LOW-DOSE HEPARIN - PRESENT STATUS AND FUTURE TRENDS

158.

P R E S E N T A N D FUTURE TRENDS

LOW-DOSE HEPARIN - P R E S E N T STATUS A N D FUTURE TRENDS

V .V . KAKKAR Thrombosis Research Unit, King's Col lege Hospital Med ica l School, Denmark Hi l l , London S E 5 8RX, Uni ted Kingdom.

Venous thromboembolism i s a frequent complication i n hospitalised

patients. Apar t from the immediate risk to l i fe, one must also consider

the late sequelae of extensive deep vein thrombosis - swell ing of the

legs, varicose veins, ulceration, and other trophic changes which

represent an equal ly distressing situation. The morta l i ty due to thrombo-

embolic disease can be ef fect ive ly controlled, on ly when a simple, safe

and ef fect ive method of prophylaxis i s ava i lab le . One o f the promising

approaches, which fu l f i l l s most of the cri teria demanded by an ideal

prophylact ic agent, i s the use of low-dose subcutaneous heparin.

I n this paper three topics w i l l be discussed : - evidence w i l l be

presented which c lear ly demonstrates that low-dose heparin prophylaxis

i s h igh ly e f fect ive not on ly i n preventing the occurrence of deep vein

thrombosis but also deaths due to fa ta l pulmonary embolism; the risk

o f bleeding complications w i l l be defined when this form o f prophylaxis

i s used, and last ly the future developments which are l i ke l y to reduce

or e l iminate the risk o f haemorrhage when this form o f prophylaxis i s

used on a large scale i n patients undergoing a variety of surgical ope-

rations.

Eff icacy o f Low-Dose Heparin Prophylaxis

1 . Prevention o f deep vein thrombosis

Dur ing the last few years, 27 c l i n i ca l trials o f low-dose heparin

prophylaxis i n a var ie ty o f pat ient populations have been reported. The

greatest experience has been acquired i n patients undergoing general

abdominal, thoracic and urological operations. The results of 17 such

trials i n patients undergoing abdominal surgery are shown i n Table 1 .

159.

PRESENT A N D FUTURE TRENDS

Table 1 : Effectiveness o f low-dose heparin i n the prevention of postoperative deep vein thrombosis.

Control Group Heparin Group Statist ical

No .o f DVT No.o f DVT Patients (%) Patients (%) (p value)

Sign i f i ca nce

Kakkar e t a l . (1 971)

Wil l iams e t a l . (1 971) Kakkar e t a l . (1 972)

Gordon-Smith e t a l . (1 972)

Nicholaides e t a l . (1 972)

Ga l lus e t a l . (1 973)

Bal lard e t a l . (1 973)

Corrigan e t a l . (1 974)

Scottish study (1 974)

Rosenberg e t a l . (1 974)

Ga l lus e t a l . (1 976) lnterna t ional M u l t i - centre Trial (1975)

Lahnberg e t a l . (1 974)

Rem e t a l . (1 975)

G e I ove n (1 975)

A bernethy (1 974)

Covey (1 975)

27

29

39

50

122

118

55

434

128

71

412

667

54

80

52

26 26

41 27

42 39

42 48

24 122

16 108

29 55

27.8 320

37 128

42 46

16 408

24.6 625

56 58

35.8

25 79

4.8

9.6 53

4 < 0.05

15 < 0.02

8 c 0.001

8.3 <0.001

0.8 -

2 < 0.001

3.6 <0.001

7.1 < 0.005

12 < 0.001

6.5 CO.001

4.2 (0.005

7.7

19 < 0.001

-

13.3 -

5.9 < 0.001

6.3 > 0.05

7.5 >0.05

160.


Despite variations i n the study designs and regimen of low-dose heparin

used, i n 15 studies there was evidence of a signif icant reduction o f the

incidence o f deep vein thrombosis i n patients having heparin. In the

two exceptions, there was a very low incidence of thrombosis reported

i n control patients and the incidence i n the heparin-treated group was

not reduced below that leve l to any signif icant extent .

Low-dose heparin prophylaxis has been found to be equal ly e f fect ive

i n reducing the incidedce of deep ve in thrombosis i n patients who

confined to bed fo l lowing a myocardial in farc t ion. One o f the f ive s tdes

investigating a rather small number o f patients showed no signif icant

benef i t whi le in others, a highly signif icant reduction i n the incidence

o f thrombosis was observed i n patients receiving prophylaxis (Table 1 1 ) .

are

Table II : Low-dose heparin prophylaxis, myocardial in farc t ion and deep vein thrombosis.

Control Group Heparin Group Statist ical

(p value) No. o f DVT N o . o f Patients (%) Patients (%)

D V T Significance

Handley e t a l . 24 29 26 23 NS (1 972) Gal lus e t a l . (1 973)

40 22.5 38 2.6 <0.025

Warlow e t a l . 64 17 63 3 < 0.025 (1 973) Emerson and Marks 41 34 37 5 c 0.005 (1 977) Marks and Teather 37 34 37 3.4 cO.05 (1 978)

Similarly, low-dose heparin prophylaxis has also been shown to reduce

the incidence of deep ve in thrombosis i n patients who are confined to

bed fo l lowing an acute stroke. I n these randomly a l located studies

reported b y McCarthy e t a l . , the incidence i n 16 acute stroke patients

i n a control group was 75 % and this was reduced to 12.5 YO i n those

receiv ing heparin (p 0.05).

161.


