A large number of clinical trials have shown that preventive strategies reduce deep vein thrombosis (DVT) and pulmonary embolism (PE).1 In addition, studies have shown the relative safety of preventive strategies of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), selective factor X_a inhibitors, or a vitamin K antagonist (VKA). When used in lower doses and within a therapeutic range, the risk of significant bleeding is minimized. Preventive strategies have also been found to be cost-effective when compared with the cost of long-term morbidities of treating DVT and PE.1 Despite these positive findings, compliance with the guidelines is less than ideal. To address this problem, various initiatives have been started, such as the National Consensus Standards for the Prevention and Care of Deep Vein Thrombosis Project between The Joint Commission and the National Quality Forum. They identified 4 domains of venous thromboembolism (VTE): risk assessment, diagnosis, prevention, and treatment.2 The following sections discuss 2 of these domains: prevention and treatment of established VTE, with specific guideline recommendations outlined in Table 1.

TABLE 1 Prevention of Venous Thromboembolism

Interventions for Prevention of VTE

Whether preventing the formation of a venous thrombus or treating an existing DVT and/or PE, clinical practice guidelines1,3,4 recommend pharmacological interventions, such as UFH, LMWH, selective factor X_a inhibitors, and VKA, and/or nonpharmacological interventions, including mechanical measures, such as inferior vena cava (IVC) filters, graduated compression stockings (GCSs), and intermittent pneumatic compression (IPC) devices.

Pharmacological Intervention

Pharmacological measures to reduce the incidence of VTE are initiated for patients at risk just before and after surgical procedures or after trauma and in patients who are immobile and/or at risk of VTE. The duration of the therapy depends on the procedure and the risk of the individual patient.1 The patient's risk can be determined in several ways, one of which are the criteria of Wells et al,5 where risk is given a value. The higher the total score, the greater the risk. Two of the criteria of Wells et al are recommended by the American College of Chest Physicians (ACCP)/American Academy of Family Physicians guidelines3: one is used to determine the probability of a DVT, and the other is used to determine the criteria for PE.

Women with risk factors beyond those identified in the criteria of Wells et al are also at an increased risk for VTE. These include women with a history of prior VTE, thrombophilia, heart disease, sickle cell disease, lupus, obesity, anemia, diabetes, hypertension, and smoking and those who are pregnant. With pregnancy, the risk is increased 4- to 5-fold and is equally as strong from the first trimester through the third trimester. This is possibly due to hypercoagulability, as various clotting factors, including factors VII, VIII, X, fibrinogen, and von Willebrand factor, are increased during pregnancy.6

Unfractionated Heparin

Low-dose UFH (LDUH) may be used in prevention of DVT. Preoperative administration of LDUH is recommended for patients undergoing gynecologic surgery, for benign as well as for malignant cases, regardless of the presence of additional risk factors for DVT. Patients undergoing open urological procedures and hip fracture surgery may also be treated preoperatively, and those medically treated patients in the critical care unit are also candidates for LDUH.1

An LDUH dosage of 5,000 U administered subcutaneously (SC) is generally given preoperatively followed by every 8 to 12 hours after surgery. Monitoring heparin with an activated partial thromboplastin time (aPTT) is not required; however, platelet count should be monitored to watch for the rare possibility for heparin-induced thrombocytopenia (HIT), which can lead to excessive bleeding.7,8

Low-Molecular-Weight Heparin

Low-molecular-weight heparin has been shown to be effective in preventing thrombosis. It is administered SC once or twice daily. (Please refer to the following section for further discussion of LMWH.)

Treatment of Existing VTE

The objective of treatment of existing DVT and acute PE is to prevent further extension of the clot. The ACCP and the American Academy of Family Physicians recommend LMWH as initial treatment for hospitalized patients with DVT.1,3,4 It has been found to be safe and effective for treatment of both DVT and PE. For patients with PE, either UFH or LMWH is acceptable as initial treatment. Both LMWH and UFH are equally effective reducing mortality; however, the risk of bleeding with LMWH is less3 (Table 1).

