Prevention of Venous Thromboembolism G. Patrick Clagett, M.D., Chairman Frederick A. Anderson, Jr., Ph.D. Mark N. Levine, M.D., M.Sc. Edwin W Salzman, M.D. H. Brownell Wheeler, M. D.

enous thromboembolism is a major cause of death V and morbidity among hospitalized patients. In this setting, it has been estimated that pulmonary embolism (PE) causes death in over 100,000 patients each year in the United States and contributes to the death of another 100,000. 1 These estimates have recently been substantiated in a community-wide study conducted in 16 short-stay hospitals in metropolitan Worcester, Massachusetts, where the annual incidence of verified PE was 23 per 100,000 central Massachusetts residents with an inhospital case fatality rate of 12 percent. 2 Extrapolation of these data suggests that approximately 260,000 cases of clinically recognized venous thromboembolism occur each year in patients hospitalized in acute care hospitals in the United States. The disease is most often clinically silent with PE being unsuspected in 70 to 80 percent of patients diagnosed at autopsy, 3·4 and because of the low rate of autopsy in the United States and the failure of the Worcester study to include nonacute care facilities such as rehabilitation hospitals and nursing homes where the incidence of PE may be higher, the actual incidence of venous thromboembolism is much greater. Such considerations led to the conclusion that fatal PE may be the most common preventable cause of hospital death. 5 The rationale for prophylaxis of venous thromboembolism is based on the clinically silent nature of the disease. Both deep venous thrombosis (DVT) and PE manifest few specific symptoms, and the clinical diagnosis is insensitive and unreliable. 6 To rely upon the diagnosis and treatment of established venous thromboembolism may expose susceptible patients to unacceptable risks. The first manifestation of the disease may be fatal PE. Although anticoagulant therapy is highly effective in treating venous thromboembolism, the majority of patients who die from pulmonary embolism do so within 30 min of the acute event, too soon for anticoagulation to be effective.' Unrecognized and untreated DVT may also lead to long-term morbidity from the postphlebitic syndrome as well as predispose patients to future episodes of recurrent venous thromboembolism. An alternative to prophylaxis would be to use serial surveillance tests such as impedance plethysmography, labeled fibrino-

gen scanning, or duplex ultrasonography in high-risk patients. 8·9 Although attractive, this approach is expensive and can be applied to only limited numbers of patients at risk. 10 Most experts believe that broad application of effective methods of prevention is more cost-effective than selective, intensive surveillance.11·12 Effective prophylaxis is available for most patient groups. 13 Application of effective prophylaxis depends upon knowledge of specific clinical risk factors in individual patients as well as an awareness of the incidence of venous thromboembolism in patient categories where the risk has been defined by epidemiologic studies. Clinical risk factors include advanced age, prolonged immobility or paralysis, prior venous thromboembolism, cancer, surgical operations (particularly those involving the lower extremities or pelvis), obesity, varicose veins, congestive heart failure, and oral contraceptive use . 14-16 In many patients, multiple risk factors may be present and the risks are cumulative. For example, elderly patients with hip fractures undergoing major orthopedic surgery who remain immobile in bed after operation are among the most susceptible to fatal PE. In addition to clinical risk factors, congenital and acquired aberrations in hemostatic mechanisms that ordinarily predispose to venous thromboembolism assume even greater risk when affiicted patients are hospitalized and undergo surgical procedures. Hemostatic abnormalities include antithrombin III deficiency, protein C deficiency, protein S deficiency, dysfibrinogenemia, disorders of plasminogen and plasminogen activation, antiphospholipid antibodies and lupus anticoagulant, heparin-induced thrombocytopenia, and myeloproliferative disorders such as polycythemia vera. 17 Despite convincing evidence of the efficacy of many agents, surveys conducted in the United States, England, and Sweden document wide practice variations among physicians; approximately one half of surgeons in these countries use specific prophylaxis in less than one fifth of their patients. 18-20 A recent study of over 2,000 patients with multiple risk factors hospitalized at 16 regional hospitals showed that only one third of these patients received prophylaxis. 21 Use of prophylaxis was greater in teaching hospitals than nonteaching CHEST I 102 I 4 I OCTOBER. 1992 I Supplement

