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HEPARIN VERSUS DEXTRAN IN THE

PREVENTION OF DEEP-VEIN THROMBOSIS

A Multi-unit Controlled Trial *

Summary Eight surgical units cooperated in a

Summary controlled clinical trial of intravenousdextran 70 and low-dose subcutaneous heparin in theprevention of deep-vein thrombosis (D.V.T.). Sodium

heparin was given subcutaneously 2500 units twohours before operation and 5000 units twice dailyuntil the seventh postoperative day. The infusionsof dextran 70, 500 ml., were given at operation and onthe first and second postoperative days. Control

patients received no specific prophylaxis. D.V.T. was

diagnosed by the 125I-fibrinogen test in 37 % of con-trols, 25 % of dextran patients, and 12 % in the heparingroup. Heparin was significantly more effective thandextran. The presence of malignant disease wasassociated with a higher incidence of D.V.T., but itdid not affect the relative efficacy of either agent.There was no significant difference in measured blood-loss between the groups. 8 pulmonary emboli werereported-4 in controls, 3 in the dextran group, and1 on heparin. All emboli were minor except in 1control patient who died of massive embolism. The

regimen of low-dose subcutaneous heparin was moreeffective than that of intravenous dextran 70 in

preventing D.V.T.

Introduction

VENOUS thromboembolic disease is a common andincreasing cause of morbidity and mortality in hos-pital patients.1-3 Prophylaxis offers the main hope ofreversing this trend. Specific methods of prophylaxishave been tested almost exclusively in surgical patientsbecause in this group the period of maximum risk canmost readily be identified. The problem now facingthe surgeon is no longer whether he should applyspecific prophylaxis for a patient undergoing a majoroperation but rather which method to apply.

Prophylactic methods can be broadly divided intotwo groups-pharmacological and mechanical. Amongthe many pharmacological methods which have beenadvocated the strongest claims have been made forintravenous dextran4-7 and for low-dose subcutaneous

heparin.11-13 To our knowledge these two agentshave not been compared in any large-scale controlledclinical trial in a general hospital surgical population.We describe here a randomised controlled clinicaltrial in surgical units of the Edinburgh region in whichselected regimens of dextran 70 and heparin werecompared.* The following took part in the trial: Mr I. M. C. MACINTYRE,

Dr C. VASILESCU, Mr D. R. B. JONES, and Mr C. V. RUCKLEY(Western General Hospital, Edinburgh); Mr D. R. HARPER,Mr A. I. S. MACPHERSON, Dr J. DOWNIE, and Dr W. P.BRADFORD (Royal Infirmary, Edinburgh); Mr P. M. RAINEand Mr M. F. MCNICOL (Bangour General Hospital);Dr J. GRANT (Eastern General Hospital, Edinburgh);Mr J. CRISPIN, Mr W. B. CLARK, and Mr A. D. F. WALLS(City Hospital, Edinburgh); Mr J. WALLWORK (DeaconnessHospital, Edinburgh); Dr P. TOTHILL, Dr J. D. SIMPSON,Mrs M. PAREKH, Mr C. M. FERRINGTON, and Mr N. LAUDER(departments of medical physics at the Royal Infirmaryand Western General Hospital); Dr R. J. PRESCOTT (depart-ment of community medicine, University of Edinburgh).

Patients and Methods

Eight units in six hospitals took part. The specialtieswere general surgery (four general surgical including onegastrointestinal unit), gynaecology (three units), andthoracic surgery (one unit). In each unit a registrar orsenior registrar undertook responsibility for the trial. Itwas coordinated by a research assistant.

Selection of Patients

Any patient over the age of forty undergoing a majoroperation was considered for inclusion. A major opera-tion was defined as one performed under general anms-thesia and likely to last for half an hour or more. Patientsin the following groups were excluded either because ofrelative low risk, technical reasons concerned with the 151scanning, or because surgeons wished to be free to takespecific prophylactic precautions: patients below the ageof forty, with gravitational ulcers, undergoing emergencyoperation, thyroid operation, left mastectomy, operationon a lower limb, or splenectomy, or taking an oral

contraceptive. ’

Hospital ethics committees examined and accepted theprotocol. The nature and purpose of the trial was ex-

plained to each patient. Written consent was obtained.

Treatment RegimensControl patients received no specific prophylaxis.Sodium heparin (’ Pularin ’) was given by subcutaneous

injection, 2500 units two hours before operation and5000 units twice daily until the seventh day. The injec-tion was made by a standard technique through a 25-gauge needle into a skin fold of the anterior abdominalwall.A four-hour intravenous infusion of dextran 70

(’Dextraven’) 500 ml. was begun in the anaesthetic room.Further infusions of 500 ml. were given on the first andsecond postoperative days.

Diagnosis of Deep-vein ThrombosisThe diagnosis of D.v.T. was by the 125I-fibrinogen test la

using the technique and criteria described elsewhere.

