Interpretation:

Increasing numbers of individuals worldwide are being seen with ACS, such as those enrolled in PENTUA. Until about 5 years ago, there were no large randomized trials looking at specific therapies for this syndrome. The development of fondaparinux continues recent efforts to inhibit ACS earlier in the coagulation system; instead of suppression of thrombin activity, the most common target of antithrombotic therapy, fondaparinux is part of a class of drugs that actually suppress the generation of thrombin.

These new agents, known as pentasaccharides, are specific inhibitors of activated factor X (factor Xa) in the clotting cascade; factor Xa leads to the formation of thrombin and subsequently to the formation of fibrin as part of the clot. Factor Xa is partly blocked by antithrombin, although this weak inhibition is strengthened when heparin binds to it. However, heparin binds to other clotting factors as well. Fondaparinux was created to bind to offer specific Xa inhibition without interfering with other clotting factors. Early trials were conducted to prevent deep vein thrombosis in orthopedic surgery patients. These trials indicated that fondaparinux reduces venous thrombotic complications by about 50% among patients undergoing orthopedic procedures. Subsequently, investigators wanted to determine whether this drug might be beneficial in patients with coronary artery disease.

During the AHA 2001 annual meeting, discussant Dr. Robert Califf noted that there is no explanation for the absence of a dose effect. Numerous clinical trials have shown that because the coagulation system is so complex, disturbing one component may cause any number of different effects, making it difficult to establish a workable hypothesis. However, to demonstrate whether fondaparinux is showing a differential effect rather than a random effect would require a “daunting” sample size, according to Dr. Califf. Another problem, he said, “There are no valid surrogate endpoints in this field. What we do have are biomarkers and intermediate medical outcomes that can give us probabilities to encourage us to either go on with the study or cut the losses and move on to attack a different biological arena.”

As these phase II results are encouraging but not definitive, certainty about clinical benefit will need to come from a large set of clinical trials. Additionally, studies of this and other drugs in active-controlled, rather than placebo-controlled, trials require a new methodology to deal with all the possible combinations present due to other therapies being used. Current U.S. therapy for ACS involves 2 types of patients: those who receive aggressive therapy (glycoprotein IIb/IIIa inhibition, early catheterization, revascularization), which involves numerous modifying factors, or those who are treated more conservatively. Dr. Califf said that both patient populations will need to be studied in a phase III trial, which also must demonstrate cost effectiveness based on the economical constraints of the current clinical practice environment.