SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991

Low Molecular Weight Heparins and External Pneumatic Compression as Options for Venous Thromboembolism Prophylaxis: A Surgeon's Perspective

During the past 5 years, various meta-analyses of the literature have shown that low-dose heparin reduces significantly the incidence of postoperative deep vein thrombosis (DVT), detected by the fibrinogen uptake test (FUT). 1-3 In general surgery the average incidence of DVT is around 9% when low-dose heparin prophylaxis is used compared with 25% when no specific prophylaxis is given. In orthopedic surgery the results of low-dose heparin prophylaxis are more controversial. Collins and coworkers2 analyzed the reported rates of DVT from prospective trials involving general, orthopedic, and urologic surgery and found a combined 68% reduction in the incidence of DVT when heparin was used; this reduction is statistically significant. However, the frequency of DVT among orthopedic patients remains unacceptably high (20 to 30%) despite low-dose heparin prophylaxis. For this reason, the current consensus is that heparin at fixed low doses is not an effective method for this surgical population.4-6 A further reduction in the incidence of DVT has been reported after total hip replacement (THR) by adjusting the doses of heparin according to the activated partial thromboplastin results.7'8 The incidence of fatal and nonfatal pulmonary embolism has been reduced when using heparin as shown in the international Multicenter Trial conducted in 1975.9 Although the interpretation of the results of this study was quite controversial, a recent review of other trials

From the Department of Surgery, Glenbrook Hospital, Glenview, Illinois and Northwestern University Medical School, Chicago, Illinois. Reprint requests: Dr. Caprini, Department of Surgery, Glenbrook Hospital, 2100 Pfingsten Road, Glenview, IL 60025. 356

supports the efficacy of heparin for preventing pulmonary thromboembolism.2 The number of patients required to demonstrate clearly a statistically significant reduction in mortality secondary to pulmonary embolism (PE) (from 0.8 to 0.4%) will be close to 20,000. Multicenter trials with objective postmortem confirmation of the PE are the only way to achieve such an objective. When confronted with the decision of which prophylaxis to adopt for their patients, surgeons consider the potential benefits derived from a reduction in the incidence of thrombotic events and are also very concerned about the potential risk of the drug prophylactic regimen, which may produce bleeding. It is remarkable that in 1990 many surgeons believe that venous thromboembolism is an unpredictable complication, inherent to the patient's condition, whereas drug-induced bleeding is the surgeon's fault. Low-dose heparin is generally considered to be safe, although the results of a recent review demonstrate a statistically significant difference in the incidence of wound hematoma when compared with patients receiving placebo.3 The fear of bleeding complications, and the lack of awareness of the importance of venous thromboembolism in surgery, perhaps are responsible for the poor implementation of prophylaxis among surgeons, as shown in multiple independent surveys.10"14 Is heparin good enough for venous thromboembolism prophylaxis in surgical patients? The answer to this question is not easy. If we consider all the information available, we probably should conclude, as de Takats15 stated in 1982, that there is still "room for improvement." Several alternatives to conventional low-dose hep-

Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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JOSEPH A. CAPRINI, M.D., F.A.C.S., JUAN I. ARCELUS, M.D., Ph.D., CLARA I. TRAVERSO, M.D., Ph.D., and JAMES H. HASTY, Ph.D.

arin prophylaxis have been proposed in the last decade: dextran, heparin-dihydroergotamine, oral anticoagulants, ultra low-dose heparin, low molecular weight heparin (LMWH) fractions, graduated compression stockings and external compression devices. The external pneumatic compression (EPC) devices, available for more than two decades, have experienced substantial improvements in their design. The new models are smaller, quieter, and receive better patient compliance, and patient tolerance to the sleeves is better. With the addition of more chambers that are sequentially inflated, their efficacy in preventing DVT has improved.16 As a result of these improvements, the use of EPC has become more accepted during the last 5 years in the United States. In contrast, in Europe there has been more interest in evaluating newer pharmacologic modalities. A relatively new group of heparin fractions, generically known as LMWH fractions, are now widely used in several European countries for different surgical populations. These LMWHs are beginning to replace conventional unfractionated heparin (UFH), at least for specific clinical settings in a number of worldwide locations. Despite all of the information published regarding heparin, external compression, and LMWHs, many surgeons still have problems in deciding which modality is the most appropriate for their patients. The correct approach to this decision-making process should be based on the information provided by reliable, randomized, prospective trials. More than simply deciding about using LMWH versus EPC, the surgeon should consider the patient's thrombotic and bleeding risks and then evaluate if the patient is going to be adequately protected by heparin (conventional or LMWH), EPC, or a combination of both methods. The type of procedure to be performed, the amount of dissection and consequences of any bleeding are also very important, especially in neurosurgery, urology, and oncologic surgery. In this population, because of the distinctive characteristics of these patients, the thrombotic risk runs parallel to the hemorrhagic risk, making any decision more difficult. Similar problems are faced by surgeons when dealing with some trauma patients when neither heparin nor compression can be used.17

