Novel Factor Xa Inhibitor for the Treatment of Cerebral Venous and Sinus Thrombosis
First Experience in 7 Patients
Background and Purpose—Thrombosis of cerebral veins and sinus (cerebral venous thrombosis) is a rare stroke pathogenesis. Pharmaceutical treatment is restricted to heparin and oral anticoagulation with vitamin K antagonists (VKAs).
Methods—Between January 2012 and December 2013, we recorded data from our patients with cerebral venous thrombosis. The modified Rankin scale was used to assess clinical severity; excellent outcome was defined as modified Rankin scale 0 to 1. Recanalization was assessed on follow-up MR angiography. Patients were then divided into 2 treatment groups: phenprocoumon (VKA) and a novel factor Xa inhibitor. Clinical and radiological baseline data, outcome, recanalization status, and complications were retrospectively compared.
Results—Sixteen patients were included, and 7 were treated with rivaroxaban. Overall outcome was excellent in 93.8%, and all patients showed at least partial recanalization. No statistical significant differences were found between the groups, except the use of heparin before start of oral anticoagulation (P=0.03). One patient in the VKA and 2 patients in the factor Xa inhibitor group had minor bleeding (P=0.55) within the median (range) follow-up of 8 months (5–26).
Conclusions—Factor Xa inhibitor showed a similar clinical benefit as VKA in the treatment of cerebral venous thrombosis. Further systematic prospective evaluation is warranted.
The current therapy of cerebral veins or sinus thrombosis (cerebral venous thrombosis [CVT]) is initiated with heparin, thereafter oral anticoagulation (OAC) with vitamin K antagonists (VKAs) for ≥3 to 6 months is recommended. In the past few years, new oral anticoagulants that inhibit factor Xa or thrombin directly have been developed. The EINSTEIN studies (EINSTEIN DVT [Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis] and Einstein-Extension [Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism]) showed a noninferior efficacy for rivaroxaban compared with enoxaparin plus a vitamin K antagonist in patients with peripheral deep vein thrombosis,1 and in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation. Moreover, intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.2 Since December 2011, rivaroxaban is an approved therapy for acute and long-term treatment of deep vein thrombosis and prevention of systemic embolism in patients with atrial fibrillation. Until now, data on new oral anticoagulants for CVT are not available.
Here, we report our experience with 7 patients having CVT, who were treated by the factor Xa inhibitor (FXaI) rivaroxaban, in comparison with 9 patients treated with phenprocoumon.
We systematically searched our database for patients who were treated for CVT in our institution between January 2012 and December 2013 and to whom clinical and radiological follow-up data were available until March 2014. Patients with septic or traumatic CVT, as well as patients undergoing endovascular recanalisation therapy, were excluded. We recorded all relevant clinical data and measured clinical severity by using the modified Rankin scale at admission, discharge, and follow-up visits. Either computed tomography or MR venous angiography was performed to establish the diagnosis in all patients. OAC was started by the choice of the treating physician with either the standard treatment phenprocoumon (VKA, target international normalized ratio, 2–3) or rivaroxaban (FXaI) on the basis of an individual treatment attempt. MR angiography was performed on follow-up to assess vessel recanalization as (overall) partial or complete according to Stolz et al3 by 2 investigators blinded to treatment on consensus basis (C.H. and S.N.). Excellent outcome was defined as modified Rankin scale 0 to 1. Patients were divided into 2 groups according to the regime of OAC. We then compared the treatment groups regarding clinical and radiological baseline data, outcome, recanalization status, and complications. All analyses were done retrospectively with the Fisher, χ2, or the Mann–Whitney test.
Of 30 patients with CVT, 14 had to be excluded because of the above mentioned criteria. Seven of the remaining 16 were treated with rivaroxaban, another 9 with phenprocoumon. Detailed characteristics of all patients are summarized in the Table. Within the whole cohort, long-term outcome was excellent in 93.75%, and 50% achieved complete overall recanalization (Figure); the rest showed at least overall partial recanalisation on the last follow-up MR angiography. No relevant complications or recurrent thrombotic events occurred. None of the variables were significantly different between the 2 groups, except the use of heparin (P=0.03). All patients of the FXaI group were treated with low molecular weight heparin until the beginning of OAC, and no patient in the VKA group switched from unfractioned heparin to low molecular weight heparin or vice versa. The starting dose of rivaroxaban varied between 2×15 mg (21 days then 20 mg, 4 of 7) and 20 mg (3 of 7) daily. Two patients of the FXaI group had recurrent nose bleeding, which led to reduction of the rivaroxaban dose by the treating general practitioner to 10 and 15 mg QD after 3 and 4 months of therapy, respectively. One patient of the VKA group had intensified menstruation.
Demographic data, risk factors, affected vessels, and brain lesions of our patients are comparable to the largest previously published and prospectively collected cohort of patients with CVT.4 Recanalization rates and clinical outcome were excellent in both groups. No relevant and statistical significant difference between the VKA and FXaI group were found, except for the concept of heparin use before OAC. This difference is explained by the more common use of low molecular weight heparin in our institution since the publication of the study of Misra et al.5 Although symptoms were not significantly different, imbalances in clinical severity on admission between both groups cannot be excluded.
The median start of OAC was 5 days after bridging with heparin. Although rivaroxaban may be started first line for the treatment of deep vein thrombosis, we still use an initial phase with heparin until stable conditions after CVT are achieved. In 3 patients with additional hemorrhage, infarction or brain edema treatment was initiated with 20 mg QD (instead of 2×15 mg for 21 days, which is recommended for the acute treatment of deep vein thrombosis), owing to the potential risk of further brain hemorrhage. Follow-up MRI, especially in these patients, showed no further complications (Figure).
One patient of the VKA group and 2 patients of the FXaI group had minor bleeding complications that led to dose reduction in the case of both FXaI patients. However, no patient had intracranial or other major bleeding complication, and no recurrent thrombotic events were observed during the median follow-up of 8 months.
Our study has a retrospective, uncontrolled design and a small sample size. Nonetheless, in these first reported cases of CVT, rivaroxaban showed a similar clinical benefit as phenprocoumon. Especially for young patients with CVT, rivaroxaban might be a desirable treatment alternative to vitamin K antagonists because of its known application and metabolism benefits. Our experience warrants further systematic prospective evaluation of rivaroxaban and other new oral anticoagulants for the treatment of CVT.
Dr Ringleb received travel expenses and speaker honoraria (<1000 Euros) from Bayer Healthcare. The other authors report no conflicts.
- Received May 16, 2014.
- Accepted May 30, 2014.
- © 2014 American Heart Association, Inc.
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