Prevention and Treatment of Thrombo-embolic Disease in Gynaecological Surgery

SOGe

CLINICAL PRACTICE GUIDELINES

POLICY STATEMENT:::

No.1,

ctober 1999

PREVENTION AND TREATMENT OF THROMBO-EMBOLIC DISEASE IN GYNAECOLOGICAL SURGERY These guidelines have been prepared by the following members of the SOGC/GOC/SCC Policy and Practice Guideline Committee and were approved by the Council of the SOGe.

Josee Dubuc-Lissoir, MD, FRCSC, Thomas Ehlen, MD, FRCSC, Mark Heywood, MD, FRCSC, Marie Plante, MD, FRCSC (Chair),

Montreal, Que, Vancouver, B.C, Winnipeg, Man, Quebec, Que.

'Policy Statement: this policy reflects e merging clinical and scientific advances as of the date ssued i and is subject

to

change. The information should not be con-

strued as dictating an exclusive course of treatment or procedure to be fo llowed. l oca l institutions can dictate amendments to these opinions. They should be well documented if modified at the loca l level. None of the contents may be reproduced in any form without prior written permiss ion of SOGe.

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,,, ABSTRACT

Objective: w identify pre-operative risk factors far venous thrombo-embolism (VTE) and w provide guidelines far risk assessment and far thrombo-prophylactic measures far VTE in women undergoing gynaecological surgery. Guidelines far diagnostic testing and far acute and long-term treatment ofVTE are also provided. Options: low, moderate and high-risk groups of patients are defined and appropriate prophylactic measures are outlined. Alternative measures w low-dose unfractionated heparin (LDUH) , far example low molecular weight heparin (LMWH) , leg swckings, dextran 70 and acetylsalicylic acid are discussed. Alternative methods far acute treatment ofVTE are also provided. Outcomes: venous thrombo-embolism remains a majar cause of marbidity and martality following gynaecological surgery. Adequate prophylaxis can decrease the incidence ofVTE. Evidence: evidence was gathered using MEDLINE (National Library of Medicine) w identify pertinent studies and from bibliographies of articles thus identified. Recommendations: prophylactic measures far VTE decrease its incidence (Levell evidence). Based on risk assessment, mare patients should be considered far prophylaxis (Grade A recommendation). The occurrence ofVTE is effectively reduced by the use ofLDUH and maybe mare so by the use ofLMWH (Levell evidence). Far treatment ofVTE, unfractionated heparin (UH) has been standard, although LMWH has now been proven w be at least as effective and safe (Levell evidence). Based on this evidence, LDUH ar LMWH should be used in prophylaxis when feasible and UH ar LMWH in treatment ofVTE (Grade A recommendation). FoUowing initial heparinization far treatment of VTE, patients should receive aral anticoagulation far at least three months (Grade A recommendation). Consideration could be given w extending prophylaxis beyond hospital discharge in high-risk patients. KEY WORDS

Venous thrombo-embolism, gynaecological surgery.

The purpose of these guidelines is to help identify specific pre-operative risk factors for VTE and to provide criteria for risk assessment, specific thromboprophylactic measures and treatment ofVTE.

INTRODUCTION

Venous thrombo-embolism (VTE) remains a major cause of mortality and morbidity following gynaecological surgery. Overall, the incidence of deep venous thrombosis (DVT) following gynaecological surgery appears comparable to, or perhaps slightly less than, that associated with general abdominal surgery.! In a general surgical population, the reported rates of DVT and pulmonary embolism (PE) are 30 percent and 14.1 percent, respectively,z,3 During the past two decades, a large number of studies and subsequent metaanalyses of the literature have clearly demonstrated that several methods of prophylaxis, pharmacological and physical, can significantly reduce the rate of postoperative VTE.4-S Primary prophylaxis is now considered to be the most effective means of preventing death and morbidity from VTE in the post-operative period. 9 In fact, prophylaxis is more effective in preventing death and morbidity from VTE than is the treatment of the established disease.lO Once VTE has occurred, prompt and adequate treatment must be initiated to reduce the morbidity and mortality from PE, to reduce the extension of DVT and the morbidity from post-thrombotic leg syndrome. ll ,12

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RISK FACTORS

Numerous studies have identified specific risk factors for the development of thrombo-embolic disease and groups of patients at risk. In 1992, the Thromboembolic Risk Factors Consensus Group (THRIFT) produced a comprehensive list of risk factors for VTE in hospital patients (Table 1).13 For women with gynaecological malignancies, the estimated risk of postoperative DVT ranges from 17 to 45 percent. 14-16 Important risk factors include age (risk increasing exponentially beyond age 40), previous VTE which confers a risk of postoperative DVT greater than 50 percent and thrombophilia. 13 Thrombophilia is a term generally used to describe "familial or acquired abnormalities of haemostasis likely to predispose to thrombosis".17 Proven inherited defects associated with familial VTE are antithrombin deficiency and abnormalities of the components or function of the protein C-protein S system. A variation in

