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Reducing Factor XI may prevent postoperative thrombotic events
SAN FRANCISCO — Targeting Factor XI using a novel agent was associated with a significant reduction in venous thromboembolism risk among patients undergoing knee surgery, according to study results presented here.
Harry R. Büller, MD, PhD, professor of medicine in the department of vascular medicine at the Academic Medical Center, University of Amsterdam in the Netherlands, described FXI-ASO (ISIS 416858, Isis Pharmaceuticals) as a second-generation single-stranded 2- methoxyethyl antisense oligonucleotide that targets Factor XI.
Harry R. Büller
“Mouse models have shown that if you lower Factor XI, you lower the risk of bleeding complications,” he said.
The analysis included 69 patients treated with enoxaparin 40 mg, 134 patients treated with FXI-ASO 200 mg and 71 patients treated with FXI-ASO 300 mg.
The rate of VTE was 30.4% in the enoxaparin group, 26.9% in the FXI-ASO 200-mg group and 4.2% in the FXI-ASO 300-mg group.
“Only three clots were present in the 300-mg group,” Büller said. “This rate, 4.2%, has never been seen in the setting of knee surgery, where the best evidence is around 10% or 15%.”
By comparison, the risk difference was –3.6 for the 200-mg formulation vs. enoxaparin and –26.2 for the 300-mg formulation vs. enoxaparin.
“If we go to the 300-mg dose, the risk really is almost zero,” Büller said. “This is a very reduced rate of VTE, and they are tiny little clots.”
Büller suggested that the larger question with these interventions is that improved efficacy traditionally came with the trade-off of increased bleeding risk. “There was always a price to pay,” he said.
Enoxaparin yielded a major bleeding rate of 8.3% vs. 2.8% for FXI-ASO 200 mg and 2.6% for FXI-ASO 300 mg.
“This is the first evidence that Factor XI plays an important role in postoperative VTE,” Büller said. “Reducing Factor XI is a very effective method of preventing of VTE. Our findings support the concept, that thromboembolism and hemostasis can be separated.”
For more information:
Büller HR. Abstract LBA-1. Presented at: ASH Annual Meeting and Exhibition; Dec. 6-9, 2014; San Francisco.
Disclosure: Büller reports associations with Bayer HealthCare, Bristol-Myers-Squibb, Daiichi-Sankyo, Isis Pharmaceuticals and Pfizer.
Perspective
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This is really exciting to me as a clinician. Although some patients never bleed, knee surgery traditionally carries a high risk of bleeding complications. There have been several publications showing that higher levels of Factor XI are associated with higher levels of venous thrombosis or stroke risk, but this is the first study in humans to really show us that.
This is a wonderful model for us to build on, so it will be really important for us to do the studies to determine whether this is really the case. We’ll see how it bears out over time.
Perspective
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This abstract, presented during the late-breaking abstract session, is not the definitive, pivotal study, but it is a 300-patient study in which patients received an antisense oligonucleotide, meaning it’s a way of knocking down the liver expression of Factor XI. It has to be given days or even weeks before the procedure because it is very slow onset. These are patients who were undergoing total knee replacement and this is, as everybody knows, is often the first entrée for antithrombotics to establish proof of concept.
These patients received either the antisense oligonucleotide or standard prophylactic doses of enoxaparin. After their discharge from the hospital, they had a venogram done on day 7 or day 10 and, again, this has been very standardized over many years as an endpoint for antithrombotic therapy in clinical trials.
It was found that these patients actually had a lowered rate of thrombosis and a significantly lowered rate of any kind of bleeding compared with the patients who were getting enoxaparin. This is exciting because the Holy Grail, if you like, of our field is to find effective anticoagulant agents that do not cause bleeding. In other words, is it possible to inhibit the coagulation system and prevent it from causing clots but not inhibit so that bleeding is a risk?
Although this is not the definitive on this approach by any means, it is a beginning proof-of-concept study that will have to be validated. I think we will see a rush to develop other small molecules and other approaches targeting Factor XI.
There is one other aspect to this that is probably important to point out. These patients are essentially given acquired Factor XI deficiency, and patients with Factor XI deficiency don’t tend to bleed with many surgeries but do with others. In this study, the patients had major surgery with knee replacement, but the bleeding risk in Factor XI-deficient patients with surgery — as is well known to hematologists — is more with surgery involving mucosal surfaces, whether it be ENT, oral mucosa or genitourinary tract. It remains to be seen whether these drugs can be safely administrated in those situations. It may be a great approach only for certain types of surgery, and also, long-term, secondary prevention of thrombosis. So, we’ll have to see how this field develops.