December 8th, 2014
New Anticoagulant Spotlights Major Role for the Intrinsic Pathway
An entirely new approach to anticoagulation will likely change our understanding of coagulation and thrombosis but the clinical implications may be less clear. FXI-ASO, under development by Isis Pharmaceuticals, is an antisense oligonucleotide that reduces the level of factor XI, a key component of the intrinsic (contact) coagulation pathway. All the currently available anticoagulants target the extrinsic (tissue factor) coagulation pathway.
In a phase 2 trial, 300 patients undergoing total knee arthroplasty were randomized to either enoxaparin or one of two doses of FXI-ASO. The incidence of venous thromboembolism, as assessed by venography, was 30% with enoxparin, 27% with the low (200 mg) dose of FXI-ASO, and 4% with the high (300 mg) dose of FXI-ASO. The low-dose FXI-ASO group was noninferior to enoxparin while the high-dose group was superior (p<0.0001). Bleeding occurred in 3% of each of the FXI-ASO groups and in 8% of the enoxaparin group, though this difference did not achieve statistical significance.
The investigators wrote in the New England Journal of Medicine that their “study showed that factor XI contributes to postoperative venous thromboembolism and that lowering factor XI levels was an effective method for its prevention and appeared to be safe.” The finding “challenges the concept that tissue factor is the main driver of thrombosis among patients undergoing surgery” and “raises the possibility that factor XI may be involved not only in the propagation of thrombosis, but also in its initiation.”
In an accompanying editorial, Robert Flaumenhaft agrees that the study “challenges the current paradigm” and offers “the best clinical evidence to date” for an important role for the intrinsic pathway in thrombus formation. But, he writes, the “results do not make a compelling case for the clinical use of the factor XI antisense oligonucleotide over anticoagulants that are currently used.” Among other limitations, he notes that the reduction in venous thromboembolism as detected by venography may not be clinically significant. The utility of FXI-ASO is also questionable given that it was initiated 36 days prior to surgery.
Overall, this is an interesting finding that provides support for the role of the intrinsic coagulation pathway in venous thrombosis post orthopedic surgery. The profound reduction in thrombotic events without adverse hemostatic events appears to be “too good to be true.”
The promising results of this open-label phase 2 trial need to be replicated in a large, adequately powered trial using clinically relevant endpoints. Eighty percent power for a noninferiority trial might be acceptable for a phase 2 trial, but not for a phase 3 trial. The noninferiority margin appears to be liberal. And the choice of the comparator (subcutaneously injected enoxaparin) when oral alternatives are available could be questioned. The risk reduction in this trial was primarily driven by asymptomatic distal thrombosis diagnosed on venography which is rarely used in clinical practice, thereby raising questions about its clinical relevance.
Other issues that might limit the clinical utility of this drug include the need to give it via weekly subcutaneous injections for 4-5 weeks prior to the procedure, and the prolonged pharmacodynamic effect with potential impact on reversibility. Bottom line: promising proof of principle results, but larger studies required to clarify the benefit-risk profile of this novel agent.
Going back 20 years the dogma has been that in developing systemic anticoagulants, there is a see-saw model with bleeding on one side and thrombosis on the other. That is, the more you inhibit thrombosis, the more you bleed, whether with increased doses of an existing drug or with drugs with increased potency. As stated in many places, it has been the holy grail of hemostasis and thrombosis research to dissociate the two and to uncover an agent that might protect against pathological thrombosis while not increasing the risk of bleeding.
Historically, almost all agents developed in this field were designed to inhibit thrombosis without much concern for what was considered to be a necessary evil — bleeding. As a result, all the agents on the market today primarily inhibit the extrinsic or tissue factor pathway. Preclinical experience in animals and our vast clinical experience tells us that this strategy will indeed result in a see-saw of safety and efficacy and that as we learn more about the real clinical cost of bleeding, we may have reached the ceiling in terms of clinical utility.
The contact pathway is relatively new in evolution. Contact pathway proteases are absent in fish and begin to show up in lower amphibians such as frogs. Since its discovery, there has been great debate about its necessity, as people born without contact pathway proteases have little or no bleeding. Of course, this exposes the bias that if there is no effect on bleeding, there is no effect. While it remains unknown why it developed, it is very clear that the contact pathway does play a role in thrombosis. Many recent and elegant animal studies have suggested that inhibition of contact pathway proteases might just offer a means toward breaking the see-saw. Perhaps activation of the contact pathway is a key driver of pathological thrombosis in surgery, acute illness, or other conditions with increases in systemic inflammation.
Investigators at ISIS pharmaceuticals developed a strategy to inhibit translation of factor XI protein by administration of an antisense oligonucleotide. The study they have published is the first significant clinical experience with this drug. The study itself is small and has many flaws, including that it was unblinded and that the protocol was changed mid-study. The drug is difficult to take, has to be administered long in advance of the “event”, and has a enormous rate of discontinuation due to injection-site issues. There is a very steep dose-response curve which is going to have to be explored more fully. However, with all these necessary caveats aside, this study represents a very exciting demonstration of how inhibition (reduction) of a contact pathway protease (factor XI) can reduce pathological thrombi after knee replacement at least as well as the standard inhibitor of the extrinsic pathway, enoxaparin. There was a tantalizing suggestion that this efficacy might come without the previously believed to be increase in bleeding. However, we have been led astray in small studies like this in the past; for right now, the best we can do is to say that this very interesting small study absolutely provides strong rationale for larger studies by ISIS and other companies developing small molecule or antibody-directed inhibitors of factor XI and perhaps factor XII.
It speaks volumes that a small study with its many warts appears in the New England Journal of Medicine. Expect lots more from this area and expect some disappointments along the way. But for now, there is great excitement about the contact pathway and the hope that we might have finally found a way to target pathological thrombosis without impacting blood clotting associated with wound healing (hemostasis).