The experience accumulated i n patients undergoing orthopaedic

operations demonstrates less evidence o f benefits than i n other groups

o f surgical patients. I n two o f six reported studies, no signif icant

benef i t was observed i n patients receiving heparin whi le i n the other

studies, the reduction from 50 % incidence of deep ve in thrombosis

i n the control group to approximately 20 % i n those receiving heparin

was much less impressive than the benef i t observed i n patients under-

going major abdominal surgery (Table 1 1 1 ) .

Table I l l : Effectiveness o f low-dose heparin i n prophylaxis o f deep vein thrombosis i n patients undergoing tota I h ip replacement.

Morris e t a l . (1 974) Hampson e t a l . (1 974) Venous Thrombosis C l i n i c a l Study Group (1975) Mannucci e t a l . (1 976) Kakkar e t a l . (1 972) Evarts and A l f i d i (1 973) Dechavanne e t a l . (1 974) Sagar e t a l . (1 976) Harris e t a l .

Hume e t a l .

(1 974)

(1 973)

Control Group

N o . o f DVT Patients I%)

32 50

52 54

27 40

46 39

18 39

27 48

32 69

- -

19 42

Heparin Group

N o . o f DVT Pa t ien ts W)

27 1 1

48 46

25 1

45 18

15 27

25 28

27 32

25 32

20 55

18 33

1 62.


One o f the reasons for the fai lure of prophylaxis i n these patients was

that torsion o f the femoral vein took place during surgery as the h ip

was dislocated, and the l imb was in ternal ly rotated. Similar damage

to the femoral vein also occurs when a posterior approach i s used for

h ip replacement. I t i s l i ke l y that such distorsion o f the femoral vein

results i n extensive in t imal damage, thus exposing the sub-intimal tissue

to p la te le t interaction. Such an interaction i s not affected by low-dose

heparin; hence, the fa i lure i n preventing the development of thrombi.

I I . Prevention o f extension o f deep vein thrombosis

The natural history o f post-operative venous thromboembolism

non-orthopaedic surgical patients has been investigated w i th the - f ibrinogen test and phlebography. I t has been found that the majori ty

o f thrombi form i n the ca l f veins. I f one were to investigate 1000pt ien ts

o lder than 40 years o f age undergoing major abdominal surgery, approxi-

mately 300 would develop isotopic deep vein thrombosis i n the ca l f

veins; a surprisingly high proportion would undergo spontaneous lysis,

and only i n about one-third of these patients would the thrombi extend

more prox imal ly form the ca l f in to the popli teal, femoral and i l i a c veins.

I t i s not known for certain i n how many of such patients w i th extending

thrombi pulmonary emboli occur because i t i s d i f f i cu l t to diagnose such

emboli accurately; however, on ly a small proportion (+ - 0.5 %) prove

fa ta l . Thus wh i le prevention o f venous thrombosis i s o f fundamental im-

portance, the e f fec t o f prophylaxis on the incidence of extending thrombi

i n the proximal veins o f the lower limbs i s o f considerable significance,

since such thrombi are the source of most major pulmonary emboli . The

ef fect of low-dose heparin prophylaxis on the extension of venous th romh is

has been evaluated i n more than 3000 patients undergoing e lect ive surgery

(Table IV). O f 1631 patients i n the control group, thrombi were detected

i n 380, and extension o f thrombus occurred i n 99, an incidence of 6.0%. O f 1,479 i n the heparin group, thrombi were detected i n 5 5 , and extension

occurred i n on ly 0.6 %. Aga in there was a signif icant reduction i n the

incidence o f extensive thrombi l i k e l y to produce major pulmonary embolism

i n heparin treated patients, not bn ly i n the aggregates of the 4 studies,

but also i n each ind iv idual t r ia l .

i n 1 251

Ta

ble

IV

:

Eff

ect

of

low

-do

se

he

pa

rin

on

th

e

pro

xim

al

ext

en

sio

n o

f th

rom

bi

in t

he

p

op

lite

al,

fe

mo

ral

an

d i

lia

c v

ein

s in

pa

tie

nts

un

de

rgo

ing

ab

do

min

al

surg

ery

.

Co

ntr

ol

Gro

up

H

ep

ari

n

Gro

up

No.

of

DV

T

No.

wit

h

No.

of

Pa

tie

n ts

E

xte

nsi

on

P

ati

en

ts

Co

rrig

an

et

al.

(1,974)

423

121

29

320

Nic

ho

laid

es

e

t a

l. (1972)

122

29

9 128

Ga

llu

s e

t a

l. (1975)

408

66

12

412

lnte

rna

tio

na

I M

u1

tic

en

tre

66

7 164

49

625

To

ta I

1631

380

99

1485

Pe

rce

nta

ge

23.3

6

Tri

al (1975)

Ta

ble

V

:

Lo

w-d

ose

h

ep

ari

n a

nd

po

st-o

pe

rati

ve

fata

l p

ulm

on

ary

em

bo

lism

. In

clu

din

g a

ll p

ati

en

ts.

Co

ntr

ol

Gro

up

No

. o

f p

ati

en

ts

Fa

tal

pu

lmo

na

ry e

mb

olis

m

C o

n t r

i bu

tory

To

ta I

2250

16 (

p<

0.005)

9 25

(p < 0.005)

DV

T

No.

wit

h

Ext

en

sio

n

23

1 11

0

13

3 48

5

95

9

5.79

0.6

He

pa

rin

Gro

up

222

1 3 3 6

73

XI

rn

VI

rn Z

-I >

Z u


I l l . Prevention o f fatal and non-fatal pulmonary embolism

I n the f ina l analysis, a cruc ia l question concerns the e f fec t of low-

dose heparin i n the prevention of fatal and non-fatal pulmonary embolism.

