIMOND : Dr. Griffith? would you comment on the effect of heparin on the amount of pain and hypotension in acute myocardial infarction? DR. GRIFFITH: I am sure heparin does nothing to the blood pressure. I have always had the impression that the heparinized patient, for some reason or another, has less severe pain. I think I learned this from patients with impending myocardial infarctions who progressed to completed infarcts; their infarctions were ushered in with less pain and less traumatically when they were heparinized. This is a difficult question to answer, really, because I give heparin and morphine together. I cannot say how patients in general respond to morphine alone, except my clinical impression is that certain patients experience pain that even morphine will not relieve. DR. DIMOND : Does anyone have anything he would like to add? DR. LYONS: I will slightly amend my last answer concerning the effect of an anticoagulant dose of heparin in hypertension. In addition to the relief of hyperlipemia, there is a reduction in the stickiness of the cells and the adhesiveness of the walls, which has been called sludging. I believe the relief of pain the patient experiences while receiving heparin is due to the reduction in the viscosity of the blood, thereby enabling the coronaries to obtain more oxygen at a more rapid rate. DR. DIMOND: Is there any information about the effect of exercise on endogenous heparin production? DR. GRIFFITH : There is no such information available. DR. DIMOND: Do we know how much heparin comes through the nursing mother’s milk? In the absence of any answer from the panel, it should be observed that the heparin molecule is too large to pass the placental barrier or to enter the nursing mother’s milk. DR. DIMOND: When heparin is given intravenously, how much is excreted by the kidney unchanged? DR. ENGELBERG: Studies have shown that practically all heparin is excreted in a changed form. This is mainly uroheparin and degraded heparin, with perhaps a small amount coming through unchanged if large doses are given. DR. DIMOND: Dr. Griffith, in your discussion you alluded to the theory of coronary thrombosis extension. There is some evidence that subintimal or subplaque hemorrhage is the cause of the final coronary occlusion or coronary thrombosis in many

lawsuit.

individuals.

I think

be in a position best interests

Dr.

in the same

JULY 1964

I think

you should to be in the

of the patient.

DR. DIMOND: heparin

this is wrong.

to do what you believe Zinn, syringe

adverse caused

can you mix insulin if the insulin

and

is a pro-

Do

effect by

in

rupture

you

think

that

myocardial

heparin

infarctions

of a hemorrhage

has

any

that

are

beneath

the

plaque? DR.

GRIFFITH:

My

answer

to this would

be no.

I think it prevents the thrombus forming at the site of the plaque rupture. DR. DIMONI): I am surprised that no one has cited data regarding heparin’s inhibition of thrombus formation and the fact that the oral anticoagulants do not do this. DR. GRIFFITH: Dr. Bauer mentioned the work of Carey and Williams, in which the jugular veins of dogs were injured with an electric current, and they found that thrombi formed in the injured veins of unheparinized animals. If the dogs were adequately heparinized (more than one and a half times the Lee-White clotting time prior to heparinization in this experiment) the veins did not form thrombi. Propagation of thrombi was prevented if thrombi were formed and the animal was then heparinized. Dicumarol and Tromexan@ did not prevent propagation of thrombus unless the prothrombin time was prolonged to dangerous levels. This work I think Dr. appears to be the best answer we have. Bauer should tell something about his venography work. He has done elegant work in which it has been shown that heparin tends to prevent propagation of a thrombus in living patients. DR. BAUER: We have shown this to be true on a number of occasions by performing venograms in cases of leg vein thromboses before and after hcparinization. We believe that heparin stops the formation of the thrombus immediately under such circumstances. DR. DIMOND: Dr. Engelberg, will you comment on the question we discussed a moment ago about the possible effects of heparin on the pain of coronary insufficiency and on pain during a myocardial infarction? DR. ENGELBERC : There are two comments that can One important pain-minimizing factor be made. in coronary occlusion is improved oxygenation. but for reasons other than the correction of sludging The lipemic clearing activity of hepin the blood. arin results in a more adequate oxygen transport. There is another interesting effect of heparin that I have seen in two cases, where this drug was administered in acute myocardial infarction and the pain increased or persisted. In each case the infarction appeared to be extending, and the patient’s pain persisted day after day while he was on heparin, until each begged to have the medication stopped. the infarctions extended. When this was done, Apparently what happened was that the pain originated in a threatened part of the myocardium. Heparin prevented necrosis from occurring, and pain therefore persisted as long as the myocardial tissue remained viable. As soon as the infarction actually This is rare, but it does extended, the pain stopped.

heparin,

happen. DR. DIMOND:

Dr.

effect

has been

of heparin

Zinn,

Archives of Internal Medicine, foot.