391$

Table 1- Venous Thromboembolism in Control General Surgery lbtients*

End Point

No. of Trials

DVf(FUT)t Confirmed DVf (FUT, phlebogram) DVf(FUT) (Malignant disease) DVf (FUT) (Europe)

54 20

DVf (FUT) (North America) Proximal DVf

14 16

All PE

32

Fatal PE

33

No. of Patients (With DVf/ Without DVf)

References 24-52, 70, 74, 75, 143-164 26, 28, 30-34, 36, 47, 51, 143, 145, 147, 149-152. 155, 158, 159 29, 30, 33-35, 41, 42. 45, 75. 146, 149, 152, 153, 155, 157. 161 24, 25, 27-29, 35, 37-41, 43-46, 48-50, 52. 70, 74, 75, 143-146, 149. 150. 154-157, 160-164 26, 30-34, 42, 47. 51, 147, 151-154 25, 28, 30, 33, 34, 36-38, 43, 45, 47, 145, 152, 153, 160, 162 24-35, 38, 39, 41, 42, 45, 47, 48, 50, 52. 53, 70, 74, 143-145, 151-153, 162, 163 24-36, 38, 39, 41, 42, 45, 47, 48, 50, 52-54, 70, 74, 143-145, l5H53. 162

16 37

Incidence, %

95% Limitsf;

I ,084/4,3IO 28811,507

25 l9

24-26 17-21

1591546

29

25-33

824/2,775

30

28-31

178/l,l ll 8311.206

16 7

14-18 6-8

82/5,091

1.6

l.3-l.9

4815,547

0.8

0.6-1.0

*From Clagett GP and Reisch JS." tFUT =llhrinogen uptake test. f;Conlidence limits for incidence.

hospitals. The sections that follow are based on disease states and hospital services to which patients are admitted. In each patient category, the overall risks of venous thromboembolism, as well as effective methods of prophylaxis are detailed. Although the order of presentation reflects the relative completeness with which each category has been studied, most patient groups have been studied sufficiently so the firm recommendations (grade A) can be made with regard to the benefits and risks of pharmacologic and physical methods to prevent venous thromboembolism. This area of medicine has been subjected to numerous randomized clinical trials, and level I data are abundant. Because of the completeness of data, general

agreement among studies, and the large number of trials, data will be pooled when appropriate. GENERAL SURGERY

The phrase "general surgery patient" is broad and includes any patient over the age of 40 years undergoing major abdominal surgery. In most trials, the bulk of these patients had elective gastrointestinal surgery. In many, patients undergoing gynecologic and urologic operations were included, and in some, patients having mastectomy, pulmonary operations, or vascular procedures, were also studied. Because it is not clear that the risk of perioperative venous thromboembolism is substantially different in these subgroups and because it is impossible to segregate these Table 2-Prevention of DVT After General Surgery*

Regimen (References)

No. of Trials

No. of Patients

No. of Patients with ovr

Incidence,

95%

%

Limits

Untreated This advantage might offset the expense and cumbersome aspects of dextran treatment in select patients prone to wound hematomas with LDH and in whom hematomas would be particularly undesirable. Intermittent pneumatic compression (IPC) is an attractive method of prophylaxis because there is no risk of hemorrhagic complications. These devices provide rhythmic external compression (ideally, one compression lasts about IO s/min with inflation pressures of3.5 to 40 mm Hg to the legs or legs and thighs). Intermittent pneumatic compression has not been studied as well as other agents used for general surgery patients. However, it is effective in reducing leg DVT in most general surgery patients and in high risk patients with malignant disease.2.1 In trials comparing IPC to LDH, both agents were equivalent in reducing leg DVT 31 •56 ·72 ·73 lt is not proven that IPC prevents PE in general surgery patients (as it is proven for LOH and dextran), but ifleg DVT is a valid marker for PE, this would he the case. Graded compression elastic stockings (ES) reduce the incidence of leg DVT (Table 2), but too few data are available to assess their protective effect on proximal DVr and PK Patients with malignant disease and other high-risk general surgical conditions have not been evaluated in sufficient numbers to allow any conclusion with regard to the efficacy of ES in these clinical settings. In some of the randomized trials, high risk patients were specifically excluded. 74 ·75 Further clinical trials are needed in order to assess the effectiveness of ES in such patients. Because ES are relatively cheap and free of side effects, it would also be important to know the efficacy of ES in comparison with other prophylactic methods. There are no studies in general surgery patients comparing ES to LOH or other agents. Combining ES with other prophylactic agents, such as LDH, 76 ·77 may give better protection 3945