This end-point has been evaluated i n several studies (Table V) . lh most

important and largest o f these was a multicentre, prospective, randomised,

control led tr ial , the results o f which have been published i n de ta i l else-

where (Int. Mul t icent re Tr ia l 1975). This t r ia l was conducted i n 28 centres,

each o f which had a separate l is t o f al locations to randomise patients

in to control and heparin groups. The heparin-treated patients received

calcium heparin, 5,000 units subcutaneously, 2 hours pre-operatively and

8 hourly for 7 days or longer un t i l they became ambulant. Patients i n

the control group d id not receive placebo inject ions.

po in t of the study was fa ta l pulmonary embolism diagnosed a t autopsy.

The fatal pulmonary embolism was defined when massive fresh emboli

were present i n the main pulmonary trunk, main pulmonary artery, or

i n a t least two lobar arteries, demonstrated a t post mortem i n patients

i n whom no other cause o f death was found. This study involved 4121

patients over the age o f 40 years undergoing a variety o f e lec t i ve maior

surgical procedures; 2076 of these were i n the control group and 2045

received heparin. The 2 groups were we l l matched for age, sex, wei$t,

blood group and other factors that could predispose to the development

o f venous thromboembolism. During the postoperative period, 180 p t i e n t s

(4.4 %) died, 100 i n the control group and 80 i n the heparin group.

Necropsies were performed on 72 % o f the patients who died i n the

control group and 66 % of those who d ied i n the heparin group. Sixteen

o f the control patients and 2 i n the heparin group were found to have

d ied from massive pulmonary embolism (p< 0.005). In addition, the &Ii

found a t necropsy i n 6 patients i n the control group and 3 i n the heparin

group were considered to have been either on ly contr ibutory to death or

acc identa l findings, since death i n these patients was attr ibuted to other

causes.

Taking a l l pulmonary emboli together the findings were again signif icant

(p< 0.005).

The major end

165.

P R E S E N T A N D FUTURE T R E N D S

N o therapeutic t r ia l has ever escaped some form of adverse criticism;

most cer ta in ly this i s true of a l l the trials invo lv ing the evaluation of

anti-thrombotic agents. Therefore, i t came as no surprise when the va l id i ty

o f the results o f the mult icentre t r ia l was cri t icised. These have been

admirably summarised by Dr . Sherry i n the proceedings o f a conference

sponsored b y N I H (Sherry 1975). The criticisms related to the fo l lowing

points : the premature termination of the trial; how comparable were two

groups; the difference i n the total mor ta l i ty i n the two groups was not

significant; the autopsy rate was not h igh enough to avoid imbalances

between autopsied and non-autopsied cases, and the errors in p t b l q ' c a l

interpretat ion could have inf luenced the results. These criticisms have

already been adequately answered (Kakkar 1979; Kakkar 1975). Since

more than two thirds o f the patients who died had autopsies performed

b y competent pathologists, bias was un l i ke ly to inf luence the result

when death was used as a primary endpoint, and therefore the conclusion

that low-dose heparin reduced the rate o f fa ta l postoperative pulmonary

embolism was real. Furthermore, the findings reported i n the multicentre

t r ia l have now been confirmed by another large scale study invo lv ing a

to ta l o f 4352 patients. O u t o f 3984 patients correctly admitted, 1993 were a l located to receive dextran 70 and 1991 to receive low-dose

heparin. O f the 75 patients who d ied w i th in 30 days after operation,

38 had been given dextran and 37 Iow-dose heparin. Necropsy was

performed i n 33 and 32 of these cases respectively. Again on ly 3 out

o f 1991 patients in the heparin group d ied due to acute massive pulnxmary

embolism and another 3 cases had emboli which had contributed to the

patients death (Table VI) . Therefore there can be no doubt that low-

dose heparin i s h igh ly e f fect ive not on ly i n reducing the incidence o f

isotopic deep vein thrombosis but also i n preventing death due to post-

operative massive embolism.

R i s k o f Bleeding Complications

The main l imi ta t ion for using anticoagulants

thromboembolic disease i n surgical patients i s the

n the prevention of

risk o f haemorrhage.

166.


Table V I : Results of two mult icentre trials o f heparin prophylaxis.

Patients who received he pa r i n p roph y la xis

Patients d ied

Autopsy rate

Fatal PE

Contr ibutory PE

Mult icentre Trial Swiss-Sca nd ina via n (1 975) Tr ia l (1979)

2 045 1991

80 37 66 % 86 %

2 (1)" 3 3 3

* 1 o f the 74 patients, who received heparin and were excluded from

the t r ia l because randomisation was not fo l lowed, also died due to

PE.

The only def in i te cri ter ion which one can use to evaluate this risk i s

the frequency o f wound haematomo formation.

In two reported studies i n which large numbers of patients were

i nvest iga ted , a signif icant dif ference was o bse rved be tween the number

o f patients receiving heparin who developed wound hoematoma and their

control counterparts (Table VII) .

Table VI I : Low-dose heparin prophylaxis and bleeding complications : frequency o f wound haema toma forma t ion.

Control Group Heparin Group Sta tistica I Sipif icance (p value) N o . of Haematomo No .o f Hoematoma

Patients Pa t ien ts

In terna tiona I Mu1 t i - 2076 117 (5.6%) 2045 158 (7.7%) < 0.01 centre Trial (1975)

Gal lus e t a l . 412 2 (0.4%) 408 10 (2.4%) < 0.01 (1 976)

K i i l e t a l . (1 978)

653 6 (0.9%) 643 4 (0.6%) NS

167.