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,,, the prothrombin gene associated with increased prothrombin levels and thrombosis has been identified. IS There are several causes of acquired thrombophilia, one of the most common being the antiphospholipid antibody syndrome. 19 The majority of patients with inherited or acquired defects of the haemostatic system remain asymptomatic.1 7,19 Therefore, it would not be appropriate to offer thrombophilia screening to all women at present. Thrombophilia screening should be offered to those women giving a personal or family history of VTE, especially if the VTE occurred in the absence of other risk factors. Estrogen therapy has been identified as a risk factor. On the topic of combined oral contraceptives (OC), the Canadian Consensus Conference on Contraception concluded the following: "Whether or not women should discontinue oral contraceptive use before elective surgey is controversial. It is reasonable to recommend that OC users discontinue use at least four weeks before surgery which will be followed by a period of

reduced activity or immobilization, or before surgery for a malignancy. Combined OC users who undergo major emergency surgery should discontinue use of combined OCs and receive prophylactic peri-operative anticoagulant therapy using subcutaneous heparin.',zo The definition of major surgery is given in Table 2. At this time, there is no evidence to suggest that progestin-only preparations are associated with an excess risk ofVTE.21 They can be used as a reliable form of contraception when combined OCs are withdrawn. There are no data to indicate whether or not hormone replacement therapy (HRT) will increase the risk of postoperative VTE or whether there would be a benefit from discontinuation ofHRT prior to surgery. However, it may be prudent to consider HRT with estrogen as a risk factor, and prescribe specific prophylaxis even if the excess risk is likely to be small.! In most circumstances, women who are taking HRT and who are undergoing gynaecological surgery are likely to have additional risk factors, particularly their age, which would be an indication for specific thrombo-prophylaxis. A consistent finding in several studies is that patients with blood group 0 are over-represented in series describing VTE.22 At present, there are no new biological explanations for this finding. A useful classification based on the studies of Salzman and Hirsh, the THRIFT and the Royal College of Obstetricians and Gynaecologists (RCOG) Working Party on Prophylaxis Against Thrombo-embolism in Gynaecology and Obstetrics, is shown in Table 2.

TABLEt RISK FACTORS FOR VENOUS THROMBO-EMBOLISM IN HOSPITAL PATIENTS Patient factors

Disease or surgical procedure factors

Age

Trauma or surgery to pelvis or lower limb

Previous VTE

Malignancy. particulary pelvic or abdominal or metatastic

Obesity Varicose veins

Cardiac failure

Deep vein insufficiency

Recent myocardial infarction

Immobility

Recent stroke

Pregnancy

Paralysis of lower limbs

Puerperium

Infection

Estrogen therapy

Inflammatory bowel disease

High fibrinogen

Nephrotic syndrome

High factor VIII levels

Myeloproliferative disorders

PROPHYLAXIS FOR VTE IN WOMEN UNDERGOING GYNAECOLOGICAL SURGERY

Prophylaxis for VTE in the individual patient should be based on risk classification! (Tables 2 and 3). The use of dextran 70 is not recommended because of the anaphylactic and haemodynamic risks.13 Acetylsalicylic acid (ASA) and other antiplatelet agents are not recommended at present.!' 23

Thrombophilia Paroxysmal nocturnal haemoglobinuria • Antithrombin deficiency Dysfibrinogenaemia • Protein C defiCiency • Protein S deficiency • Factor V Leiden • Prothrombin gene variant • Hyperhomocysteinaemia • Lupus anticoagulant • Antiphospholipid antibodies

SIDE EFFECTS AND COMPLICATIONS OF LDUH AND LMWH

Modified with permission from Greer IA.'

Bruising at the injection sites is common and can

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, , , day of hospital discharge which is usually approximately five days postoperatively. No data are available to allow specific recommendations for continued prophylaxis after discharge from hospital. It is important to note that the majority ofVTEs occur after hospital discharge, and 28 percent occur more than two weeks postoperatively.29 This fact and the trend towards earlier hospital discharge in Canadian hospitals indicate that continuation of prophylaxis for a total of two weeks postoperatively in high-risk patients could be considered. Postoperative outpatient prophylaxis has not been studied to date. The regimens that would appear to be most suitable in this setting are: 1. Very low-dose warfarin (lmg/day).3o At present, this method does not require outpatient laboratory monitoring of the International Normalized Ratio (INR), unless the patient is anorectic. Its effectiveness has not yet been tested in cancer patients (high risk)_ 2. Low molecular weight heparins have been found in several studies to be as effective as standard heparin. The studied doses were: daIteparin 2,500 IU once a