against venous thromboembolism than either approach alone. Warfarin, given either as a fixed low dose (2 mg! day)7H or adjusted dose, to mildly prolong the prothrombin time (low intensity warfarin)49 appears effective in preventing leg OVT. However, the method is cumbersome, requires monitoring, probably requires preoperative treatment, and may be subject to bleeding complications if drug effects are not closely monitored. Because of these shortcomings and the ready availability of other effective agents, there is little rationale to use warfarin in general surgery patients except in unusual circumstances. Aspirin alone or in combination with dipyridamole is ineffective and cannot be recommended for prophylaxis in general surgery patients. 23 An appropriate preventive strategy in individual general surgery patients takes into account the risk of venous thromboembolism, the potential benefits of the various agents, and the expense and possible complications incurred by their use. 10•79 In low-risk patients undergoing minor or relatively short operations, who are less than 40 years of age and have no clinical risk factors, no specific prophylaxis other than early ambulation is necessary. In moderate risk patients who are over 40 years of age and are undergoing major operations, but who have no additional clinical risk factors, ES or LOH given every 12 h would be sufficient. Intermittent pneumatic compression would be a good alternative to these agents. In patients over 40 years of age undergoing major surgery with additional risk factors and who are at higher risk of venous thromboembolism, several effective prophylactic methods are available. Low-dose heparin given every 8 h, LMW heparin, or LOH/OHE are all effective, but the latter two agents are not available in the United States. Oextran or IPC would also be good choices in higher risk patients, particularly if they are prone to wound problems. Adding ES to any of these methods may give additional protection. In very high risk general surgery patients with multiple risk factors, combining the most effective pharmacologic methods with IPC offers excellent protection. In selected high risk patients, perioperative warfarin, as prescribed for high risk orthopedic patients, may be an appropriate choice. ELECTIVE SURGERY ON THE HIP AND KNEE AND PATIENTS WITH HIP FRACTURES

Orthopedic operations and treatment of orthopedic trauma are high risk conditions in which the most frequent cause of death is often PE. Fatal PE occurs, for example, after total hip replacement in up to 6 percent of patients who receive no antithrombotic prophylaxis. 80 The mortality of hip fractures without prophylactic therapy is over 3 percent and may be as Prevention of Venous Thromboembollsm (Clagett et al)

high as 12 percent. 80 After reconstructive surgery of the knee, the incidence of DVT is reported to be over 50 percent and may reach 80 percent. s1-1i4 Despite these figures, many orthopedic surgeons do not employ antithrombotic prophylaxis in their practice because of the fear of bleeding complications, which in the patient receiving anticoagulant therapy are all too readily assumed to be iatrogenic, or because of their dissatisfaction with the evidence for efficacy in orthopedic patients of antithrombotic regimens that in association with general surgical procedures have become standard practice. Tables 3 and 4 tabulate published studies, mostly in English, of prophylaxis against thromboembolism in which phlebography was the method of detection of postoperative DVT. The pooled data include the results of studies comparing the effect of active agents with a placebo control as well as comparisons with some other form of therapy previously established as effective. The literature is sufficiently large to permit confining analysis to such trials, without recourse to reports in which the diagnosis of DVT was less sure than when based on routine phlebography.