P R E S E N T A N D FUTURE TRENDS However, a recent double-bl ind study fa i led to confirm such a difference.

The reason for this discrepancy l i e s i n the fact that i n the international

multicentre t r ia l and the study reported by Gal lus e t a l . , heparin was

administered every eight hours wh i le K i i l e t a l . d id so every 12 hours.

Similar results have been reported by other workers.

that there i s a small but def in i te risk o f bleeding when an e ight hourly

regimen i s used, but not when a 12 hourly regimen i s fol lowed. Further-

more, the number of patients who died due to haemorrhage, who recpired

re-operation for haemorrhage or had increased bleeding during the operaticn

was similar when the 12 hourly regimen was used ( K i i l e t a l . 1978). I n

the mult icentre t r ia l nine patients d ied due to haernorrhage, f ive i n the

control group and four i n the heparin group. There was no dif ference

i n the number o f patients requiring transfusions.

I t therefore appears

A much higher incidence o f bleeding complications has been d s s e r d

i n some of the studies reported i n the Uni ted States, however (Pachter

and Riles 1977). T h i s dif ference could be due to several factors : the

plasma heparin levels af ter subcutaneous administration depend not on ly

on the molecular weight but also on the type of heparin salt used, as

w e l l as thestandard which i s used by manufacturers for the cal ibrat ion

of heparin. In two prospective, double-bl ind randomly a l located trials

i n healthy volunteers, for example, s ign i f icant ly lower plasma heparin

levels were obtained fo l lowing a subcutaneous calcium heparin in ject ion

compared w i th sodium heparin obtained from the same source and having

a similar molecular weight (Johnson e t a l . 1976; Thorns e t a l . 1976).

I n both of thesestudies, peak plasma levels fo l lowing administration o f

5,000 units (IU) o f calcium heparin (measured by a specif ic heparin

assay) were only 60-70 % of the comparable levels obtained w i th N o

heparin. I t was not simply a question o f delayed absorption; the plasma

curve fo l lowing calcium heparin was lower throughout the entire time

course o f the experiment.

+

The other factor which might have contributed to a higher incidence

o f bleeding complications i s , as previously mentioned, the standard vvhich

i s used by manufacturers for the cal ibrat ion o f heparin. Unfortunately,

two standards are used : American heparin i s cal ibrated according to

the USP unit, which i n the past has been 15 % more potent than the


international un i t (IU) established by the Wor ld Heal th Orgn isa t ion .

Most European studies have been carried out using heparin cal ibrated

i n international units. The dif ference between the two standards i s

re la t i ve ly small, but together w i th other factors, l i k e l y to a f fec t heparin

absorption, i t may give rise to much higher levels which may produce

serious bleeding.

FUTURE DEVELOPMENTS

Several new approaches are currently being investigated i n order

to improve the ef f icacy and reduce the frequency of complications

associated w i th low-dose heparin prophylaxis. These include a semi-

synthetic heparin analogue which has the capacity to selectively potentiate

the a c t i v i t y o f anti-Xa; the combination o f ha l f the amount of heparin

w i th dihydroergotamine; and the use o f low-molecular weight heparin,

which has been shown to have similar properties ( i .e . specif ic potentiat ion

o f anti-Xa). Below, I w i l l discuss the first two alternatives br ie f l y .

Semi -Synthetic Ana I ogue o f Heparin

T h i s new analogue i s isolated from the respiratory tract of horned

cat t le . I t contains no signif icant quanti ty o f heparin; rather, i t i s a

g lycon polysulphate containing approximately 95 % of galactosamine

w i th 5 % glucosamine; sulphamine groups are absent. It differs from

heparin i n that pure heparin contains no galactosamine wh i le a large

proportion o f its glucosamine and amino groups are sulphated (Sensch;

personal communication). The mean molecular weight o f the analogue

i s approximately 7,000 compared to approximately 13,000-15,000 for

most o f the commercially avai lab le heparins. The analogue has an

a c t i v i t y of about 90 p/mg (Studer and Winterstein 1951).

When heparin and the analogue were compared i n v i t ro and i n

vivo, the two drugs dif fered s t r ik ing ly i n their behaviour (Thomas e t

a l . 1977). The results of i n v ivo studies showed that both heparin

and the analogue are cleared from the c i rcu la t ion w i th similar kinetics,

and consequently, probably the same mechanisms (Lane e t a l . 1977).

169.


The ana logue was approximately three times more specif ic than heparin

i n potentiat ing ant i -Xa ac t i v i t y (Michalski e t a l . 1977). Furthermore,

the analogue behaved i n a similar manner to heparin i n several tests

o f p la te le t function but had a lower thrombin-inhibit ion capacity (Kakkar

e t a l . 1978). The e f f i cacy of the analogue i n preventing postoperative deep

ve in thrombosis was compared w i th heparin i n 200 patients over the

age o f 40 years undergoing major e lec t i ve abdominal surgery. They were

randomly a l located to either a calcium heparin or analogue regimen.

The first group received 5,000 units (IU) o f heparin administered sub-

cutaneously two hours before surgery, and then repeated every e ight

hours for the first 10 postoperative days.

7,500 units (IU) o f the analogue administered two hours before surgery

and then every 12 hours for the first 10 postoperative days. A radioactive

f ibr inogen uptake test was used to determine the incidence of postoperative

vein th rom bosis .