Statistical Design and Organisation °

For each of the units participating in this trial a

separate list of allocations to control, heparin, or dextrantreatment regimens was prepared. A system of restrictedrandomisation was used to prepare each list so that therewas no possibility of any unit contributing an excessivenumber of patients to any treatment group. The alloca-tions were placed in numbered envelopes, which remainedsealed until a firm decision was made to enter a patientinto the trial. The next envelope in sequence was thenopened to determine the treatment.

Once a patient had been entered into the trial, he orshe was monitored to conclusion, and the data recordedon precoded forms, regardless of whether the allocatedtreatment regimen was correctly followed or not. Thiswas considered an essential safeguard (although often

disregarded in published clinical trials) not only to preventbias but because failure to follow a particular regimenmust be considered as a feature of its clinical application.To be worthwhile, it was felt that the trial should have

at least an 80% probability of detecting a statisticallysignificant difference at the 0-05 level if either treatmentwas capable of halving an assumed frequency of D.v.T.of 35% in control patients. This demanded a trial withat least 360 patients. In practice the trial continueduntil 386 patients had been observed.

Results

386 patients were included-control 128, heparin

119

TABLE I-SPECIALTY, AND AGE AND SEX DISTRIBUTION OF PATIENTS

. average ages ou, 3.), ana tu, respecuvety.

TABLE II-RISK FACTORS BY TREATMENT

——————————————————————!————————t————————t________

128, dextran 130. The division according to specialtyis shown in table i, as is the comparability of thetreatment groups for age and sex. Treatment groupswere broadly similar for potential risk factors (table 11).The scanning records of 5 patients were lost. Thusthe analysis of the ’I-fibrinogen tests comprises 381cases (table m).

D.V.T.

D.v.T. was significantly less common in the patientstreated with heparin (12%) than in either of the othergroups (p<0’05). The frequency of D.v.T. in thedextran group (25&deg;&deg;) was lower than in controls

(37%), but this difference was not significant (table ill).The results by treatment were very similar in the

general surgical and thoracic units, but the frequencyof D.V.T. in the gynaecological cases was considerablylower. The numbers in the gynaecological series weresmall, and no statistical significance can be attachedto the apparently different effect of dextran in this

group.Malignant disease was recorded in 107 patients in

the series. D.v.T. was much more common in these

patients, but the effects of the prophylactic agentswere not altered by the presence of malignant disease(table iv).

TABLE III-l2sl SCANS RELATED TO SPECIALTY AND TREATMENTGROUP

Pulmonary Embolism

Pulmonary embolism was diagnosed in 8 patients.4 of these were controls: in 2 the diagnosis was con-firmed by perfusion lung scan and in 2 it was con-firmed at necropsy (massive embolism being thecause of sudden collapse and death in a man of fifty-six who had had an operation for peptic ulcer).Embolism was reported in 3 patients in the dextrangroup and 1 in the heparin group. Each was a minor

episode, and, since lung-scanning facilities were notavailable in the hospitals concerned, these were

clinical diagnoses only.

ComplicationsThe planned treatment regimen was prematurely

stopped in 15 patients. The dextran regimen was notcompleted in 2 patients because of human error andin 2 because the surgeon was concerned about bleed-

ing. The heparin regimen was discontinued in 11

patients: in 7 this was because at operation or in theearly postoperative period the surgeon was concernedabout bleeding, 1 patient was transferred to anotherunit where the clinician refused further heparin, theheparin regimen in 1 was converted to full therapeuticlevels, and in 2 the regimens were stopped in error.

TABLE IV-MALIGNANT DISEASE

The protocol required that whenever bleedingappeared to be excessive, blood should be obtainedfor a thrombin clotting-time. In the 3 patients inthe heparin group in whom this request was observed,this investigation was normal.

Surgeons were asked to record blood-loss by swab-weighing and measurement of suction volume. Thiswas recorded for 63% of patients and these showedno significant difference in blood-loss between thethree groups (table v). The observation of those

taking part was that the operations in which measure-ments of blood-loss were not recorded (37%) werethose in which the blood-loss was trivial. If this is

so, the comparison between the three groups will notbe misleading as the blood-loss was recorded to a

similar extent for all treatments.1 patient in the heparin group developed a terminal

bleeding state after complications following vagotomyand gastrojejunostomy for duodenal ulcer. The blood-

sample was technically unsatisfactory, and adequatelaboratory tests of coagulation could not be done, so

120

we cannot say whether heparin contributed to theoutcome.

Discussion

Many regimens for dextran and heparin administra-tion have been used. We are concerned to find pro-phylactic methods which are not only effective butalso practical. Dextran has been described as provid-ing effective prophylaxis if given simply on the day ofoperation.’ At the other end of the scale intermittentinfusions for up to twelve postoperative days havebeen advocated.4 The dextran regimen of 3 dayschosen for this study was a compromise correspondingto the normal duration of intravenous therapy in ahigh proportion of patients undergoing major opera-tions.