In an outpatient setting, LMWH is recommended in uncomplicated patients. Patients at high risk would not be good candidates for outpatient treatment. This includes those who have had prior VTE or thrombophilic conditions, where the propensity to develop blood clots exists because of an abnormality in the coagulation system,8 such as factor V Leiden, or for those with significant comorbid conditions,4 such as recent hemorrhagic stroke, renal dysfunction, gastrointestinal or genitourinary bleeding, recent trauma, or a history of HIT.9

In pregnancy, ACCP guidelines recommend the use of either LMWH (SC) or UFH (intravenously [IV]) for the treatment of acute VTE, as both forms of heparin do not cross the placental barrier. Dosage adjustments of UFH (IV) should be made based on aPTT levels, and LMWH can be monitored by using anti-X_a levels. The guidelines recommend either agent be continued SC throughout the pregnancy and for a minimum of 6 weeks postpartum; total duration of therapy should be a minimum of 6 months.5

The risk of developing a PE is higher in persons with a proximal vein thrombosis, which is a clot most commonly lodged in the femoral vein, the popliteal vein, or the veins in the pelvis. In these patients, ACCP guidelines2 recommend GCSs in addition to anticoagulation as part of the routine treatment of PE. The purpose for using GCSs is to prevent postthrombotic syndrome, a complication of DVT that can result in chronic pain, cellulitis, purpura, skin discoloration, and peripheral edema.10

Unfractionated Heparin

A continuous IV infusion of UFH is one choice of treatment of VTE. The initial dosing of UFH is based on the patient's weight: 80-U/kg bolus followed by a continuous infusion at 18 U/kg per hour.4 Because the individual response to UFH can vary significantly, monitoring of UFH is important to maintain an effective therapeutic level and minimize the risk of excessive bleeding. The test most commonly used test to monitor heparin is an aPTT, with a targeted goal of 1.5 to 2.5 times the mean of the control value. Otherwise, a patient may be at an increased risk of recurrent VTE or excessive bleeding. In patients weighing more than 150 kg or those with apparent heparin resistance, anti-factor X_a monitoring may be superior to measurement of aPTT.4 Because of variability in maintaining the therapeutic blood levels of UFH (IV), LMWH is the preferred method of treatment.4,11

Low-Molecular-Weight Heparin

Low-molecular-weight heparin has been found to be as effective as LDUH (SC or IV) for both treatment and prevention of VTE. It has greater bioavailability than UFH and a longer duration of effect. One study that measured the effects of LMWH versus LDUH in trauma patients showed that LMWH was better at decreasing the rate of proximal DVT.12 In addition, it has been found to be safe and effective both in treating patients diagnosed with VTE and as initial treatment in the outpatient setting in uncomplicated patients.4,13

Several LMWHs are available, each with its own pharmacokinetic and dosing characteristics. Depending on which agent is selected, dosing can vary and may need to be reduced for patients with severe renal impairment (creatinine clearance <30 mL/min).

Selective Factor X_a Inhibitors

A newer class of anticoagulant agents includes factor X_a antagonists. Some pharmacokinetic/pharmacodynamic advantages this class of drug has versus heparin include a long half-life (approximately 18 hours) and greater anti-X_a activity. Thus, factor X_a antagonists may produce a more stable anticoagulant effect than heparin. In addition, they do not induce a rebound in thrombin production upon discontinuation as is seen with heparins. This rebound may cause higher thrombin levels and a potential for clot growth. Another advantage is that factor X_a inhibitors have not induced HIT.1

Fondaparinux is currently the drug in this class recommended by the clinical practice guidelines and may represent an improved safety profile compared with LMWH.14 As a parenteral synthetic compound, administered SC or IV, fondaparinux specifically targets factor X_a, a key component of the coagulation cascade.15