The other group received

Twelve of 96 patients (12.5 %) i n the heparin group developed

a deep ve in thrombosis compared to six o f 94 patients (6.3 %) who

received the analogue. Serious bleeding d id not occur i n either group

and the difference between operative and postoperative bleeding was

not stat ist ical ly signif icant. In this entire series of 190 patients, wound

haematomo developed i n three, a l l were i n the heparin group.

I n 50 patients (25 per group) plasma heparin levels, the par t ia l

thromboplastin time (PTT) and anti thrombin I l l (AT I l l ) ac t i v i t y were

measured i n samples withdrawn before, during and immediately a f ter

surgery as we l l as on the first postoperative day. The analogue had a

greater potentiat ing ef fect on AT Ill a c t i v i t y compared to heparin ; the

difference was stat ist ical ly signif icant (p< 0.005) (Fig. 1). Signi f icant ly

higher (p( 0.005) mean plasma heparin levels were obtained i n patients

receiving the analogue than i n those receiving heparin (Fig. 2). Ye t

there was no difference i n the prolongation o f the PTT observed

i n the two groups when measured b y the c lo t t ing assay (Fig. 3 ) .

These findings provide further evidence for our prel iminary observations

that heparin analogue selectively potentiates AT I l l ac t i v i t y i n v ivo

170.


150 - 140 - - -

Q

0 z 130-

.c ; 120-

3 110- Y 7 loo-

- * Od .-

I -

Figure 1

Mean (+ S.E .M. ) Anti thrombin I l l A c t i v i t y (%) fo l lowing the administration o f 5,OO IU o f heparin (solid line), and 7,500 units o f heparin analogue (interrupted l ine). S ign i f icant ly greater increase i n the AT Ill a c t i v i t y was observed fo l lowing in jec t ion o f the analogue. (Reproduced from Thrombosis Research).

wh i le having l i t t l e e f fect on overa l l c lo t t ing . The results presented indicate

that i t i s as ef fect ive as heparin i n preventing postoperative deep vein

thrombosis.

These encouraging results provide evidence that analogue i s as effective

as heparin i n preventing the deep vein thrombosis. As already mentioned

the cruc ia l questions which the c l in ic ians would l i k e to know whether i t

i s as ef fect ive and more safe than commercial ly avai lab le heparin, that

i s i n preventing deaths due to postoperative fatal pulmonary embolism

and yet associated w i th reduced frequency o f postoperative wound haematoma

formation, To answer those questions, another multicentre t r ia l has been

171.


organised. In this double-blind, randomly a l located trial, 6,000 patients

w i l l be included. They have been randomised in to 3 groups - those receiv ing

N a heparin, Ca heparin or the analogue. Approximately 3,000 patients

have been so far included i n this t r ia l . The protocol which i s being used

i n this t r ia l i s similar to that used i n our previous multicentre t r ia l (Int.

Mul t icent re Trial 1975).

+ ++

n 0.06

1 - a E ""1 v

E

a P

.- L

0-04

0-02

1

0.005 0-005

Figure 2

Mean (+ S . E .M.) plasma heparin levels obtained af ter the administration o f 5,003 IU of heparin (solid l ine) and 7,500 units o f the analogue (interrupted l ine). Higher levels were obtained fo l lowing the administration o f the analogue compared to heparin, and the dif ference was stat ist ical ly signi f i ca n t .

1 72.

50 KCCT in Seconds

40


Figure 3

M e a n (+ S.E.M.) plasma KCCT values following injection of 5,000 IU o f heparin (solid line) and 7,500 units of the analogue (interrupted line). The difference in the mean KCCT values was not statistically significant.

1 73.

P R E S E N T A N D FUTURE T R E N D S Combi no t i on o f D i hydroergota mine and Heparin

Changes i n blood coagulation and stasis i n the deep veins o f the

lower limbs are both considered to be important factors i n the patkgnssis

o f deep vein thrombosis. I t i s therefore log ica l to propose that prophylaxis

might be better achieved by methods which minimize or el iminate both

o f these factors rather than by methods directed a t counteracting e i ther

factor a lone.

Dihydroergotamine i s a potent vasoconstrictor i n man (Ae l l ig 1975).

Its site of act ion seems to be the capacitance vessels o f the limbs alt-

there i s an associated relaxation of muscle resistance vessels; these actions

form the pharmacological basis for i ts use i n vasomotor disorders (Mellancler

1970).

The ef f icacy o f dihydroergotamine, heparin and a combination of

the two i n preventing post-operative deep ve in thrombosis has been assessed

i n three separate randomised trials invo lv ing 300 patients. The results

o f these studies have been published i n de ta i l elsewhere (Kakkar e t a l .

1979); br ie f ly , they were as follows. O f 100 consecutive patients under-

going maior abdominal surgery, 50 received 0.5 mg o f dihydroergotamine

and 50,

receiving dihydroergotamine and 4 % of those receiving heparin developed

thrombosis detected by the I-f ibr inogen test, the dif ference being

signif icant in favour o f heparin (p 0.05). Another 100 consecutive p t ien ts

undergoing major abdominal surgery were randomly a l located to a regimen

o f either 5,000 units o f heparin or a combination o f 2,500 units o f

heparin and 0.5 mgs o f dihydroergotamine. Four per cent o f the patients

receiving heparin and 6 % receiving the combination developed a deep

vein thrombosis. The remaining 100 patients underwent to ta l h ip replacement

arthroplasty; 50 received 5,000 units of heparin and 50 the combination

of 5,000 units o f heparin and 0.5 mg o f dihydroergotamine. O f the

patients receiving heparin, 52 % developed a thrombosis detected by

the I-f ibr inogen uptake test and/or phlebography wh i le 20 % o f

the other group d id so; the dif ference was signif icant i n favour o f the

combination (p 0.062).

