The oral factor XIa inhibitor milvexian across a range of doses is associated with a lower risk of venous thromboembolism (VTE) after knee arthroplasty than subcutaneous enoxaparin (Lovenox) without an uptick in bleeding, a phase 2 dose-ranging study suggests.
The results were reported at the virtual American Heart Association (AHA) Scientific Sessions 2021 and simultaneously published in the New England Journal of Medicine.
“Factor XI is an exciting targeting for new anticoagulants because there’s mounting evidence that factor XI is important for thrombosis but mostly dispensable for hemostasis,” said lead author Jeffrey I. Weitz, MD, McMaster University, Hamilton, Canada. “Therefore, factor XI inhibitors have the potential to be safer than targeting downstream targets like factor Xa or thrombin.”
Previous studies of parenteral factor XI inhibitors have shown that abelacimab is superior to enoxaparin for VTE prevention after knee surgery and that factor XIa inhibition with osocimab is noninferior, he said.
“It’s important that we’ve now moved from parenteral agents to having an oral agent that was tested here showing a high degree of efficacy and safety compared to a very well-established existing therapy,” Geoffrey Barnes, MD, University of Michigan, Ann Arbor, told theheart.org | Medscape Cardiology.
He noted that these drugs are usually tested in patients undergoing hip or knee surgery because of the high rate of VTE, but that the results clearly raise the question of whether they might have potential benefit, for example, in patients with mechanical valve replacement (who currently require warfarin therapy) or in those with other prothrombotic conditions like atrial fibrillation.
“It’s obviously phase 2 and a [long way] away from routine clinical practice, but it has me excited for what may be coming in the future to help care for our patients in an effective and even safer manner than we’re able to do now,” said Barnes, who is a member of the American College of Cardiology’s Peripheral Vascular Disease Council but was not involved with this research.
For the AXIOMATIC-TKR trial, Weitz and colleagues randomly assigned 1242 patients after knee arthroplasty to receive one of seven doses of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or once-daily enoxaparin 40 mg administered subcutaneously.
Enrollment in the once-daily 25-mg milvexian group was stopped early after just 34 patients because of insufficient efficacy, and the 50 mg-milvexian group added. In all, 941 patients were randomly assigned to milvexian and 301 patients to enoxaparin, with 85% and 84%, respectively in the modified intention-to-treat analysis.
The primary efficacy endpoint was VTE, defined as a composite of asymptomatic deep vein thrombosis detected by mandatory venography of the operated leg, confirmed symptomatic VTE, or all-cause death.
Among patients taking milvexian twice daily, VTE occurred in 21% taking 25 mg, 11% taking 50 mg, 9% taking 100 mg, and 8% taking 200 mg. A dose-response relationship was also present in the milvexian once-daily groups, with VTE reported in 25% on 25 mg, 24% on 50 mg, and 7% on 200 mg, compared with 21% of patients taking once-daily enoxaparin.
The findings for VTE compared with enoxaparin were significant for the once-daily milvexian groups at 50 mg (P < .01), 100 mg (P < .002), and 200 mg (P < .001) and for twice-daily milvexian 200 mg (P < .0001). In addition, the combined 12% incidence of VTE in the twice-daily milvexian groups was significantly lower than the trial's prespecified benchmark of 30% (one-sided P < .0001).
The principal safety outcome of any bleeding (major, clinically relevant nonmajor, and minor bleeding) occurred in 38 (4%) patients given milvexian and 12 (4%) given enoxaparin. The composite of major or clinically relevant nonmajor bleeding occurred in 7 patients vs 5 patients, respectively, and major bleeding in 0 vs 1, respectively.
Adverse events were reported in 39% of patients given milvexian and 38% given enoxaparin. Serious adverse events were reported in 2% and 4%, respectively.
“Obviously in a modestly-sized trial like this, it’s great to see that major bleeding and even clinically relevant nonmajor bleeding was not very high, but it also doesn’t give you the full story about whether there’s a bleeding signal here,” said session moderator Stephen D. Wiviott, MD, Brigham and Women’s Hospital, Boston. “Did you see anything with all bleeding or any signal that might suggest a dose response?”
Weitz replied, “No, nothing with all bleeding or with the composite of major and clinically relevant bleeding, which I showed you in the presentation. So, no, but I agree with you. The amount of data we have on bleeding is limited.”
He noted that further safety information is expected from the ongoing phase 2 AXIOMATIC-SSP study examining secondary stroke prevention with milvexian or placebo on top of dual-antiplatelet therapy with aspirin and clopidogrel for the first 21 days and then aspirin alone for 3 months. Study completion is set for March.
During the discussion, Weitz noted there is no specific reversal agent currently available for milvexian but that the drug has a short half-life of about 12 hours. “What we’re finding with factor XI inhibitors is that if you do run into trouble, you can use tranexamic acid, an antifibrinolytic agent, to manage bleeding and in some cases in patients with congenital factor XI deficiency, what is being used successfully is very low doses of factor 7a.”
Dedicated discussant Tracy Y. Wang, MD, MHS, Duke University, Durham, North Carolina, said this was a well-designed phase 2 trial but “beyond looking at efficacy with factor XI inhibitors, we really need to confirm if there is a bleeding advantage to this. This will affect how we start the drug and how long we use the drug.”
Bleeding information will also be important for certain populations, such as patients with severe renal insufficiency or those at high post-op bleeding risk for whom neither dual-antiplatelet therapy nor enoxaparin will be preferred, she added. More information is also needed about symptomatic vs asymptomatic VTE events and whether the location of the VTE was proximal or distal.
The trial was funded by Bristol-Myers Squibb and Janssen Research & Development, which were responsible for data collection, maintenance, and analysis. Weitz reports significant honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Novartis, Pfizer.
N Engl J Med. Published November 15, 2021. Abstract
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