be decreased by the use of appropriate injection technique. In patients with Pfannenstiel incisions, the injection site should probably be away from the incision site and above the iliac crest to reduce the risk of wound haematoma formation. 1 The risk of major bleeding complications, including fatal bleeding, does not appear to be increased with LDUH or LMWH. 6,25-27 Minor and moderate bleeding complications appear to be increased with heparin, and one major study suggests that this risk may be decreased with LMWHs.28 Allergies to LDUH and LMWH are uncommon. l Heparin-induced thrombocytopaenia caused by heparin-dependent antibodies is an uncommon but serious complication. It could be less common when LMWHs are used. 24 Heparin-induced osteoporosis is not an issue in patients receiving heparin prophylaxis. SPECIFIC PROBLEMS IN TH ROM BO·PROPHYLAXIS

The risk of thrombo-embolism extends beyond the

TABLE 2 INCIDENCE OF VTE AND RISK ASSESSMENT PROFILE FOR TH ROMBO-EMBOLISM IN GYNAECOLOGICAL SURGERY Deep venous thrombosis

Proximal vein thrombosis

Fatal pulmonary embolism

Low-risk group Moderate-risk group High-risk group

<10% 10-40% 40-80%

<1% 1-10% 10-30%

0.01% 0.1-1% 1-10%

Low-risk group:

Early mobilization and hydration • minor surgery ($30 min.); no risk factors other than age • major surgery (>30 min.); age < 40; no other risk factor

Moderate-risk group:

Consider one of t he variety of available prophylactic measures • minor surgery (:530 min.) In patients with personal or family history of DVT, PE or thrombophilia • major surgery (~30 min.); age ~ 40 or other risk factor • extended laparoscopic surgery • obesity (>80 kg) • gross varicose veins • current infection • immobility prior to surgery (> 4 days) • major current illness (e.g. heart or lung disease, inflammatory bowel disease, nephrotic syndrome, non-gynaecological malignancy) • heart failure or recent myocardial infarction

High-risk group:

Heparin prophylaxis, with or without leg stockings • atotal of three or more moderate-risk factors above • major pelvic or abdominal surgery for gynaecological malignancy • major surgery (>30 min.) in patients with personal or family history of DVT, PE or thrombosis; paralysis or immobilization of lower limbs.

Modified with permission from Greer IA.'

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,,, TREATMENT OF VENOUS TH ROMBO-EMBOLISM

day (moderate risk) or 5,000 IU once a day (high risk) versus heparin 5,000 IU twice a day; enoxaparin 30 mg twice a day versus heparin 7,500 IU twice a day; tinzaparin 3,500 IU once a day versus heparin 5,000 IU three times a day.2s,31-33 The use of LMWHs does not require blood monitoring, and injections may be given once a day. However, where injection requires a nurse home-visit, costs will be considerably higher than those of the drug alone. In morbidly obese patients (more than 100 kg body weight), the added use of pneumatic compression devices should be considered peri-operatively until the patient is mobile. Graduated elastic compression stockings are difficult to fit for this group of patients, and poorly fitted stockings may actually increase the risk ofVTE. The use of heparin prophylaxis may be problematic when regional anaesthesia is recommended. Consultation with the anaesthesiology department should be obtained to discuss alternate methods of prophylaxis or alternate schedules of heparin administration if needed.

DIAGNOSIS

A high index of suspicion for VTE should be maintained. Clinical suspicion is inaccurate, and confirmatory diagnostic tests must be used. For DVT, venous ultrasound is the primary diagnostic tool. A venogram remains the "gold standard" but is infrequently indicated today. For PE, a ventilation-perfusion scan (VQ scan) is the primary tool. Pulmonary angiography, while still the "gold standard", is invasive and carries a significant rate of morbidity and mortality. It should probably be considered only in the presence of high clinical suspicion, an indeterminate VQ scan and the absence of confirmed DVT. INITIAL TREATMENT

Treatment should be initiated using unfractionated heparin (UH) or LMWH.

TABLE 3 PROPHYLAXIS FOR VfE IN GYNAECOLOGICAL SURGERY Risk Group

Prophylaxis

Low-risk group:

Early mobilization and hydration.

Moderate-risk group:

One prophylactic measure of the following options: • Low-dose unfractioned heparin (LOU H). 5,000 IU s.c. every 12 hours (for patients over 80 kg consider 5,000 IU s.c. every 8 hours). Start two hours pre-operatively and continue for five days or until hospital discharge (whichever comes first). • Low molecular weight heparins (LMWH). • Enoxaparin 20 mg s.c. once a day or • Dalteparin 2,500 IU s.c. once a day Start LMWHs the night before or at least two hours pre-operatively and continue for five days or until hospital discharge (whichever comes first). • Graduated elastic compression stockings or intermittent pneumatic calf compression. (Use when heparin is contra-indicated.)