CLINICAL EXPERIENCE WITH LOW MOLECULAR WEIGHT HEPARINS A number of studies have shown that heparin fractions with an average molecular weight between 4 and 10 kd are able to prevent venous thrombosis in different experimental models without altering the coagulation mechanism to the degree observed with unfrac-

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tionated heparin. The proposed explanation for this apparent dissociation in the anticoagulant-antithrombotic effects using LMWH is that these agents exert a markedly higher anti-Factor Xa activity, while their anti-IIa action remains similar to UFH. In addition, these agents have increased bioavailability and exhibit minimal interference with platelet function compared with UFH. These potential benefits led, in the early 1980s, to a great interest in evaluating the results of LMWH in clinical populations to verify if these agents were superior to UFH in terms of a better prophylactic effect with less bleeding and other complications. Several prospective studies have been conducted involving different surgical populations, in order to demonstrate the efficacy of a number of LMWHs administered at different doses, but following a similar schedule to conventional UFH; namely, starting 2 to 12 hours before surgery and continuing the drug for at least 7 days. In most of the studies, the control group received UFH (10,000 to 15,000 IU/day), assuming that this regimen represented the current standard, particularly in general surgery. However, in orthopedic patients the control group received a placebo in some studies18; in the majority heparin, at fixed19 or adjusted doses20 was given. Some authors consider that in patients undergoing THR the standard for comparison should be adjusted dose heparin instead of fixed doses of UFH heparin.21 The several commercially available LMWH preparations are produced by different methods and have different molecular weights with distinctive biologic actions. Therefore, the results of one individual LMWH cannot be extrapolated to another.22,23

Results in General Surgery In general surgery (Table 1), two multicenter studies have shown a significant reduction in the incidence of DVT with the use of 7500 Anti-Xa units once a day of Fraxiparin (CY 216), when compared to patients receiving UFH.24,25 In both trials the incidence of DVT in the group receiving the LMWH was remarkably low, around 2.8%. In one of these studies, however, all patients wore graduated compression stockings.25 The addition of this compression prophylactic modality could explain the very low incidence of DVT reported in the control group (4.5%), and lower than the average 9.5% described when only UFH is used.1-3 These findings are similar to the incidence found by other investigators when combining heparin and graduated compression stockings.26-28 Bergqvist and associates29 did not find a statistically significant reduction using the Kabi 2165 heparin fraction. In a further study, they started the LMWH administration the night before surgery instead of 2 hours

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VENOUS THROMBOEMBOLISM PROPHYLAXIS—CAPRINI ET AL

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SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991 TABLE 1. Studies Performed in General Surgery, Using Radiolabeled Fibrinogen Uptake Test as Endpoint to Diagnose Deep Vein Thrombosis

2 2

7500/24 hr 5000/12 hr

196 199

2.5 7.5*

5.1 3.5

Kabi 2165 UFH

2 2

5000/24 hr 5000/12 hr

215 217

6.4 4.3

11.6† 4.6

Bergqvist et al30 (1988)

Kabi 2165 UFH

12 2

5000/24 hr 5000/12 hr

505 497

5.5 8.3

5.9t 3

Encke et al 25 (1988)

Choay 216 UFH

2 2

7500/24 hr 5000/8 hr

960 936

2.8 4.5*

8.6‡ 9.2‡

Samama et al 31 (1988)

Enoxaparin UFH

2 2

1600/24 hr 5000/8 hr

159 158

3.8 7.6

0.6‡ 2.5‡

Enoxaparin UFH

2 2

3200/24 hr 5000/8 hr

106 110

2.8 2.7

9.4‡ 13.6‡

Enoxaparin UFH

2 2

4800/24 hr 5000/8 hr

137 133

2.9 3.8

10.9‡ 12.0‡

Sasahara et al 32 (1986)

Sandoz-DHE UFH-DHE

2 2

1500/24 hr 5000/12 hr

134 126

10.4 10.3

3.0* 3.7*

Kakkar et al 33 (1989)

Sandoz-DHE UFH-DHE

2 2

1500/24 hr 5000/24 hr

88 91

11.4 10.9

2.2* 1.1*

Kakkar and Murray 24 (1985)

Choay 216 UFH

Bergavist et al 29 (1986)

* UFH: unfractionated heparin; DHE: dihydroergotamine; DVT: deep vein thrombosis. †p