Study Suggests Method of Reducing Blood Clots Without Risking Bleeding

It’s long been assumed that clinicians who treat patients to avoid blood clots must risk consequences: the potential for bleeding. But a study outlined Sunday at the 56th Annual Meeting of the American Society of Hematology and simultaneously published in the New England Journal of Medicine works around that problem, and could give clinicians a safer way to limit blood clots, with enormous safety potential for patients.¹

Factor XI, a component in the pathway of coagulation, is naturally reduced in some people, and this group is at less risk of venous thromboembolism, or VTE. So, the reasoning went, if Factor XI was reduced by other means in patients undergoing a surgical knee replacement—a procedure with high risk for blood clots—would the patients have reduced VTE? In the study presented at Sunday’s press conference, Harry Büller, MD, PhD, of the Academic Medical Center of the University of Amsterdam, the Netherlands, described how researchers used injectable nucleic acid engineered to reduce Factor XI expression.

Dr Büller could barely contain his excitement about the results and confessed he had grown weary of holding in his secret. “This is the holy grail,” he said. The ability to decouple treatment for blood clots from bleeding episodes could revolutionize surgical care and reduce medical costs. His study was one of 4 related to blood clots discussed at Sunday’s news conference, and he is scheduled to formally present the results Tuesday at the late-breaking abstract session.²

In a randomized controlled trial, approximately 300 patients receiving total knee replacement received an interfering agent for Factor XI, in doses of either 200 or 300 mg, or the anticoagulant enoxaparin at 40 mg. Patients received subcutaneous injections of Factor XI starting 36 days before surgery, to allow time for the treatment to interfere with FXI production, with the last dose 3 days after surgery. Those in the control group received enoxaparin for at 8 days after surgery.

Afterward, patients receiving 300 mg of a Factor XI interfering agent had the lowest occurrence of VTE (4.2%, 3 of 71 patients) when compared to those receiving 200 mg of the Factor XI agent (26.9%, 36 of 134 patients) or enoxaparin (30.4%, 21 of 69 patients). Also, those who received the Factor XI interfering agent had fewer bleeding incidents than those who had enoxaparin (bleeding rate of 2.6% in the high-dose Factor XI agent group compared with 2.8% in the low-dose group and 8.3% for anti-coagulant group.) Researchers found the Factor XI interfering agent did not increase bleeding and did not interfere with other aspects of coagulation.

Blood Clots and Cancer. A pair of studies involving blood clots and cancer were presented at Sunday’s press conference. Data gathered by researchers from the Netherlands examined 926 cancer patients from 11 studies or registries who had lung scans for other reasons that recorded incidental pulmonary embolism (IPE). Researchers found that the chance of developing a second clot were nearly double in cancer patients with IPE who did not receive continued anticoagulant treatment, compared with those who had low-molecular weight (LMWH) heparins or vitamin K antagonists (12% compared with 6.2% or 6.4%). Six-month mortality was higher in untreated patients (47%) than in patients with LMWH or VKAs.³

Another study found that tinzaparin, a LMWH, was more effective than warfarin for treating actue VTE in cancer patients. The results discussed by Agnes Lee, MD, of the University of British Columbia in Vancouver, Canada, will also be formally presented at the late-breaking session Tuesday; they essentially confirm a single trial on which current guidelines are based. Dr Lee explained that study participants received either tinzaparin once daily for 6 months or tinzaparin once daily for 5 to 10 days, followed by 6 months of warfarin. During the treatment period, 31 patients (6.9%) treated with tinzaparin experienced recurrent VTE compared with 45 (10%) patients treated with warfarin. Tinzaparin was only statistically significant in reducing recurrent DVT in veins above the knee. Researchers did not observe a difference in the mortality or incidence of major bleeding events (2.9% in the tinzaparin arm and 2.7% in the warfarin arm), but noted that significantly fewer patients experienced clinically relevant, non-major bleeding with tinzaparin than warfarin (11% vs 16%). Under questioning, Dr Lee acknowleged that warfarin is significantly less expensive than tinzaparin and other LMWH, and the panel moderator Mary Cushman, MD, of the University of Vermont in Burlington, said that her hospital defaults to warfarin if patients cannot get insurance coverage for heparins.⁴

NOACs in Real-World Settings. Newer medications than warfarin, known as novel anticoagulants (NOACs), do cost more but require less monitoring to assess bleeding risk, and there is no recommended stardardized dose. Three newer anticoagulants—dabigatran, apixaban, rivaroxaban—may help patients avoid these other non-medication costs. The study presented Sunday examined bleeding risks outside of a clinical trial setting. Martin H. Ellis, MD, of Meir Medical Center in Kfar Saba, Israel, presented a population analysis that looked at 18,249 patients with atrial fibrillation who took warfarin or a NOAC (dabigatran or rivaroxaban) between January 1, 2011 and December 31, 2013. Patients taking warfarin had 3.9 bleeding episodes per 100 patient years, while those taking dabigatran had 2.8 (150 mg twice daily) or 4.6 (110 mg twice daily) and 4.3 on rivaroxaban. Dr Ellis said the slightly higher bleeding rate on the lower dose was explained by doctors managing the doses of patients who started out with higher risks of bleeding. He noted that while the newer therapies present advantages, there are still risks, and patients and physicians must be alert.⁵

References

1. Buller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med [published online December 7, 2014] DOI: 10.1056/NEJMoa1405760.
2. Buller HR, Bethune C, Bhanot S, et al. Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. Blood, 2014; 124 (21): Poster LBA-1
3. T van der Hulle, P L den Exter, G Meyer, et al. Risk of recurrent venous thromboembolism and major bleeding in cancer-associated incidental pulmonary embolism amongst treated and untreated patients: a pooled analysis of 926 patients. Blood, 2014; 124 (21): Poster 590.
4. Lee AA, Kamphuisen PW, Meyer G, et al. Randomized trial of long-term tinzaparin, a low molecular weight heparin (LMWH), versus warfarin for treatment of acute venous thromboembolism (VTE) in cancer patients — the CATCH study. Blood, 2014; 124 (21): Poster LBA-1.
5. Ellis, MH, Neumann T, Ginsberg, JS, et al. Bleeding in patients with atrial fibrillation treated with non vitamin K antagonist oral anticoagulants: a population-based study. Blood, 2014; 124(21): Poster 343.