Elective Hip Replacement In total hip replacement (Table 3), heparin in adjusted doses, LMW heparin, and oral anticoagulants appear to be the most effective prophylactic agents available at present. Less certain protection against thromboembolism, but still a substantial prophylactic effect, is obtained with LDH, with or without DHE,

dextran, IPC, and ES. Aspirin appears to have an unequivocal but modest effect. Heparin in adjusted doses&S provides a high degree of protection against venous thrombosis after total hip replacement. The dosage of subcutaneous heparin in this regimen is adjusted to keep the activated partial thromboplastin time (APTT) in the upper normal range (for example, 31 to 36 s), 6 h after the heparin injection. This has been found to reduce the rate of proximal DVT as well as distal thrombi, an important point since large PE usually arise in large veins of the thigh. However, judging from previous clinical experience, this method may not become widely popular in view of the tedium of the laboratory control that it requires. Low molecular weight heparin has received attention in randomized trials of orthopedic patients, and the results are impressive to date. In patients undergoing total hip replacement, for example, Turpie et al86 reported a reduction in the incidence of DVT from 51 percent in control subjects to 11 percent in patients receiving LMW heparin. Proximal DVT rates of 4 to 5.4 percent have been obtained with this preparation, in contrast to 20 to 23 percent in control subjects. In a recent paper, Leyvraz and associates117 compared the adjusted dosage of unfractionated heparin, which requires laboratory control, with a fixed dosage of LMW heparin without laboratory control. The total incidence of DVT was similar in the two patient groups, but there were significant differences in proximal thrombi: 13 percent with adjusted dose unfrac-

Table 3-Prevention ofDVT After Elective Hip Replacement• Regimen (References)

No. of Trials

No. of Patients

No. of Patients with DVf

Incidence,

95%

Reduction of Relative Risk,

%

Limits

%

Untreated control subjects (86, 95, l66a-l73) Low dose heparin (85, 166a, 167, 174-176) Adjusted dose heparin (85, 87) Low dose heparin/DHE (176, 180, 183) LMW heparins (86, 87, 174, 177, 178, 182) Oral anticoagulants (175, 179, 181) Dextran 70 (171, 173, 175, 181, 183) Aspirin (170-172, 175, 179, 184) Leg compression (92, 95, 96) Elastic stockings (169, 169a)

IO

459

232

50

46-55

6

257

88

34

29-40

32

2

78

9

11

4-19

77

3

223

83

37

31-43

26

6

581

93

16

13-19

68

3

162

30

18

12-24

63

5

229

68

30

24-36

41

6

418

189

45

40-50

11

3

261

54

21

16-25

60

2

137

52

38

30-46

25

*From Gallus AS, Salzman EW, Hirsh J. Prevention of DVf. In: Colman R, Hirsh J, Marder V. et al, eds. Hemostasis and thrombosis. 3rd ed. (In press) Pooled data from trials based on routine phlebography. CHEST I 102 I 4 I OCTOBER, 1992 I Supplement

395$

Table 4-Prevention of DVT After Hip Fracture*

Hegimen (Ht>forences) Untreatt·sis. Br J Surg 1986; 73:204-08 Kline A, Hughes LE, Campbell JI, et al. Dextran 70 in prophylaxis of thromboemlx>lic disease after surgery: a clinically oriented randomized double-blind trial. BMJ 1975; 2: 10912 Gntber UF, Saldeen T, Brokop T, et al. Incidences of fatal ix>stoperative pulmonary embolism after prophylaxis with dextran 70 and low-dose heparin: an international multicentre study. BMJ 1980; 280:69-72 Muhe E. Intermittent sequential high-pressure compression of the leg: a new method of preventing deep vein thrombosis. Am J Surg 1984; 147:781-85 Nicolaides AN, Miles C, Hoare M, et al. Intermittent sequential pneumatic compression of the legs and thromlx>emlx>lismdeterrent stockings in the prevention of postoperative deep venous thromlx>sis. Surgery 1983; 94:21-5 Turner GM, Cole SE, Brooks JH. The efficacy of graduated compression stockings in the prevention of deep vein thromlx>sis after major i..'Ynaecological surgery. Br J Obstel Gynaa.il 1984; 91:588-91 Allan A, Williams JT, Bolton JP, t'l al. The use of graduated