5,000 units (IU) o f heparin. Twenty per cent of the patients

125

125

174.


CONCLUSIONS

The value o f low-dose heparin i n the prophylaxis o f postoperative

deep vein thrombosis can no longer be serioi

prophylactic the ropy can be wide I y adopted,

be easily administered, i s readi ly avai lable,

a l l , o f minimal risk. I t is basical ly o quest

ra t io .

, l y disputed. Before any

i t i s essential that i t can

of low cost, and above

on o f the benef i t : risk

There i s now good reason to be l ieve that the potent ia l benefits of

prophylact ic low-dose heparin far outweigh the risk o f haemorrhage.

A n 88 % reduction i n the incidence of fatal pulmonary embolism, for

example, can be bought a t the cost o f a 2.5 % increase i n the incidence

o f postoperative bleeding i n the form o f wound hoematoma formation.

The main question which remains to be answered i s the selection

o f patients who need prophylaxis. As i n the case i n any type o f prophylactic

therapy, large numbers o f patients must be treated so that the re la t i ve ly

few patients who would otherwise have suffered from overt disease may

benef i t . I t i s the lack o f selection o f these three out o f every 10 p t i e n t s

who may require therapy, which has prevented widescale adoption o f

the form o f prophylaxis. Before such a predic t ive index becomes a

real i ty, what should the role of the practising physician be ? As already

mentioned, low-dose heparin prophylaxis seems to meet most o f the

cr i ter ia demanded b y an ideal prophylactic agent. Its use can now be

conf ident ly recommended i n 0 1 I non-orthopaedic patients over the age

o f 40 years undergoing ma ior e lec t i ve non-orthopaedic operations, as

w e l l as high-risk medical patients.

The contra-indications for this form o f prophylaxis include a known

haemostaticdefect or a def in i te history o f bleeding disorders, an ac t ive

pept ic u lcer disease and receipt of oral anticoagulants before admission

to hospital. O the r contraindications, such as surgery under epidural

anaesthesia or for mul t ip le trauma, should be considered as re la t ive

contraindications, depending upon the number of risk factors present

predisposing the pat ient to the development of deep ve in thrombosis or

risk o f haemorrhage.

1 75.


1 .

2.

3 .

4 .

5 .

6 .

7.

8.

9 .

10.

1 1 .

Abernethy, E .A . (1974) Postoperative embolism. A prospective study ut i l is ing, low-dose heparin. Amer. J. Surg. 128, 739.

Ae l l ig , W .H. (1 975) Untersuchung uber d ie venenkonstringierende Wirkung von Ergotverbindungen am Menschen. Triangle 14, 39.

Bal lord, R.M., Bradley, Watson, P . J . and Johnstone, F.W. (1973) Low-doses o f subcutaneous heparin i n the prevention of deep ve in thrombosis a f te r gynaecological surgery. J. Obstet. Gynaec. B r i t . Cwl th . 80, 469.

Corrigan, T.P., Kakkar, V . V . and Fossard, D.P. (1974) Low- dose subcutaneous heparin - optimal dose regimen. B r i t . J. Surg. 61, 320.

Covey, T.H., Sherman, L. and Baue, A.E. (1975) Low-dose heparin i n postoperative patients. A prospective, coded study. Arch . Surg. 110, 1021.

Dechavanne, M., Saudin, F . and V io la , J. J. (1974) Prevention des thromboses veineuses. Succes de I 'h6parine b fortes doses lors des coxarthroses. Nouv. Presse m6d. 3, 1317.

Emerson, P .A . and Marks, P . (1977) Preventing thromboembolism af ter myocardial infarct ion - e f fec t of low-dose heparin or smoking. B r i t . Med. J. 1, 18.

Evarts, M. and A l f i d i , S . (1 973) Low-dose heparin prophylaxis. J. Amer. Med. Ass. 225, 515.

Gallus, A.S., Hirsh, J., Tutt le, R.J., Trebilcock, R . and O'Br ien, S.E. (1973) S m a l l subcutaneous doses of heparin i n the prevention o f venous thrombosis. N e w Engl. J. Med. 288, 545.

Gordon-Smith, I .C., Grundy, D . J., Lequesne, L.P. and Newcarbe, J.F. (1972) Control led t r ia l of two regimens o f subcutaneous heparin i n the prevention o f postoperative deep ve in thrombosis. Lancet I , 1133.

Hampson, W.G.J . , Harris, F.C., Lucas, H.K., Roberts, P.H., McCal l , I .W., Jackson, N.C. , Powell , N . L . and Staddon,G.E. (1974) Fai lure of low-dose heparin to prevent deep ve in thrombosis a f te r h ip replacement arthroplasty. Lancet I I , 795.

176.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.


Handley, A.J., Emerson, P.A. and Fleming, P .R . (1972) Heparin i n the prevention of deep ve in thrombosis after myocardial in farc t ion. B r i t . Med . J. 2, 436.

Harris, W.H. , Salzman, E.A. and Athanosoulis, C. (1974) Comparison o f warfarin, low molecular weight dextran, aspirin, and subcutaneous heparin in prevention o f venous thromboembolism fo l lowing total h ip replacement. J. Bone Jt. Surg. 50, 1552.

