Stephan Moll, MD writes (on Dec 8th, 2014)… A publication this week in the New England Journal of Medicine reports on an investigational drug that protects patients from VTE without increasing the risk of bleeding [reference below]. Too good to be true? Possibly, but may be not. Additional studies will have to tell.
It has been observed that patients with congenital mild or moderate deficiency of coagulation factor XI (a) often do not have an increased bleeding tendency and (b) seem to have a lower risk of DVT and PE. This has led to the idea that one might be able to lower factor XI levels in patients by and, thus, prevent thrombosis without causing bleeding. Such dissociation of thrombosis and hemostasis is a desirable concept. May be the wideheld assumption that every anticoagulant must automatically increase the risk for bleeding is not necessarily true. A drug has been developed (company: Isis Pharmaceuticals), a “Factor XI Antisense Oligonucleotide” (FXI-ASO or ISIS 416858), that can lower plasma factor XI levels in humans by reducing factor XI messenger RNA expression in the liver. The study published this week in the New England Journal of Medicine examined the rate of bleeding and of post-operative DVT in patients receiving this drug and undergoing knee replacement surgery.
- The study enrolled 300 patients who were to undergo knee replacement surgery.
- 100 patients were treated routinely, i.e. they received post-operative enoxaparin 40 mg once daily, for at least 8 days.
- 100 patients received a lower dose (200 mg) of the investigational drug and another 100 a higher dose (300 mg), starting 5 weeks before surgery. These patients did NOT receive any postoperative enoxaparin.
- The investigational drug was given as a s.c. injection, started 5 weeks before the surgery: 3 doses were given during in the first week of treatment, followed by 4 once weekly doses before surgery and 2 once weekly doses afterwards.
- All patients had a contrast venogram of the legs done 8-12 days after surgery.
- The investigational drug lowered, as expected, the factor XI levels: It was 93 % in the enoxaparin control group, 38 % in the lower-dose investigational drug group, and 20 % in the higher-dose group.
- In spite of the low factor XI levels, major (and clinically relevant non-major) bleeding during the knee replacement surgery and postoperatively was similar in the 3 groups (8 % in the enoxaparin group, 3 % in each of the investigational drug groups).
- DVT occurred in 30 % of the patients treated with enoxaparin, 27 % of the patients on the lower dose of the investigational drug, and only 4 % of patients treated with the higher dose of the new drug.
- The majority of DVTs were asymptomatic distal DVTs.
- The main side effect of the investigational drug was a local injection site reaction (erythema, pain, pruritus, swelling, hematoma).
The new drug reduced the rate of post-operative DVT more than the conventional anticoagulant enoxaparin, 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 (albeit asymptomatic distal DVT) than patients who received routine LMWH prophylaxis. However, the real fascinating aspect about this study is that the findings support the concept that a drug may protect from thrombosis without increasing the risk for bleeding. If this holds true, then that is huge: A safe “anticoagulant”. Further studies are, of course, needed to verify these very interesting findings.
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