4045

76

77

78

79 80 81

82

83

84

85

86

87

88

89

90

91

92

93

94

compression stockings in the prevention of postoperative deep vein thromlx>sis. Br J Surg 1983; 70:172-74 Wille-Jorgensen P, Thontp J, Fischer A, et al. Heparin with and without graded compression stockings in the prevention of thromlx>emlx>lic C.'Omplications of major abdominal surgery: a randomized trial. Br J Surg 1985; 72:579-81 Torngren S. Low dose heparin and sis following total knee replacement. J Bone Joint Snrg 1984; 66:194 Leyvraz PF, Richard J, Bachmann F. Adjusted versus fixeddose subcutaneous heparin in the prevention of deep vein thromlx>Sis after total hip replacement. N Engl J Med 1983; 309:954-58 Turpie AGG, Levine MN, Hirsh J, el al. A randomized c_.introlled trial of a low-molecular-weight heparin (Enoxaparin) to prevent deep vein thromlx>Sis in patients undergoing elective hip surgery. N Engl J Med 1986; 315:925-29 Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thromlx>sis after hip replacement: randomized comparison l>etween unfractionated heparin and low molecular weight heparin. BMJ 1991; 303:531-32 Bergqvist D, Kettunen K, Suomalainen 0, et al. A prospective randomized mmparison between Org 10172 and dextran 70 in hip fracture patients-thromboprophylaxis and safety [abstract]. Thromlx>s Haemostas 1989; 62(suppl):ll05 Gerhart TN, Yett HS, Robertson LK, et al. Low-molecularweight heparinoid compared with warfarin for prophylaxis of deep-vein thromlx>sis in patients who are operated on for fracture of the hip. J Bone Joint Surg 1991; 73:494-502 Chong BH, Ismail F, Cade J, et al. Heparin-induced thromlx>eytopenia: studies with a new low molecular weight beparinoid, Org 10172. BlSis [letter]. Aust NZ J Med 1986; 16:719 Paiement GD, Bell D, Wessinger SJ, et al. New advances in the prevention diagnosis and c.•>St effectiveness of venous thromboembolic disease in patients with total hip replacement. In: Brand RE, ed. The hip. St. Louis: CV Mosby, 1987; 94-119 Balderston RA, Graham TS, Bth RE, el al. The prevention of pulmonary emlx>lism in total hip arthroplasty: evaluation of low-dose warfarin therapy. J Arthroplasty 1989; 4:217-22 Coventry MB, Nolan DR, Beckenbaugh RD, et al. Delayed prophylactic antk'>agulation: a study of results and complications in 2012 total hip arthroplasties. J Bone Joint Surg 1973; 55:1487-92 Prevention of Venous Thromboembolism (Clagett et al)

15 Gallus A, Raman K, Darby T. Venous thrombosis after elective hip replacement: the influence of preventive intermittent calf compression and of surgical technique. Br J Surg I983; 70:I79 l6 Hull RD, Raskob GE, Gent M, et al. Effectiveness of inter-