Dosing of fondaparinux for patients with DVT or PE can be affected by extremes in body weight, which may impact the maximum concentration of the drug in the blood and thus prothrombin times. The less the patient weighs, the greater the risk of bleeding if dosing is not adjusted. Therefore, the recommended dose of fondaparinux administered SC once daily for patients weighing less than 50 kg is 5 mg; for those weighing 50 to 100 kg, 7.5 mg; and, for patients weighing more than100 kg, 10 mg.16,17 Treatment should continue for at least 5 days and until a therapeutic anticoagulant effect is measured, with an international normalized ratio (INR) of 2.0 to 3.0. Because the drug is eliminated renally, fondaparinux is contraindicated in patients with severe renal insufficiency (creatinine clearance <30 mL/min).17

Two drugs in this class currently in development can be administered orally, making them more convenient for long-term use rather than daily injections. Both rivaroxaban and apixaban are oral direct factor X_a inhibitors in phase 3 of clinical development. Both are being studied for the prevention of VTE after major orthopedic surgery, for chronic use in the prevention of stroke in atrial fibrillation, and for the treatment of acute coronary syndrome.18

In March 2009, an advisory panel recommended rivaroxaban be approved by the Food and Drug Administration for prevention of DVT and PE in patients undergoing hip or knee replacement, despite the drug's nearly 2-fold increase in bleeding when compared with LMWH and potential for liver toxicity.19

Vitamin K Antagonists

Although several VKAs are available, warfarin is considered the prototype of this class of drugs. In preparation for long-term anticoagulation, warfarin therapy may be initiated when heparin is started, with the starting dose based on the patient's age, comorbidities, risk of bleeding, and potential for drug interactions with current medications. An initial starting dose of warfarin can range from 5 to 10 mg; in elderly or debilitated patients, those with liver disease, and those who have had recent surgery or taking medications that potentiate warfarin, the starting dose may be 2 to 4 mg.4

It takes 4 to 7 days for warfarin to impact clotting factors II, VII, IX, and X; therefore, heparin should be continued for at least this length of time when used in combination with warfarin to allow these clotting factors to be reduced. Once the INR is within the therapeutic range, between 2.0 and 3.0, heparin can be discontinued.1 However, the INR should be monitored closely and remain in this range so as to reduce the chance of further clot formation (INR <2.0) or excessive bleeding (INR >3.0). The length of treatment is based on the individual's clinical problems, but generally, a minimum of 3 months is recommended following a thromboembolic event.1,20

Mechanical Interventions

Beside pharmacological intervention, clinical practice guidelines also recommend the use of mechanical interventions.1 The rationale for using some mechanical forms of treatment, such as GCSs or IPC devices, is to increase venous return and decrease the risk of pooling of blood in the leg veins. Some studies have shown that when mechanical forms of treatment are used as monotherapy for VTE prevention, the frequency of DVT was reduced by 66%; however, the reduction in PE was significantly less at 31%.21 This type of treatment can be safely used in patients who may be at high risk of bleeding, although guidelines do not recommend their use as monotherapy in this population.1

IVC Filter

The ACCP guidelines recommend an IVC filter be used in patients with proximal DVT if anticoagulant therapy is contraindicated or has been ineffective. Currently, there are 13 IVC filters approved by the US Food and Drug Administration.

An IVC filter may be inserted through the infrarenal, jugular, femoral, or antecubital veins.22 Although an IVC filter relieves pulmonary vascular obstruction, it does not prevent venous thrombosis from occurring in the lower extremities. Anticoagulation should be used in combination with the IVC filter when possible to reduce the risk of further development of thrombus.23

Graduated Compression Stockings

The rationale for using GCSs is that venous stasis is prevented by providing a graduated amount of compression over the foot and calf, with the lightest compression at the proximal limb. To ensure that the stockings fit appropriately and are comfortable, the length and circumference of the calf should be measured. The ACCP guidelines recommend the use of GCSs based on a number of small studies that have shown they reduce the risk of DVT.1 Recently, other studies have been published that may change future guidelines.