I - f ib r i n o w 125

Hume, A . , Kariakose, T . .and Xavier, Z . L . (1973) and the prevention of -venous thrombos-is. Arch. Surg. 108, 803.

International Mul t icent re Trial (1975) Prevention o f postoperative pulmonary embolism by low doses of heparin. Lancet I I , 45.

Johnson, E.A., Kirkwood, T.B.L. and Stir l ing, Y . (1976) Four heparin preparations : Ant i -Xa potentiat ing ef fect of heparin after subcutaneous in jec t ion . Thromb. Hoemostasis 35, 586.

Kakkar, V .V. (1979) The logist ic problems encountered i n the Mul t icent re Trial o f low-dose heparin prophylaxis. The challenges o f c l i n i ca l trials i n thrombosis. Pub. F.K. Schattauer Ver lag. Stuttgart. Newport p . 105.

Kakkar, V.V. (1975) Eff icacy o f low-dose heparin i n preventing postoperative fatal pulmonary embolism : Resu l ts of an International Mult icentre Trial. DHEW Pub l ica t ion No. (NIH) 76-866, p . 207.

Kakkar, V.V., Corrigan, T.P., Spindler, J., Fossard, D.P., Flute, P.T., Cre l l in , R . Q . , Wessler, S . and Yin, E . T . (1972) Eff icacy o f low doses of heparin i n the prevention o f deep ve in thrombosis after maior surgery. A double bl ind, randomised tr ia l . Lancet II, 101.

Kakkar, V.V., Field, E.S. , Nicholaides, A . N . e t a l . (1971) Low doses of heparin i n prevention o f deep ve in thrombosis. Lancet II, 669.

Kakkar, V .V. , Lawrence , D . , Bentley, P . , de Haas, H .A . , Ward, V . and Scully, M.F. (1978) A comparative study of low doses o f heparin and a heparin analogue i n the prevention o f postoperative deep v e i n thrombosis. Thromb. Res. 13, 1 1 1 . Kakkar, V.V. , Stamatakis, D . , Bentley, P .G. , Lawrence, D . , de Haas, H .A. and Ward, V . (1979) Prophylaxis for postoperative deep vein thrombosis. Synergistic e f fec t o f heparin and dihydro- ergotomine. J. Amer. Med. Ass. 241, 39.

K i i l , J., Axelsen, F., K i i l , J . and Anderson, D . (1978) Prqhylw's against postoperative pulmonary embolism and deep ve in thrombosis b y low-dose heparin. Lancet I, 1115.

177.


Lahnborg, G., Friman, L., Bergstrom, K . and Lagergren, H . (1974) E f fec t o f low-dose hepar in on inc idence o f postoperat ive embolism detected b y photoscanning. Lancet I, 329.

2 4 .

25.

26 .

27 .

2 8 .

29.

30 .

31 .

32 .

33 .

34 .

35 .

Lane, D.A., M icha lsk i , R . , van ROSS, M.E. and Kakkar, V . V . (1977) Comparison o f hepar in and a semi-synthet ic hepar in analogue A73025 . I . K ine t i cs o f c learance from the c i r cu la t i on o f man f o l l o w - i ng intravenous i n j e c t i o n . B r i t . J .Haemat . 37, 239.

Mannucc i , P .M., C i t t e r i o , L.E. and Panajotapoulos, N. (1976) Low-dose hepar in and DVT a f te r t o t a l h ip rep lacement . Thromb. Haem. 36, 157.

Marks, P . and Teather, D . (1978) Subcutaneous hepar in . A l o g i c a l prophylax is for deep ve in thrombosis a f te r myocard ia l infarction. P r a c t i t i o n e r 220, 425.

Me l l ander , S . (1 970) Comparat ive e f fec ts o f d ihydroergotamine and noradrenal ine on resistance, exchange and capaci tance funct ions i n the per iphera l c i rcu la t ion . C l i n . S c i . 39, 183 .

M icha lsk i , R . , Lane, D . A . and Kakkar , V . V . (1977) Comparison o f hepar in on a semi-synthet ic hepar in analogue A73025. II. Some ef fects o f p l a t e l e t func t ion . B r i t . J . Haemat. 37, 247.

Morris, G .K. , Henry, A . P . J . and Preston, B . J . (1974) P r e w t i o n of deep v e i n thrombosis b y low-dose hepar in i n pat ients undergoing to ta l h i p rep lacement . Lancet II, 797.

Mu l t i - un i t cont ro l led t r i a l (1974) A m u l t i - u n i t con t ro l l ed t r i a l : hepar in versus dext ran i n the prevent ion o f deep v e i n thrombosis. Lancet I I , 118.

N icho la ides , A . N . , Dupont, P . A . , Desai, S . , Lewis, J .D. , Douglas, S.N., Dodsworth, H. , Fourides, G., Luck, R . J . and Jamieson, C . W . (1972) S m a l l doses o f subcutaneous sodium heparin i n prevent ing deep venous thrombosis a f te r m a j o r surgery. Lancet 1 1 , 890.

Pachter, H . L . and R i les , T . S . (1977) Low-dose hepar in : b leed ing and wound compl icat ions i n the surgical pa t i en t . A n n . Surg. 108, 669.

Rem, J . , Duckert , F . and Fr idr ich, R . (1975) Subkutane k le ine heparindosen zur thromboserophylaxe i n der a l lgemeines ch i ru rg ie und uro log ie. Schwe iz . med. Wschr. 105, 827.