17

l8

l9

lO

11

>2

l3 l4

15

l6

>7

>8

l9

.0

.I

.2

.3 .4

.5 .6 .7

mittent pneumatic leg compression for preventing deep vein thrombosis after total hip replacement. JAMA I990; 263:23I3I7 Sheppeard H, Henson J, Ward DJ, et al. A clinico-pathological study of fatal pulmonary embolism in a specialist orthopaedic hospital. Arch Orthop Traum Surg I98I; 99:65-7I Ljingstrom K-G, Renck H, Strandberg K, et al. Adverse reactions to dextran in Sweden I970-I979. Acta Chir Scand I983; I49:253 Sevitt S, Gallagher NG. Prevention of venous thrombosis and pulmonary embolism in injured patients. Lancet I959; 2:98I89 Stringer MD, Steadman CA, Hedges AR, et al. Deep vein thrombosis after elective knee surgery. J Bone Joint Surg (Br) I989; 71:492-97 Jones TK, Barnes R\V, Greenfield L. Greenfield vena cava filter: rationale and indications. Ann Thorac Surg I986; 42:54855 Roehm JOF, Johnsmde IS, Barth KH, et al. The Bird's Nest inferior vena cava filter: progress report. Radiology I989; I68:745 Fullen WD, Miller EH, Steele WF, et al. Prophylactic vena cava interruption in hip fractures. J Trauma 1973; I3:403-10 Golueke PJ, Garrett WV, Thompson JE, et al. Intermption of the vena cava by means of the Greenfield filter: expanding the indications. Surgery I988; I03:11I-I7 Vaughn BK, Knezevich S, Lombardi AV, et al. Use of the Greenfield filter to prevent fatal embolism associated with total hip and knee arthroplasty [abstract]. J Bone Joint Surg 1989; 7I:I542 Rosenthal D, Cossman D, Matsumoto G, et al. Prophylactic interruption of the vena cava: a retrospective evaluation. Am J Surg I979; I37:389-93 Cerrato D, Ariano C, Fiacchino F. Deep vein thrombosis and low-dose heparin prophylaxis in neurosurgical patients. J Neurosurg 1978; 49:378-8I Turpie AGG, Hirsh J, Gent M, et al. Prevention of deep vein thrombosis in potential neurosurgical patients. Arch Intern Med I989; I49:679-8I Waring WP, Karunas RS. Acute spinal cord injuries and the incidence of clinically occurring thromboembolic disease. Paraplegia I99I; 29:8-I6 Green D, Lee MY, Ito VY, et al. Fixed- vs adjusted-dose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA I988; 260:I255-58 Green D, Lee MY, Lim AC, et al. Prevention of thromboembolism after spinal cord injury using low-molecular weight heparin. Ann Intern Med I990; 113:57I-74 Frisbie JH, Sasahara AA. Low dose heparin prophylaxis for deep venous thrombosis in acute spinal c.~>rd injury patients: a c.~mtrolled study. Paraplegia 1981; 19:343-46 O'Malley KF, Ross SE. Pulmonary embolism in major trauma patients. J Trauma 1990; 30:748-50 Shackford SR, Davis JW, Hollingsworth-Fridlund P, et al. Venous thromboembolism in patients with major trauma. Am J Surg I990; I59:365-69 Ruiz AJ, Hill SL, Berry RE. Heparin, deep venous thrombosis, and trauma patients. Am J Surg I99l; 162:159-62 Purdue CF, Hunt JL. Pulmonary emboli in burned patients. J Trauma 1988; 28:218-20 Sevitt S, Gallagher N. Venous thrombosis and pulmonary study in injured and burned embolism: a clinic.~>-pathological

patients. Br J Surg l96I; 48:475-89 118 Handley AJ. Low dose heparin after myocardial infarction. Lancet I972; 2:623-24 119 Gallus AS, Hirsh J, Tuttle RJ, et al. Small subcutaneous doses of heparin in prevention of venous thrombosis. N Engl J Med I973; 288:545-51 I20 Warlow C, Beattie AG, Terry G, et al. A double-blind trial of low doses of subcutaneous heparin in the prevention of deepvein thrombosis after myocardial infarction. Lancet 1973; I:934-36 I21 Emerson PA, Marks P. Preventing thromboembolism after myocardial infarction: effect of low-dose heparin or smoking. BMJ 1977; l:I8-20 I22 Handley AJ, Emerson PA, Fleming PR. Heparin in the prevention of deep vein thrombosis after myocardial infarction. BMJ 1972; 2:436-38 123 Wray R, Maurer B, Shillingford J. Prophylactic antic.~iagulant therapy in the prevention of calf-vein thrombosis after myocardial infarction. N Engl J Med 1973; 288:815-17 I24 Medical Research Council. Assessment of short-term antieagulant administration after cardiac infarction. BMJ I969; I:335-42 125 Drapkin A, Merskey C. Anticoagulant therapy after acute myocardial infarction. JAMA 1972; 222:541-48 126 Veterans Administration. Anticoai.,'ltlants in acute myocardial infarction. JAMA I973; 225:724-29 127 Wright IS, Marple CD, Beck DF. Report of the committee for the evaluation of antie PF. Prt>vention of postopnative deep vein thrombosis with dipyridamole and aspirin. BMJ 1976: 1:992-94 Stephenson CBS, Wallace JC, Vaughan JV. Dextran 70 in tht> prt>wntion of postoperative deep-vt>in thrombosis with observations on pulmonary embolism: report on a pilot study. NZ Med J 1973; 77:302-05 Tsapogas MJ, Goussous II, Peabody RA, t>l al. Postopnative wnous thrombosis and the t>fft>cti\'t>ness of prophylactic meastirt>s. Arch Surg 1971; 103:561-67