In a study reported by Winslow and Brosz,24 142 postoperative patients were assessed for the correct size of the GCSs, whether the placement of the stockings was correct, the comfort to the patient, and whether patients understood the purpose of the stockings. Investigators found that nearly one-third of the stockings, primarily thigh-high stockings, were incorrectly placed, and 25% of the patients were not properly sized. Although 85% of the patients felt that the stockings were comfortable, 41% of those rated the thigh-length stockings as uncomfortable, as did 6% who wore the knee-length stockings; 80% of patients understood the purpose of the stockings.

The CLOTS Trial 125 evaluated more than 2,500 patients who were immobile after having an acute stroke. The primary outcome evaluated the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins. Patients were randomized to routine care plus thigh-length GCSs or to routine care plus no stockings. Doppler ultrasound was performed on both legs from days 7 to 10 and days 25 to 30.

Results showed that 10% of patients wearing GCSs developed proximal DVT versus 10.5% of patients who were not wearing stockings. In addition, patients who wore GCSs had a higher incidence of skin breaks, ulcers, and necrosis than those patients who did not. Investigators concluded that GCSs do not reduce DVT or overall VTE in patients with recent stroke.25

IPC Devices

Intermittent pneumatic compression devices consist of a garment that fits around the legs and is intermittently inflated and then deflated in a cyclic manner with compressed air via an electrical pneumatic pump. Five different devices are available and vary based on the patterns of compression, length of sleeve, and cycle length, and all patterns of compression are effective. These devices have been used prior to, during, and following surgery and found to be effective in preventing DVT.26,27

A meta-analysis from a review of the medical literature reveals that IPC devices are effective in reducing the incidence of DVT.28 These authors concluded that prophylaxis with IPC devices reduced the risk of acute VTE by 60% among surgical patients.

Intermittent pneumatic compression devices have also been used safely in conjunction with anticoagulants. The APOLLO study29 showed that the combination of LMWH (SC) and IPC device was superior in reducing the rate of VTE compared with the IPC device alone for patients undergoing abdominal surgery. Similar results were found when patients undergoing unilateral total hip or total knee replacement surgery were given LMWH plus IPC device. This combination was more effective than LMWH plus GCSs for preventing DVT; however, these devices are not recommended in the treatment of DVT or PE.30

Despite guideline recommendations surrounding mechanical interventions, compliance with these devices may not be ideal.31 In patients undergoing total knee arthroplasty, Westrich and Sculco32 studied the relationship between DVT and the length of time an IPC device was worn. Results showed that patients who wore the device only for 13.4 +/- 4.3 hours a day developed a DVT, whereas those who used devices for 19.2 +/- 5.1 hours a day did not experience a DVT (P < .001). Investigators concluded that IPC devices may be appropriate where pharmacological treatment may be contraindicated in selected patients; however, if these devices are worn improperly during the entire course of a 24-hour period because of comfort, they are ineffective.32

Although there are differences between the various devices in length of sleeve and method of compression, Proctor et al27 were unable to show a difference in DVT incidence based on these variations. One might conclude that the comfort of the garment may have a direct correlation to the length of time the patient will use a device.

CONCLUSIONS

In summary, VTE is a significant threat to individuals with limited mobility, whether in the hospital or recovering in an outpatient setting. Methods of treatment, both pharmacological and nonpharmacological, either alone or in combination, can be used to prevent and also treat existing VTE. Mechanical forms of treatment create more challenge for the healthcare provider. Proper measurement and application are essential not only to maximize the benefit and reduce risk of complications, but also for the patient's comfort and compliance with treatment.

Clinical application of the guidelines is imperative to protect this large population of patients. Nurse practitioners are in a position to enhance the awareness of VTE prophylaxis. Improvements in patient education concerning awareness and risks of VTE as well as the importance of compliance with treatment are essential elements to preventing VTE, and the nurse practitioners can implement that education. Nurse practitioners s are key providers in the implementation of standards for anticoagulation monitoring in the outpatient setting and also recommend and implement VTE prophylaxis for preoperative patients. Awareness of the problem is the first step in changing the paradigm of noncompliance.

Acknowledgment

Thanks to Robert E. Lamb, PharmD for his assistance in the preparation and review of this paper.

REFERENCES