Similarly, a variety of regimens for heparin admini-stration have been described.8-12 There is evidencethat a thrice-daily injection may be the most effective.16However, increased bleeding has been reported fromother studies in which this regimen was usedl-i3 Wetherefore decided to test a twelve-hourly regimen inthe hope of retaining efficacy while lessening dis-comfort and risk of bleeding for the patient and work-load for the nurses.The preoperative dose of 2500 units of heparin was

chosen to try to avoid excessive operative blood-loss.Sharnoff considers that this dose should reduce therisk of bleeding while retaining a prophylactic effect 1’

Patients tolerated the regimen well, and no statisticalevidence of increased bleeding was forthcoming ineither the heparin or the dextran group. Bleeding con-tributed to death in 1 patient in the heparin group,but the critical hxmatological data were lacking inthis case. We believe that further studies are requiredto determine whether a few individual patients mightbe susceptible to bleeding problems on heparinregimens which would be safe for the majority. Ideallyit would be prudent to ensure that patients beingtreated with a pharmacological prophylactic agentshould have a pretreatment coagulation screen,including a platelet-count, prothrombin-time, andthrombin clotting-time.We have shown that low-dose subcutaneous heparin

was highly effective in reducing D.V.T. Furthermore,a seven-day course of subcutaneous heparin was

clearly more effective than a three-day course ofintravenous dextran. Dextran should not be dismissedas ineffective on this evidence since alternative regi-mens may be appropriate in different individuals orgroups of patients. Furthermore, the effects of bothheparin and of dextran when combined with otherpharmacological or mechanical methods require study.There is currently no universal prophylactic method.The results of this trial are only important if a

direct relationship exists between 111-fibrinogen-diagnosed D.V.T. and major thrombosis and embolism.Data concerning the extent and time of onset ofthrombosis and their relationship to clinically detectedD.V.T. and pulmonary embolism have been separatelypunch-carded for statistical analysis and will bedescribed elsewhere. Meanwhile a growing body ofevidence, albeit indirect, suggests that prevention of"2’1-fibrinogen-detectable thrombus in thigh and calf

will prevent the development of both postphlebiticsymptoms 18 and embolism.19,20

’ When asymptomatic thrombus is shown by the 1251-fibrinogen test to affect popliteal or femoral veins, therisk of clinically detectable embolism is reported to beapproximately 40%, whereas calf-vein thrombosiscarried a very low risk.19 Furthermore, evidence fromprospective studies in which patients were monitoredby 125I-fibrinogen scanning has shown an incidence ofpulmonary embolism of approximately 10% in thosepatients with positive leg scans, while there were noclinically detectable emboli in those with negativescans 2&deg; Entirely consistent with this evidence is ourfinding that all 8 emboli reported in this trial developedin patients within that group of 25 % of the series whohad positive 125I-fibrinogen scans.

This trial would not have been possible without the co-

operation of the consultant surgeons and gynaecologists of theparticipating units. We also thank the members of the South-Eastern Regional Hospital Board for their support. Prof.A. P. M. Forrest and Mr A. N. Smith provided support andfacilities in the Department of Clinical Surgery. Fisons Ltd.and Evans Medical Ltd. provided generous assistance. Secre-tarial help was provided throughout by Mrs M. Ramsayand Mrs M. Stuart.

Requests for reprints should be addressed to Mr C. V.Ruckley, Department of Clinical Surgery, Western GeneralHospital, Edinburgh EH4 2XU.

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D. P., Crellin, R. Q., Wessler, S., Yin, E. T. ibid. 1972, ii, 101.12. Gallus, A. S., Hirsh, J. Tuttle, R. J., Trebilcock, R., O’Brien,

S. E., Carroll, J. J., Minden, J. H., Hudecki, S. M. New Engl.J.Med. 1973, 288, 545.

13. Gordon-Smith, I. C., LeQuesne, L. P., Grundy, D. J., Newcombe,J. F., Bramble, F. J. Lancet, 1972, i, 1133.

14. Flanc, C., Kakkar, V. V., Clarke, M. B. Br. J. Surg. 1968, 55, 742.15. Milne, R. M., Gunn, A. A., Griffiths, J. M. T., Ruckley, C. V.

Lancet, 1971, ii, 445.16. Corrigan, T. P., Kakkar, V. V., Fossard, D. P. Br. J. Surg. 1974,

61, 320.17. Sharnoff, J. G. Personal communication, 1973.18. Browse, N. L., Clemenson, G. Br. med. J. 1974, ii, 468.19. Kakkar, V. V., Howe, C. T., Flanc, C., Clarke, M. B. Lancet,

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" The really important questions about the cosmos have notbeen answered, or even asked, in this book, full though it is ofdiscussions by learned cosmologists. This avoidance is basicallybecause such questions are so difficult to answer as to be a realembarrassment, so we shrug them off by the traditional replythat science is inherently unable to cope with them ... to answerthe impossible questions I have listed above, it would seem

necessary to jettison the scientific approach, if only because thebases of these questions do not appear to involve processesobservable from our limited vantage point on earth. This makesme extremely suspicious. If we accept that the scientific approachhas been highly successful in extending our understanding of theuniverse about us ... then why should it fail for questions of thiskind ? Could it be that the questions themselves are somehowinvalid ? "-Prof. JOHN TAYLOR in Cosmology Now; p. 157.London: British Broadcasting Corporation. 1974. E2.75.