4068

160 \Villiams HT. Prevention of postoperative deep-win thrombosis with perioperative subcutant>ous heparin. Lancet 1971; 2:95052 161 Hills NH, Pflug JJ, Jeyasingh K, et al. Prevention of det>p vein thrombosis by intermittent pneumatic compression of calf. BMJ 1972: 1:131-35 162 Holford CP. Graded compression for preventing deep venous thrombosis. BMJ 1976; 2:969-70 163 Huttunen II, Mattila MAK, Alhava EM, et al. Preoperative infusion of dextran 70 and dextran 40 in the prevention of postoperative deep venous thrombosis as confirmed by the I125-labelled fibrinogen uptake methods. Ann Chir Gynaecol 1977; 66:79-81 164 Jackaman FR, Perry BJ, Siddons H. Deep vein thrombosis after thoracotomy. Thorax 1978; 33:761-63 165 Ockelford PA, Patterson J, Johns AS. A double-blind randomized placebo controlled trial of thromboprophylaxis in major elective general surgery using once daily injections of a low molecular weight heparin fragment (fragmin). Thromb llaemost 1989: 62:1046-49 166 Zekert F, Schemper M, Neumann. Acetylsalicylic acid in combination with dihydroergotamine for preventing thromboembolism. Haemostasis 1982; 11:149-53 166a Paiement GD, Wessinger SJ, Harris WH. Survey of prophylaxis against venous thromboembolism in adults undergoing hip surgery. Clin Orthop 1987; 223:188-93 167 Moskovitz PA, Ellenberg SS, Feffer !IL, et al. Low-dose heparin for the prevention of venous thromboembolism in total hip arthroplasty and surgical repair of hip fractures. J Bone Joint Surg 1978; 60:1065-70 168 Rogers PH, Walsh PN, Marder VJ, et al. Controlled trial of low-dose heparin and sulfinpyrazone to prevent venous thromboembolism after operation of the hip. J Bone Joint Surg 1978; 60:758-62 169 Ishak M, Morley KO. Deep venous thrombosis after total hip arthroplasty: a prospective study to determine the prophylactic effect of graded pressure stockings. Br J Surg 1981; 68:429-32 169a Barnes R\V, Brand RA, Clarke W, et al. Efficacy of gradedt,,mpression antit>mbolism stockings in patients undergoing total hip arthroplasty. Clin Orthopaed 1978; 132:61-77 170 Harris WH, Salzman EW, Athanasoulis CA, et al. Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med 1977: 297:1246-49 171 Soreff J, Johnsson II, Diener L, et al. Acetylsalicylic acid in a trial to diminish thromboembolic complications after elective hip surgery. Acta Orthop Scand 1975; 46:246-55 172 Belch JJF, Meek DR, Lowe GOO, et al. Subcutaneous ancrod in prevention of deep venous thrombosis after hip replacement surgery. Thromb Res 1982; 25:23 173 Evarts CM, Feil EJ. Prevention of thromboembolic disease after elective surgery of the hip. J Bone Joint Surg 1971; 53:1271-80 174 Hoek J, Nurmohamen MT, ten Cate H, et al. Prevention of deep vein thrombosis (DVT) following total hip replacement by a low molecular weight heparinoid (Org 10172) [abstract]. Thrombos Haemost 1989; 62(suppl I): 1637 175 Harris WH, Salzman EW, Athanasoulis C, et al. Comparison of warfarin, low-molt>cular-weight dextran, aspirin, and subcutaneous heparin in prevention of venous thromboembolism following total hip replacement. J Bone Joint Surg 1974; 56:1552-62 176 Kakkar VV, Stamatakis JD, Bt>ntley PG, et al. Prophylaxis for postoperative deep-win thrombosis: synergistic effect of heparin and dihydroergotamine. JAMA 1979; 241:39-42 177 Planes A, Vochelle N, Mazas F, et al. Prt>vt>ntion of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight ht>parin in patients Prevention of Venous Thromboembolism (Clagett et al)

178

179

180

181

182

183

184

185

186

187

188

189

190 191

192

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