DR. ZINN : I am aware of the article, but I have not seen this complication. DR. DIMOND: A member of the audience would like to make a plea for Lee-White clotting times, when heparin is administered daily, to make sure the dose is sufficient. He suggests 150 mg. twice daily is often inadequate, and that some patients may require up to 200 mg. every eight hours in order to prolong the Lee-White clotting time to a therapeutic level of 30 minutes. I do not disagree with him, because he may be right. He is on less solid ground when he states that he thinks “the Lee-White time must be prolonged to 30 minutes.” This is a judgment rather than a statement of fact. Other members of the panel are using more heparin than we are, and perhaps one of the reasons we have seen no alarming complications other than an occasional hematoma is that we don’t use enough heparin. We use heparin for other reasons than for the anticoagulant effect, and we have not wished to sustain the Lee-White time at a level of 45 or 60 minutes immediately prior to the next dose. We use twice-daily injections. up to 300 mg. in a large person. Of course, if a hematoma develops, we promptly check the Lee-White clotting time. DR. ZINN: I would like to comment. There are problems in titrating the anticoagulant activity of heparin under the conditions of normal daily life. In attempting to assess this, we have been using clotting times or the amount of lipemia after an intrafat dose of heparin as indexes of activity. The hourto hour curves fluctuate with meals, before or after the injection, the degree of activity, even the strain of freeway driving. An arbitrary level of clotting time would be discouraging to the patient, since five or six blood samples each day would be necessary. I believe the practical problem has been solved if there is a statistical improvement in the condition of the patient on a dosage schedule such as Dr. Dimond mentioned. We do not really know the specific clotting time which is going to protect every individual. As has been pointed out, there are many variables, and the dose of heparin may well have to be changed from time to time in a given individual. DR. ENCELBERC : I would like to disagree with this. There is experimental evidence that prolongation of the Lee-White time to 25 or 30 minutes results in a therapeutic effect. In actually using Lee-White times, we should be more concerned if it is down to eight or ten minutes twelve hours after the previous injection rather than with the maximal prolongation period. There are evidently resistant individuals who require larger doses of the drug. Dr. de Takats, who has had an extensive experience with

Have you seen this?

one complication

believes

that some individuals

or side

500 to 600 mg. in twenty-four

described

recently

in the

Lee-White

namely,

burning

of the

pick

out

clotting those

times

individuals

hours.

early

require One

in the therapy

who

need

more

over

or two will than

the usual dose. THE AMERICANJOURNAL OF CARDIOLOGY

Panel

FXscussion

DR. LYONS: I agree with Dr. Dimond and also with Dr. Griffith? who mentioned giving morphine Practicality dictates and heparin at the same time. that chest pain has to be treated, and I don’t believe that one should wait for laboratory results before accomplishing this. DR. DIMOND: Dr. Bauer, in a patient who has had a pulmonary embolus with hemoptysis, do you proceed with heparin and papaverine therapy? DR. BAUER: Certainly, we do proceed in exactly the same fashion. DR. DIMOND : Do the patients bleed more if you give them heparin? If they have a pulmonary embolus with hemoptysis and heparin is administered, is the amount of blood lost by way of the sputum increased? DR. BAUER: I have not observed this. DR. DIMOND: I would like to ask if anyone taking heparin has complained of unilateral transient I have read articles on the use tinnitus or deafness. of heparin in treating tinnitus. DR. LYONS: There was an article in one of the journals which stated that a patient developed tinnitus and vertigo with partial hearing loss following heparin therapy. The author’s conclusion was were rather an assumption : that the complaints caused by the release of fats into solution, thus plugging up the minute, hairlike vessels. DR. DIMOND : Dr. Griffith, does pericardial hemorrhage occur more frequently in patients with acute myocardial infarction who are getting heparin? DR. GRIFFITH: No, it does not. We do not stop our heparin unless cardiac tamponade occurs, and if we tap the pericardium, and if bleeding continues it is then time to give surgical treatment; we then cut the amount of heparin so that the Lee-White time is near normal. DR. DIMOND : Dr. Griffith, in those patients whom you reported, you had seven fatalities. Were these during the first few years or the last few years of your How long after heparin had been given were series? the seven fatal occurrences in the series of 115 patients? DR. GRIFFITH : Most were in the first five years of Most

the series.

of the patients

do very well,

espe-

cially after they survive five years. DR.

