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Prevention of venous thromboembolic disease

Graham F Pineo, MD


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INTRODUCTION — Pulmonary embolism is responsible for approximately 150,000 to 200,000 deaths per year in the United States [1,2]. Despite significant advances in the prevention and treatment of venous thromboembolism (here taken to include both venous thrombosis and pulmonary embolism), pulmonary embolism remains the most common preventable cause of hospital death. Thus, it is vital that efforts continue to find means of preventing and managing venous thromboembolism that are safer and more effective [3].

Venous thromboembolism often complicates the course of sick and hospitalized patients, but it can also occur in ambulatory and otherwise healthy individuals (see "Hospitalization" below). Effective and safe prophylactic measures are now available for most high-risk patients [4-8]. Prophylaxis is more effective for preventing death and morbidity from VTE than is the treatment of established disease.

Practical approaches to the prevention of venous thromboembolism (VTE) in medical and surgical patients will be reviewed here. Detailed discussions about specific pharmacologic agents are presented separately. (See "Clinical use of heparin and low molecular weight heparin" and see "Clinical use of warfarin").

RISK OF VTE — Fatal pulmonary embolism occurs with the following frequency in patients who do not receive prophylaxis:

0.1 to 0.8 percent in patients undergoing elective general surgery
2 to 3 percent in patients undergoing elective hip replacement
4 to 7 percent in patients undergoing surgery for a fractured hip
RIsk factors — Most risk factors for venous thromboembolic disease have been identified in surgical populations. In one large prospective cohort study, 21,903 consecutive surgical patients were followed for 30 days postoperatively [9]. Deep vein thrombosis and pulmonary embolism were rare, diagnosed in 0.11 and 0.14 percent of patients, respectively. Independent risk factors for thromboembolism included:

Age >50 years
History of varicose veins (OR 7.2, 95% CI 3.8-13.7)
History of myocardial infarction (OR 2.9, 95% CI 1.8-4.8)
History of cancer (OR 2.4, 95% CI 1.9-3.2)
History of atrial fibrillation (OR 2.1, 95% CI 1.2-3.4)
History of ischemic stroke (OR 1.8, 95% CI 1.3-2.7)
History of diabetes mellitus (OR 1.7, 95% CI 1.2-2.2)
Additional risk factors that increase the risk of venous thrombosis include previous venous thromboembolism, obesity, heart failure, paralysis, or the presence of an inhibitor deficiency state. Factor V Leiden is the most common cause of inherited thrombophilia, accounting for 40 to 50 percent of cases. The prothrombin gene mutation, deficiencies in protein S, protein C, and antithrombin account for most of the remaining cases. (See "Activated protein C resistance and factor V Leiden").

The risk is enhanced in patients with more than one predisposition to thrombosis. One study, for example, noted a 10-fold increase in risk of any venous thromboembolism and a 20 fold increase in risk of idiopathic thromboembolism among men who had both the Leiden mutation and hyperhomocysteinemia when compared to men with neither abnormality [10]. The risk of VTE among individuals with both hyperhomocysteinemia and factor V Leiden was far greater than the sum of the individual risks associated with either abnormality alone. Medical patients who are immobilized (eg, with congestive heart failure, cancer, stroke, or following myocardial infarction) also present a significant risk for venous thromboembolism. (See "Overview of the causes of venous thrombosis").

Pregnancy — The risk of VTE is increased in association with pregnancy. This phenomenon may relate in part to the progressive increase in resistance to activated protein C that is normally observed in the second and third trimesters [11].

The risk during both the intrapartum and the postpartum periods appears to be accentuated in those women who have an inherited deficiency of a naturally occurring anticoagulant, such as antithrombin III, protein C, or protein S. In one study, for example, the frequency of developing venous thrombosis during pregnancy or the postpartum period was approximately 8-fold greater in deficient compared with non-deficient women [12]. (See "Deep vein thrombosis and pulmonary embolism in pregnancy" and see "Anticoagulation during pregnancy").

Hospitalization — There is a high risk of developing VTE while hospitalized for a reason other than DVT or pulmonary embolus. Based upon a review of residents of Olmsted County for the period from 1980 through 1990, the age- and sex-adjusted incidence of VTE was more than 130 times greater among hospitalized patients (960 per 10,000 person-years) than among community residents (7.1 per 10,000 person-years) [13]. For both groups, the incidence of VTE increased with advancing age, and, with the exception of women <40 years of age, was higher in hospitalized men than women.

Approximately one-half of community-based cases occurred in patients who developed VTE while residing in a nursing home or within 90 days of hospital discharge. The net result was that approximately 60 percent of all cases of VTE occurred in hospitalized, recently discharged, or nursing home patients [13,14].

Surgery — Patients undergoing surgical procedures are divided into the following risk categories (show table 1) [15]:

Low risk — Low risk patients are under the age of 40, have none of the risk factors listed above, will require general anesthesia for less than 30 minutes, and are undergoing minor elective, abdominal, or thoracic surgery. Without prophylaxis their risk of proximal vein thrombosis is less than 1.0 percent, and risk of fatal pulmonary embolism is less than 0.01 percent.

Moderate risk — Moderate risk patients are over the age of 40, will require general anesthesia for more than 30 minutes, and have one or more of the above risk factors. Without prophylaxis, their risk of proximal vein thrombosis is 2 to 10 percent, and their risk of fatal pulmonary embolism is 0.1 to 0.7 percent.

High risk — High risk patients include those over the age of 40 who are having surgery for malignancy or an orthopedic procedure of the lower extremity lasting more than 30 minutes, and those who have an inhibitor deficiency state or other risk factors. The risk of proximal vein thrombosis and fatal pulmonary embolism in this group is 10 to 20 percent and 1.0 to 5.0 percent, respectively.

The high risk associated with orthopedic surgery results from a number of factors that contribute to venous stasis, including the supine position on the operating table, the anatomic positioning of the extremity, and, in patients undergoing total knee replacement, inflation of a thigh tourniquet to obtain a bloodless field [15]. In addition, intimal injury may result from positioning of the extremity, and compression of the femoral vein may occur due to flexion and adduction of the hip during surgery on this joint.

PREVENTION OF VTE — There are two approaches to the prevention of fatal pulmonary embolism [15]:

Primary prophylaxis is carried out using either drugs or physical methods that are effective for preventing deep vein thrombosis.
Secondary prevention involves the early detection and treatment of subclinical venous thrombosis by screening postoperative patients with objective tests that are sensitive for venous thrombosis.
Primary prophylaxis is preferred in most clinical circumstances; it is more cost-effective than treatment of complications when they occur. Secondary prevention should never replace primary prophylaxis; it is reserved for patients in whom primary prophylaxis is either contraindicated or ineffective.

Primary prophylaxis — Characteristics of the ideal primary prophylactic method are described in Table 2 (show table 2). The prophylactic measures most commonly used include:

Low dose heparin
Low molecular weight heparin
Use of the substituted pentasaccharide fondaparinux
Oral anticoagulants (International Normalized Ratio [INR] of 2.0 to 3.0)
Intermittent pneumatic compression (IPC)
Prophylaxis is ideally started before or shortly after surgery and continued until the patient is fully ambulatory [15]. For a patient undergoing total hip or total knee replacement, the minimum duration of prophylaxis with LMWH or warfarin should be 7 to 10 days [15]. Seven published reports and two meta-analyses support the need for continued prophylaxis with LMWH for 28 to 42 days following total hip replacement [16-24]. There is less of a need for extended prophylaxis beyond 10 days for patients undergoing total knee replacement (see "High risk surgical patients" below) [21].

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