Roundup: Formulary Considerations for VTE

Dr. Le is a pharmacy practice resident at Fountain Valley Regional Hospital and Medical Center in Fountain Valley, California. Dr. Pham is assistant professor of pharmacypractice at Western University College of Pharmacy and Health Sciences in Pomona, California.

A major cause of morbidity and mortality in the health system is venous thromboembolism (VTE). VTE includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Evidence-based practice guidelines have been developed for the prophylaxis of VTE. Currently, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and selective factor Xa inhibitor (fondaparinux) are all approved for the prevention of VTE.

Guidelines for DVT Prophylaxis

The most current guidelines for VTEprophylaxis are based on the 2004 Seventh American College of Chest Physicians (ACCP) Conference on Antithromboticand Thrombolytic Therapy.¹ The guideline for VTE prophylaxis is based on solid principles, and recommendationsare made based on risk levels. All recommendations have been considered Grade 1, which indicate a strong benefit-to-risk ratio. Regardless, it is important to emphasize that the final decision regardingthe use and nature of prophylaxis lies with the individual clinician.

Table

Risk Levels for VTE

Low risk: minor surgery in patients <40 years old with no additional risk factors

Moderate risk: minor surgery in patients with additional risk factors;surgery in patients aged 40-60 years with no additional risk factors

High risk: surgery in patients >60 years, or aged 40-60 years with additional risk factors

Highest risk: surgery in patients with multiple risk factors, hip or knee arthroplasty, and major trauma

VTE = venous thromboembolism.

VTE prophylaxis methods are divided into 2 categories: mechanical methods and pharmacologic methods. Mechanical methods include the use of graduatedcompression stockings (GCS), intermittentpneumatic compression (IPC) devices, and venous foot pumps which all help increase venous blood outflow and reduce stasis within the leg veins. Mechanical methods have been shown to reduce the risk of VTE in a number of patient groups; however, they have been studied less than anticoagulant-based prophylaxis and are generally less efficacious. The use of mechanical devicesshould be considered in patients at high risk for bleeding. Mechanical devices can be used alone or in combination with pharmacologic methods. Although concerns have been raised regarding the bleeding complications associated with pharmacologic thromboprophylaxis, abundant data exist to show a desirable risk-to-benefit ratio.

Assess All Patients for Risk

The guidelines recommend that all patients be assessed for their risk of VTE. The selection of prophylaxis depends on the individual's risk factors for VTE and the type of surgery he or she may be undergoing. After identifying a patient's risk factors, it is important to assign risk levels based on the type of surgery (Table). Several key recommendations include the following:

• All patients: recommend against the use of aspirin alone as thromboprophylaxis.
• Moderate-risk general surgery patients:prophylaxis with low-dose unfractionated heparin (LDUH) 5000 units twice daily, or LMWH ≤3400 units once daily.
• Higher-risk general surgery patients: thromboprophylaxis with LDUH 5000 units 3 times daily, or LMWH >3400 units once daily.
• High-risk general surgery patients with multiple risk factors: prophylaxiscombining pharmacologic methods of LDUH 3 times daily, or LMWH >3400 daily with the use of GCS and/or IPC devices.

It also is recommended that pharmacologicthromboprophylaxis with LDUH be given 2 to 3 times daily and used in all patients undergoing major gynecologicsurgery or major open urologic procedures.

For patients undergoing elective total hip or knee arthroplasty, 1 of the following3 anticoagulant agents can be used: LMWH, fondaparinux, or adjusted-dose warfarin with international normalized ratio target range from 2.0 to 3.0. For patients undergoing hip fracture surgery, routine use of fondaparinux, LMWH, warfarin,or LDUH can be used and continued for at least 10 days. All trauma patients with at least 1 risk factor for VTE should receive thromboprophylaxis. In acutely ill medical patients who have been admittedto the hospital with heart failure or severe respiratory distress, or who are confined to the bed and have 1 or more additional risk factors, prophylaxis with LDUH or LMWH should be considered.

The required duration or extended use of prophylaxis may need to be continuedin some patients after discharge. Further studies are required to address this issue, and individual clinical judgmentshould be used.

Recent Studies Comparing Agents

In July 2007, Wein et al performed a meta-analysis that included 36 randomizedcontrolled trials to determine which pharmacologic agents were most effectivein preventing VTE in hospitalized medical patients.²

This meta-analysis concluded that the use of LMWH, LDUH, and fondaparinux were associated with a statistically significantreduced risk of DVT and PE and increased risk of total bleeding, comparedwith no prophylaxis. DVT was preventedmore effectively when LDUH was administered 5000 units 3 times daily, compared with 5000 units twice daily. Neither LDUH nor LMWH were shown to have any effects on mortality reduction. When compared directly, it appeared that LMWH was one third more effectivethan LDUH in preventing DVT. Also, patients taking LMWH exhibited lower risk of injection site hematoma than LDUH. Furthermore, no significant differencewas observed between LMWH and LDUH in terms of bleeding and thrombocytopenia.No statistically significant differences were observed between the 2 agents in regard to PE.

Before we can implement any major changes and deviate from current practice,we must weigh the strengths and weaknesses of this meta-analysis. For example, only 10 of the 36 trials reviewed directly compared LMWH with LDUH. Also, the patient population from the 36 trials was not homogeneous. Finally, the type of LMWH used among the trials reviewed was not consistent.

How Health Systems Should Choose Medications for Formulary

Pharmacy and therapeutic committeeswithin the health system should evaluate the use of LDUH, LMWH, and fondaparinux, as all 3 agents have been recommended for VTE prophylaxis in the ACCP guidelines. Priority should be given to agents that produce the most therapeuticbenefit with the least adverse effects and the least cost.

Conclusion

The ACCP guidelines recommend the use of LDUH, LMWH, and fondaparinux in medical patients at risk for VTE. Pharmacists must keep abreast of this information in order to select the best agents for their patients.

Case Studies

• TL is a 63-year-old obese woman who has had multiple episodes of falls. TL is to undergo hip fracture surgery. She has a medical history significant for hypertension, diabetes mellitus, hypercholesteremia, and myocardial infarction, status-post (MI s/p), 1 year ago. What level of risk for venous thromboembolism (VTE) does TL have?Low riskModerate riskHigh riskHighest risk
• What therapeutic interventions might decrease the risk of deep vein thrombosis or pulmonary embolism in TL?LDUH BIDLMWH >3400 units dailyIPCb and c
• Since TL had an MI s/p 1 year ago, she can use acetylsalicylic acid 325 mg by mouth daily for VTE prophylaxis.TrueFalseCannot be determined

Answers:1. d; 2. d; 3. b

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References

• Geerts WH, Pineo GF, Heit JA, et al. Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004:126(suppl 3);338S-400S.
• Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1476-1486.