Milvexian for the Prevention of Venous Thromboembolism
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With this podcast, we recap innovative, practice changing studies in ten minutes or less. And remember, nothing here is medical advice; we just present the evidence and our (sometimes hot) takes.
What’s the Evidence for Using Milvexian to Prevent Venous Thromboembolism after a Knee Replacement?
Nobody likes blood clots, and everybody wants to prevent them. We all know how finicky warfarin can be with trying to keep things in the therapeutic range. Newer direct acting oral anticoagulants target factor ten or thrombin. These have made dosing a heck of a lot easier, but the problem is…. all our tools for prevention are double-edged swords. Every anticoagulant also carries a significant risk of bleeding…and for some patients the risk of bleeding may even outweigh the benefits of anticoagulation. So today, we’re going to look at a new anticoagulant with a novel mechanism.
Milvexian is an oral factor eleven A inhibitor. Before we get too far let’s remember our clotting cascade really quick here…. There’s an extrinsic pathway that is critical for normal hemostasis. This pathway relies on tissue factor from surrounding tissues entering the blood due to damage, and thus activating factor seven and beginning the clotting process. The other pathway is called the intrinsic pathway and it’s less important for normal hemostasis but can still play a role. It’s activated by contact with surfaces such as glass and subsequently factor twelve begins the clotting cascade. Factor eleven is only a part of the intrinsic pathway. Both pathways converge into a common pathway, where factor ten is activated and subsequently thrombin is activated. Therefore, the current factor ten and thrombin inhibitors are so potent…they target critical parts of the clotting cascade common to both pathways.
Milvexian is different though. Since it targets factor eleven, it affects only the intrinsic pathway. Patients with a congenital deficiency of factor eleven have lower risk of venous and arterial clots, but they don’t commonly get spontaneous bleeding. So, the thought here is, maybe we can get the benefits of anticoagulation, while significantly diminishing the risk of bleeding.
So, in this randomized, open label, multicenter phase 2 trial of milvexian, over twelve hundred adult patients over the age of 50 who had undergone a knee replacement were randomized to receive various doses of milvexian or enoxaparin 40 mg once daily. Since milvexian is given orally and enoxaparin is given subcutaneously, the researchers didn’t blind patients or clinicians to which arm they were in, however they did blind the milvexian dosing regimen. Basically, milvexian could be given once or twice daily at total daily doses ranging from 25 to 400 milligrams. The medications were started 12–24 hours after surgery and continued for 10 to 14 days.
Patients were followed for 30 days, and the primary efficacy outcome was a composite of asymptomatic DVT, confirmed symptomatic venous thromboembolism, or death from any cause. If you’re wondering how they caught asymptomatic DVT’s we’ve got your answer…. they made everyone do a venography study 10 to 14 days post-surgery.
The primary safety outcome was a composite of major bleeding, clinically relevant non-major bleeding, and minimal bleeding.
Across all once and twice daily milvexian dose groups, the primary outcome occurred in 20 and 12% of patients respectively, while in the enoxaparin group it was seen in 21%. Interestingly, the researchers compared milvexian to a pre-specified rate of 30% and found the difference to be significant for the twice daily group. The 30% number was an estimate of the rate of the primary composite outcome in patients not taking any anticoagulant or anti-platelet medication.
That being said, in their supplementary material we were able to track down some direct comparisons to enoxaparin. At total daily doses above 100 milligrams, both the once and twice daily groups had significantly lower rates of the primary outcome than in the enoxaparin group. A significant dose response relationship was seen in both the once and twice daily groups.
There didn’t appear to be an increased risk of bleeding compared to enoxaparin either. Any bleeding episode occurred in 4% of both the milvexian and enoxaparin arms. Even at higher milvexian doses, any bleeding event never reached more than 6%. Clinically relevant bleeding was seen in 1% of the milvexian group and 2% of the enoxaparin group. Again, at the higher milvexian doses this number stayed at 1%!
So, what can we take from this study….? Well, milvexian does appear to decrease venous clots after a knee replacement, and at higher doses it appears to be better than enoxaparin. While it seems safe, we really need more overall bleeding events to occur to be sure of its safety, so a larger trial would be warranted. While the trial did monitor both prothrombin time and activated partial thromboplastin time or aPTT for short, they only saw a dose response relationship between the milvexian dose and the aPTT. And remember…this makes sense because the prothrombin time measures the extrinsic pathway, while the aPTT measures the intrinsic pathway, which factor eleven is a part of. The interesting part of all this is we didn’t see more bleeding at higher doses. We know that in patients with a congenital factor eleven deficiency, there is a poor correlation between elevated aPTT and bleeding propensity. This may be because factor eleven just isn’t all that important for normal hemostasis, but it does play a big role in prolonging the aPTT.
So, in conclusion, the data is promising and the intrigue of a possible safer anticoagulant warrants further study. But we clearly need a larger phase 3 trial to confirm the safety of milvexian at the higher doses where the best efficacy was seen. The primary outcome should compare milvexian to a standard of care and not just a pre-specified venous thromboembolism rate of 30%. It would also be nice to blind the trial. While this would mean injecting everyone with either enoxaparin or saline, it would solidify the results. Lastly, the need for any therapeutic drug monitoring would need to be nailed down as well. While it appears the aPTT correlates with dose intensity, it’s unclear how clinically significant this is for bleeding.
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