Benefit of Selective Factor Inhibition

Venous thromboembolism (VTE) is a common disease carrying significant morbidity and mortality. In as many as 20% of patients, the initial presentation is sudden death from pulmonary embolism (PE). Despite improved prophylaxis, the incidence of VTE events has not changed significantly since 1980. This situation is not unlike the problem in the prevention of primary and secondary events from coronary heart disease (CHD); lack of progress has hinged on the failure to consider the potential for clinical events in high-risk patients and the need for improved pharmacologic interventions. In the case of CHD, the Adult Treatment Panels of the National Cholesterol Education Program have increased the public's and the medical community's awareness of individual risk factors for CHD events and the importance of risk-factor stratification. In a similar fashion, the American College of Chest Physicians has conducted consensus conferences on VTE, issuing reports discussing risk-factor stratification and describing recent developments in antithrombotic therapy. In the same vein, the contributors to this supplement hope that increased identification and prophylaxis of high-risk populations will decrease the incidence of VTE disease.

Unfortunately, conventional antithrombotic agents are not completely efficacious in accomplishing these goals. Until recently, clinicians have had limited options in antithrombotic medications: heparins and coumarins. Low-molecular-weight heparin (LMWH) was introduced within the last 10 years and has replaced unfractionated heparin in the prophylaxis and treatment of VTE events because of certain distinct advantages: a longer half-life, improved bioavailability, simple once- or twice-daily dosing, and absence of the requirement for laboratory monitoring. Meta-analyses have documented the superiority of LMWH in terms of efficacy and safety.

Some of the limitations of current antithrombotic compounds stem from their mechanism of action affecting multiple steps in the coagulation cascade. The resulting inconsistent dose-response relationships lead to the need for regular monitoring. Newer antithrombotic interventions target a single coagulation factor. The pharmacokinetic and pharmacodynamic profiles of these drugs are consequently more predictable. These new antithrombotic agents (some are still investigational) include direct thrombin inhibitors, selective factor Xa inhibitors, and inhibitors of the factor VIIa-tissue factor complex.

Fondaparinux (Arixtra^©; Organon Sanofi-Synthelabo LLC, West Orange, NJ), a selective factor Xa inhibitor, was studied in large, international multicenter randomized clinical trials involving more than 7000 patients. The results of these studies, which were done in high-risk orthopedic surgery populations, were presented. Meta-analysis of these studies showed a significant reduction in VTE events-55%-in fondaparinux-treated patients compared with the enoxaparin group. The safety profiles of the two agents were similar. Fondaparinux has also been studied in the treatment of symptomatic proximal DVT and PE, and future studies in this population are planned.

To date, the results of these studies indicate that selective factor Xa inhibition offers superior efficacy compared with LMWH and is associated with fewer major bleeding events. Other advantages of this strategy for thromboprophylaxis have been described. Selective factor Xa inhibition does not affect the activated partial thromboplastin time and shows no cross-reactivity with platelet factor 4. It also has no effect on platelet function or aggregation. Fondaparinux displays nearly complete bioavailability, with a half-life that allows once-daily injection. As a result of the large-scale phase III studies of fondaparinux, the drug has been approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for the prophylaxis of VTE events in high-risk orthopedic surgery patients.

Despite these advances, a number of unresolved issues in the field of thromboprophylaxis and the treatment of acute VTE events exist. Alternative antithrombotic medications that have a more targeted mechanism of action and that do not require laboratory monitoring would be an important advantage in the chronic treatment of patients at high risk of VTE events. Resolving the issue of thromboprophylaxis initiation in the surgical population and extending the duration of prophylaxis for the prevention of initial and recurrent VTE events are other important issues that remain controversial.

Although VTE events can be prevented, they remain a major source of morbidity and mortality. Sufficient clinical evidence now exists to indicate that risk-factor stratification and selective factor inhibition in patients at high risk for VTE events can improve outcomes in this disorder.