High-risk group:

Heparin prophylaxis, ideally with leg compression stocking • LDUH: 5,000 IU s.c. every 8 hours. Start two hours pre-operatively and continue for five days or until hospital discharge (whichever comes first). • LMWH: enoxaparin 40 mg s.c. once a day or Dalteparin 5,000 IU S.c. once a day· Start LMWHs the night before or at least two hours pre-operatively and continue for five days or until hospital discharge (whichever comes first). Consider continuation of LDUH or LMWH for a total of two weeks postoperatively even after hospital discharge .

• Dalteparin: if started two hours pre-operatively, consider giving 2,5000 IU s.c. pre-operatively and 2,500 IU s.c. 8 to 12 hours postoperatively. Modified with permission from Greer IA.'

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, ,, UNFRACTIONATED HEPARIN

Normalized Ratio (INR) in the therapeutic range of two to three. Warfarin therapy should overlap with heparin for four to five days until the INR is greater than two on two consecutive days. Leg oedema can be reduced by raising the leg and using graduated elastic compression stockings (prescribe two: one to wash, one to wear). The stockings decrease the risk of post-thrombotic leg syndrome (Grade A recommendation}.12

Patients should be given a bolus of 5,000 IU (or 80 IU per kilogram), followed by an infusion of 30,000 to 35,000 IU per 24 h ours (or 18 IU per kilogram per hour) . For patients who have a history of surgery or stroke within the previous two weeks, a low platelet count or any increased risk of bleed ing, the bolus of 5,000 IU should be maintained but the infusion rate should be started at 30,000 IU per 24 hours. 34 Activated partial thromboplastin time (AnT) should be measured four to six hours after starting the heparin or after any dose adjustment and then every 24 hours, once therapeutic levels are obta ined (Table 4). The APTT should be within 1.5 to 2.5 times the control value.

CONCLUSION

Venous thrombo-embolism remains a major cause of morbidity and mortality following gynaecological surgery. Primary prophylaxis has been proven to be most effective in preventing death and morbidity from VTE with relatively minor side effects and complications (Levell evidence). Based on identifed risk factors, prophylaxis should be given to alarger number of patients undergoing gynaecological surgery (Grade A recommendation) . Although LDUH has b~en widely used for prophylaxis, LMWH may be more effective (Levell evidence). Continuing prophylaxis for up to two weeks postoperatively in high-risk patients may be warranted, based on published data on the occurrence of delayed VTE. For treatment of VTE, UH has been the standard for many years. Low molecular weight heparin has now been proven to be at least as effective and probably more effective and practical, although comparative cost-effectiveness studies are still needed (Levell evidence). Recommendations have been graded according to the level of evidence on which they are based: Grade A: randomized trials or meta-analysis (Level 1 evidence). Grade B: other robust experimental or observational studies (Level 2 evidence). Grade C: more limited evidence, but advice relies on expert opinion and has the endorsement of respected authorities (Level 3 evidence).

Low MOLECULAR WEIGHT HEPARIN

Based on published meta-analyses, LMWHs have been found to be more effective and safer than UH. A reduction in thrombus size, recurrences, major bleeding complications and mortality has been noted. 3s -37 It appears, therefore, that LMWHs should be initial standard therapy (Grade A recommendation). The two LMWH preparations available in Canada for treatment are the following: tinzaparin 175 IU/kg s.c., given once daily for at least five days and dalteparin 200 IU/kg s.c. given once daily for at least five days.3s,38,39 LONG-TERM TREATMENT

Fo llowing initial heparinization, non-pregnant patients with VTE should receive maintenance oral anticoagulation for at least three months. IO ,12 This is a Grade A recommendation. An initial dose of warfarin 7.5 mg s hould be given on days one and two. Dosage should then be adjusted to achieve an International

TABLE 4 TITRATION OF INTRAVENOUS UNFRACTIONATED HEPARIN APTT(sec) Dosage change (lU/h) Additional action <45

+240

repeat APTI 4-6 hrs.

46-54

+120

repeat APTI 4-6 hrs.

55-85

0

ACKNOWLEDG EM E NT

none.

stop heparin infusion for 1 hr. repeat APTI 4-6 hrs. after restarting heparin. stop heparin infusion for 1 hr. repeat APTI 4-6 hrs after restartinQ heparin. Modified with permission from Hull et a/.40

86-110

-120

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Caroline Berube, MD, FRepC of Montreal, Quebec for in-depth review of these guidelines.

J SOC OBSTET GYNAECOL CAN 1999;21(11):1087-94

OCTOBER 1999

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Comparison of efficacy and safety of low-molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ 1994;309:299-304. 37 . Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996;100:269-77.

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