Rosenberg, I . L . , Evans, M., P o l l o c k , A . V . (1974) P reven t ion o f postoperat ive l e g ve in thrombosis : a comparison o f low-dose hepar in and e l e c t r i c a l c a l f muscle s t imu la t i on . B r i t . M e d . J . I, 153.

1 78

3 6 .

37 .

38.

39.

40.

41.

42.

43.

44.

45.

PRESENT A N D FUTURE TRENDS Sagar, S . , Stamatakis, J .D. , N e w i n , D., Maf fe i , F .H. , Higgins, A.F., Thomas, D . P . and Kakkar, V . V . (1976) Eff icacy of l o w - dose heparin i n prevent ion o f extensive deep ve in thrombosis i n patients undergoing total hip replacement. Lancet I , 1151.

Sensch, H . Personal communicat ion.

Sherry, S,. (1 975) Prophylact ic t rea tment o f deep ve in thrombosis and pulmonary embolism. DHEW publ icat ion (NIH) 76-866. Rest . Virgsta. p . 226.

Studer, A . and Winterstein, A . (1951) Probleme der Blutgerinnung. I . Mi t te i lung . Bestimmung des Heparins auf gerinnungsphysiologischen Wege. Helv . Physiol. Acta 9, 6.

Thomas, D.P. , Lane, D.A. , Michalsk i , R . , Johnson,E.A. and Kakkar, V . V . (1977) A heparin analogue w i th specif ic act ion on anti thrombin 1 1 1 . Lancet I , 120.

Thomas, D.P., Sagar, S . , Stamatakis, J .D. and Kakkar, V . V . (1976) Plasma heparin leve ls after administration of c a l c i u m and sodium sal ts of heparin. Thromb. Res. 19, 241.

van Ge loven , F . J . M . Personal commun ica t i on .

Venous Thrombosis C l i n i ca l Study Group (1975) Sma l l doses of subcutaneous sodium heparin i n the prevention o f deep v e i n thrombosis af ter e l e c t i v e hip operat ions. B r i t . J. Surg. 62, 348.

Warlow, C., Beatt ie, A . G . , Terry, G., Ogston, D., Kenmura, N .C .F . and Douglas, A .S . (1973) A double-bl ind t r i a l of low doses o f subcutaneous heparin i n the prevention of deep ve in thrombosis af ter myocardial in farc t ion. Lancet II, 934.

Will iams, H . T . (1971) Prevention of postoperative deep ve in thrombosis w i th perioperative subcutaneous heparin. Lancet I I , 950.

DISCUSSION

L. W i in ia : Which test do you use for the diagnosis of femoral thrombi

i n patients who have been operated on for a to ta l h ip replacement ?

V . Kakkar : Phlebography i s the only test which can be used to demxlstrate

accurate ly the absence or presence of deep ve in thrombosis. Whi le i t i s

t rue that impedance plethysmography and/or ul t rasonic methods can be

179.


used to diagnose femoral ve in thrombi; bu t the results o f such invest igat ions

are sometimes inaccurate.

M . Vers t rae te : D r . Kakkar, you had a n increase o f ant i thrombin con-

centrat ion i n the group treated w i t h hepar in and dihydroergotamine,

w h i c h was upto 122 percent, i f my memory i s correct . C o u l d you e x p l a i n

that ?

V . Kakkar : I t i s be l i eved that accumu la t i on o f a c t i v a t e d pro-coagulants

leads to thrombin generat ion. Therefore prevent ion o f stasis leads to less

generat ion o f thrombin and hence less consumption o f AT 1 1 1 . DHE i s

known to prevent poo l i ng o f b lood i n capaci tance vessels. Therefore i t

i s no t surprising that the levels o f AT I l l concentrat ion were h igher i n

the samples wi thdrawn from the femoral ve in i n the group o f pat ients

who had received DHE or DHE and hepar in compared to the contro l

group.

J . Sixma : W i t h regard to phlebography, the Amer i can data reports a n

i nc idence o f about 6 percent o f thrombosis induced b y the procedure

o f venography. Is this your exper ience too ?

V . Kakkar : The risk o f post ph lebography to large ex ten t has been

over-emphasized. i f proper precaut ions are taken, then the risk i s minimal.

O n e must use a l ow concentrat ion contrast medium, small amounts o f

w h i c h should be i n jec ted and a t the end o f the procedure, the contrast

medium should be washed a w a y from the deep veins b y i n j e c t i n g 150 ml

o f sal ine con ta in ing 2,500 uni ts o f hepar in .

J . Sixma : B u t how low ?

V . Kakka r : I n our series, the i nc idence o f post-phlebography thrombosis

has been less than 1 %. Ano the r p o i n t I wou ld l i k e to emphasize i s the

f requency o f la te onset o f venous thrombosis i n pat ients undergoing to ta l

h i p rep lacement . Several studies have now shown that many 0.f the pat ients

1 ao


undergoing to ta l h i p rep lacement deve lop thrombi a f t e r 10 operat ive days.

Therefore, the opt imum t ime for ph lebographic assessment i n such pat ients

wou ld seem to be 14 to 18 postoperat ive days.

T . Schandorf :

hepar in 3 times a day w i thou t the combinat ion. This would be the d i r e c t

D id you ever compare a group r e c e i v i n g 2,500 Un i t s o f

comparison.

V . Kakkar : I th ink that i s a very good p o i n t . W e have no t performed

such studies.

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LOW-DOSE HEPARIN - PRESENT STATUS AND FUTURE TRENDS