Bayer Pharma AG

Vitamin K antagonists

Vitamin K antagonists

Vitamin K antagonists (VKAs) have been used as anticoagulants for over 50 years, because vitamin K is an essential part of the coagulation process. Warfarin is the most commonly used VKA, although other coumarin derivatives are also used. VKAs have many limitations and are difficult to manage — studies show that fewer than half of patients using warfarin are within the therapeutic range in the community setting. Because of the variability in the dose–response with VKA medications, monitoring the degree of anticoagulation is essential. The international normalized ratio (INR) provides a standardized measure of the VKA anticoagulant effect.

Risk factors for venous thromboembolism

Data indicate that several factors can increase the risk of venous thromboembolism (VTE) and if a patient has multiple risk factors, there is generally a cumulative impact. Surgery and immobilization are two prominent risk factors. Although general surgery is associated with a risk of VTE, the highest risk is observed after major orthopaedic surgery. However, although VTE is often associated with recent trauma or surgery, 50–70% of symptomatic cases, as well as the majority of cases of fatal pulmonary embolism (PE), occur in medical patients.

Anticoagulant Therapy Overview

For more than 20 years, routine preventive anticoagulant therapy has been the standard of care after major orthopaedic surgery. It has been shown to be both effective and associated with a low risk of postoperative bleeding complications. Thromboprophylaxis has proven to be cost-effective in moderate- and high-risk general surgery patients. In acutely ill, hospitalized medical patients, pharmacological prophylaxis is also recommended. Anticoagulant drugs are designed to inhibit the coagulation cascade to modulate the formation of thrombi. Traditional agents tend to target multiple factors in the cascade. Since 2008, a number of single-target novel oral anticoagulants have become available.

Strategies for venous thromboembolism prophylaxis

The oral, direct Factor Xa inhibitor betrixaban has been investigated for the prevention of venous thromboembolism (VTE) after orthopaedic surgery. The phase II EXPERT study randomized patients undergoing elective total knee replacement surgery to receive betrixaban 15 mg or 40 mg twice daily, or enoxaparin 30 mg twice daily, for 10–14 days after surgery. The incidence of VTE was 20% with betrixaban 15 mg twice daily, 15% with betrixaban 40 mg twice daily and 10% with enoxaparin 30 mg twice daily. There was no bleeding with betrixaban 15 mg twice daily and 2% of patients had clinically relevant non-major bleeding with betrixaban 40 mg twice daily. No phase III study of betrixaban is currently underway in orthopaedic surgery.

Other options for venous thromboembolism prevention

Although mechanical prophylaxis methods have been shown to reduce the risk of deep vein thrombosis (DVT), they have been studied much less intensively than the major pharmacological treatment options. Mechanical methods of prophylaxis include graduated compression stockings, intermittent pneumatic compression and venous foot pumps. Mechanical prophylaxis should be used primarily in patients who are at high risk of bleeding, or as an adjunct to anticoagulant therapy.

Balancing the benefits and risks of anticoagulant therapy

Therapies to prevent venous thromboembolism (VTE) vary in efficacy and risk of adverse events, so the decision to provide anticoagulant prophylaxis must take these factors into consideration. Generally, the benefits of thromboprophylaxis after major orthopaedic surgery have been shown to outweigh the risks of bleeding, regardless of the therapy used. Immobilized medical patients are also at risk of VTE, and although thromboprophylaxis is effective, it has not been shown to reduce mortality in this population. Extended thromboprophylaxis has been associated with an increased risk of bleeding. Simple scores that assess the risk of bleeding, such as that developed using the IMPROVE registry, can help physicians identify patients suitable for anticoagulant prophylaxis.