DIMOND :

Dr. Griffith,

of a collapsed

vertebra

administration

of heparin?

have

in a man

you ever heard

resulting

from

In this patient,

the

aged 50,

there was no history of trauma. DR. GRIFFITH:

No, I cannot

and-effect

relation

vertebra,

but

anatomic DR.

between

perhaps

information BAUER:

Dr.

conceive

heparin Bauer

of any cause-

and collapse would

have

of a some

to contribute.

This

has

not

occurred

in my ex-

DR. DIMOND : onist, is heparin

Dr. Dolowitz,

as a histamine

of value in treating

DR. DOLOWITZ : JULY 1964

DR. DIMOND: Dr. Griffith, is it tribe that in your series you excluded all deaths such as those from cerebral accidents? Our patients were all with myocarDR. GRIFFITH: We did not include any other illnesses dial infarctions. in this series, and the seven deaths all occurred either from recurrent myocardial infarction or serious cardiac arrhythmia. DR. DIMOND: Dr. Zinn, you mentioned patients on chronic anticoagulation with coumarin who deYou stated veloped acute myocardial infarctions. that you then began heparin, and you mentioned the of Christmas factor.” problem of “the depletion Why do you single out this one of the four vitamin K-dependent clotting factors? I single out the Christmas factor priDR. ZINN: marily because this was found to be important by Dr. Grieg, who published a paper on this subject in The Lancet. would you care to DR. DIMOND : Dr. Rapaport, comment on the dangers that may be present in the administration of heparin to a patient with Christmas factor depletion? DR. RAPAPORT: A good general rule is that if you have one cause for failure of coagulation or failure of hemostasis, you may encounter another cause as well. I would think this would apply to all the factors; but PTC might be singled out because the activation of this factor is inhibited by heparin, and therefore this factor might play a more important role if a low level is present when heparin is given. DR. DIMOND: When I talked about this, I meant that I had not yet seen it as a clinically dangerous situation. I still feel fairly confident about giving heparin to an individual who has been on prolonged anticoagulant therapy and who has had a recurrent I have not seen dangerous bleeding infarction. from this form of treatment. Dr. Bauer, is there a return of normal function of the venous valve after venous thrombosis is resolved? DR. BAUER: No, I do not think so. If a vein is fully occluded by a thrombus, then organization The valves are sets in, followed by recanalization. thin and delicate in structure and are imbedded in the thrombus matrix so that in every instance when the vein becomes recanalized, it is not healed as a normal vein, but as a thick tube with thick walls and no valves. DR. DIMOND : If the valve function does not return, then do you recommend ligation for postphlebitic syndromes? DR. BAUER: That depends upon what the symptoms are. The valves cannot be repaired. A specific vein may be ligated, but this must be done under very strict rules of indication. DR.

perience.

No.

migraine?

antag-

53

IT

deep one

DIMOND :

A patient

or superficial, week

old

or

still acute and active.

with

is not seen more.

The

thrombophlebitis, until

the process

thrombophlebitis

What is your treatment?

is is

I)R.

BArmiK: l’hat \WUlct dCpc”d 011 wtlclllcl~ (II< was sup~~rlicial or deep. If the thrombosis is deep, I would start heparin immediately. If the patient had a little episode of thrombosis in the lower leg, subsiding by itself, nothing of necessity is to be If the phlebitis involved the big saphenous done. vein, I would do nothing at all. DR. DONALDY: Flow long, Dr. Bauer, after venous thrombosis would it take for full recanalization to occur? DR. BAUER: We must recognize that time is different in different patients. The shortest time I process

Ilavc, heard of is two yrarb. but I kno\v it usually takes a f~:\v years more, perhaps five or ten. Drx. IIIMOND : ‘l’here are a few questions left pertaining to the Danish report of no decrease in morbidity or mortality of patients on heparin. All we can do is state that there have been, particularly in the last few years, indications that anticoagulants, either heparin or coumarin, are not having useful clfects. The editor of the anticoagulant section in the IY~ar i30orl on Cardiovascular Diseases this year makes the point that in any form of therapy as controversial as anticoagulants, something must be wrong.

End of Symposium

THE

AMERICAN

JOURNAL

OF CARDIOLOGY