Stephan Moll, MD writes (on Dec 8th, 2014)… A publication this week in the New England Journal of Medicine reports on a drug in development that protects patients from blood clots (DVT), without increasing the risk of bleeding. Too good to be true? Possibly, but may be not. Additional studies will have to tell.
When our blood clots, multiple blood clotting factors participate in the clot formation process. One of them is factor XI (eleven). It has been observed that patients with a congenital mild or moderate deficiency of factor XI often do not bleed and seem to have a lower risk of DVT and PE. Based on this observation, scientists have developed a drug that can lower factor XI levels to see whether such a drug can protect from blood clots without increasing the risk of bleeding. The drug is referred to as “Factor XI Antisense Oligonucleotide” (FXI-ASO or ISIS 416858; from Isis Pharmaceuticals). The study published this week examined the rate of bleeding and post-operative DVT in patients who received this drug and underwent major knee replacement surgery.
The study enrolled 300 patients who were to undergo knee replacement surgery. 100 patients were treated routinely, i.e. is they underwent surgery and then received enoxaparin (Lovenox®) 40 mg once daily for at least 8 days. Another 100 patients received a lower dose (200 mg) of the investigational drug, and another 100 patients a higher dose (300 mg), starting 5 weeks before surgery; neither of these 2 groups received enoxaparin (Lovenox®) after the surgery. The investigational drug was given as an injection into the skin (s.c. = subcutaneously) and was started 5 weeks before the surgery: three doses were given during the first week of treatment, followed by 4 once weekly doses before the surgery and 2 once weekly doses after the surgery. All patients had an imaging study (contrast venogram) of the legs 8-12 days after surgery to look for DVT.
- The new drug lowered, as expected, the factor XI levels: from 100 % (which is the level in normal people) before drug treatment, to 38 % in the lower dose investigational drug group, and to 20 % in the higher-dose group.
- In spite of the low factor XI levels, major bleeding during the knee replacement surgery and afterwards was similar in the 3 groups (8 % in the enoxaparin [Lovenox®] group, 3 % in each of the investigational drug groups).
- DVT occurred in 30 % of the patients who were treated with enoxaparin (Lovenox®), 27 % of patients treated with the low dose of the investigational drug and only 4 % of patients treated with the high dose of the new drug.
The new drug reduced the rate of post-operative DVT more than the conventional blood thinner, enoxaparin [Lovenox®], without increasing bleeding.
In spite of the major surgery, patients with the lowered factor XI levels did not bleed more than patients on enoxaparin. That is noteworthy. Of course, it is also remarkable that patients in the (higher-dose) investigational drug group had much less DVT than patients who received routine enoxaparin (Lovenox®) prophylaxis. However, the real fascinating aspect about this study is that the findings support the concept that a drug may protect from blood clots without increasing the risk for bleeding. If this holds true, then that is huge: An effective, yet safe “blood thinner” – the Holy Grail of anticoagulation. This was only a first and a relatively small studies. Further studies are, of course, needed to verify these very interesting findings. For anybody already thinking about availability in clinical practice of such a drug: At least 3-4 years, if not more, will still have to go by before this/such a drug, if successful, would make it onto the market.
Bueller HR et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med, Dec7,2014. ePub ahead of print.
Last updated: Dec 8th, 2014