Are direct oral anticoagulants safe and effective for the treatment of adults with cerebral venous thrombosis (CVT)?
Background
Cerebral venous thrombosis (CVT) is a rare manifestation of deep vein thrombosis (DVT) where a clot forms in the cerebral veins or dural venous sinuses.1 The incidence of CVT in the general population is estimated at 1 to 2 cases per 100,000 person-years; approximately 0.5% to 1% of all strokes are caused by CVT.2 Patients of any age may present with CVT, but it is most common among younger patients and women of reproductive age.1,2 Approximately 75% of CVT cases occur in women, and 80% of cases affect patients aged less than 50 years.2 Despite its relative rarity, CVT is considered a leading cause of stroke among patients less than 45 years of age.1 It is associated with significant morbidity and mortality, particularly if diagnosis is delayed. An estimated 10% to 15% of patients with CVT will die or lose their functional independence; those without long-lasting functional impairments may still experience decreased quality of life or disability related to cognitive impairment, mood, fatigue, or pain.2
Initial symptoms of CVT can include headache, seizure, focal neurologic symptoms, and depressed level of consciousness.2 About one-third to one-half of patients will present with acute stroke-like symptoms or thunderclap headache, but many patients with CVT have a more subacute presentation and may not seek care until 48 hours to 2 weeks after symptom onset. Goals of therapy in CVT include restoring blood flow, preventing permanent damage to brain tissue, and preventing thrombus propagation or recurrence. The mainstay of treatment for CVT is anticoagulant therapy, which typically includes parenteral anticoagulation (eg, unfractionated or low-molecular weight heparin) in the acute phase and oral anticoagulation in the post-acute phase. Given the rarity of CVT, there are few clinical trials available to inform management; however, in recent years, there has been increased interest in the use of direct oral anticoagulants (DOACs) for post-acute anticoagulant therapy in this disease state. This article will discuss current practice recommendations for the treatment of adults with CVT and examine new literature pertaining to DOAC use in this setting.
Guideline recommendations on the treatment of CVT
The American Heart Association (AHA) and the American Stroke Association (ASA) published a joint statement on the diagnosis and management of CVT in 2011.3 This guideline recommends initial anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular weight heparin, followed by treatment with an oral vitamin K antagonist (eg, warfarin). This recommendation applies to all patients without major contraindications to anticoagulation (eg, recent major hemorrhage); of note, intracranial hemorrhage secondary to CVT is not considered a contraindication to anticoagulant therapy. Anticoagulant therapy should generally be continued for 3 to 12 months, but may be continued life-long, depending on the underlying etiology of CVT. Patients who continue to deteriorate despite anticoagulant therapy may require endovascular therapy or decompressive hemicraniectomy. Supportive care (eg, antiseizure medication for seizures, acetazolamide for intracranial hypertension) should be initiated as necessary to manage acute complications of CVT.
Unfortunately, this statement does not address the possible utility of DOACs in the setting of CVT, likely due to the age of the document. Updated guidance from American professional societies is lacking. The 2021 American College of Chest Physicians (ACCP) guideline on antithrombotic therapy for venous thromboembolism (VTE) recommends that patients with CVT receive anticoagulant therapy for at least 3 months; however, no formal recommendations are made regarding choice of anticoagulant.4 The European Stroke Organization published a guideline on CVT in 2017 that makes more specific treatment recommendations.5 This guideline suggests low-molecular weight heparin over unfractionated heparin for acute-phase treatment of CVT, unless the patient has a contraindication to low-molecular weight heparin. This should be followed by warfarin therapy for 3 to 12 months to prevent recurrence of CVT. At the time of guideline publication, only 2 case series describing the use of DOACs in CVT were available; as a result, the guideline authors recommended against the use of DOACs in CVT, particularly during the acute phase.
New evidence on DOAC use in CVT
Since the publication of the above-mentioned guidelines, larger studies of DOACs in adult CVT have become available (Table).6-13 Although most of these studies have been observational in nature, one randomized controlled trial (RCT) has compared dabigatran to warfarin, and another smaller RCT has compared rivaroxaban to warfarin.6-9 These trials found no significant differences in efficacy or safety between warfarin and DOACs; however, both trials were small and not adequately powered to conclude statistical noninferiority between treatments. A recently published retrospective observational study (ACTION CVT) included data from 845 patients and represents the largest study on this topic to date.10 This study found that DOAC treatment was associated with a lower risk of major bleeding compared to warfarin, and similar risks of recurrent VTE, death, and CVT recanalization. Other, smaller observational studies have generally found no differences in safety or efficacy between warfarin and DOACs, although one study did find that apixaban was associated with greater improvements in functional impairment scores compared to warfarin.11-13 A recent systematic review and meta-analysis including 23 RCTs and observational studies reported no significant differences between warfarin and DOACs in terms of mortality, major bleeding events, recurrent thromboembolism, net clinical benefit, excellent neurologic outcome, and recanalization.6 Therefore, the review concluded that DOACs may be a safe and effective alternative to warfarin in CVT. Of note, most patients in these studies initiated DOAC therapy after a period of initial heparin treatment.
| Table. Overview of large cohort studies and RCTs examining DOAC use for the treatment of CVT.7-13 | ||||
|---|---|---|---|---|
| Study design and duration | Subjects | Interventions | Results | Conclusions |
| RCTs | ||||
| Ferro 20197,8 RE-SPECT CVT Exploratory OL, MC, RCT Treatment for 24 weeks; follow-up for 25 weeks total | N=120 patients aged 18 to 79 years with CVT who achieved clinical stability after acute CVT treatment Mean age: 45.2 years | Dabigatran 150 mg twice daily (n=60) Warfarin dose-adjusted to maintain an INR between 2.0 and 3.0 (n=60) Randomization took place 5 to 15 days after initiating acute treatment with UFH or LMWH Mean time in therapeutic range for the warfarin group was 66.1% | Primary: Number of patients with major bleeding or recurrent VTE: 1.7% (95% CI, 0% to 8.9%) vs. 3.3% (95% CI, 0.4% to 11.5%) for dabigatran vs. warfarin Secondary: No patients in either group had recurrent VTE Cerebral venous occlusion scores were improved in 60% (95% CI, 45.9% to 73%) and 67% (95% CI, 52.9% to 79.7%) of patients treated with dabigatran and warfarin, respectively; the remaining patients in each group had stable occlusion scores Safety: Overall AE rates were 78.3% and 70% in the dabigatran and warfarin groups, respectively Major bleeding events occurred in 1.7% and 3.3% of patients treated with dabigatran and warfarin, respectively Clinically relevant non-major bleeding occurred in 1 patient receiving warfarin (1.7%) and 0 patients receiving dabigatran New intracranial hemorrhage or worsening of the hemorrhagic component of a baseline lesion occurred in 1 patient receiving dabigatran (1.8%) and 2 patients (3.8%) receiving warfarin No deaths were reported in either group | Dabigatran may be a safe option for the prevention of recurrent VTE in patients with CVT. However, this trial was limited by its small, exploratory nature; no formal statistical comparisons were conducted, and authors of the study stated that in order to have adequate power to confirm noninferiority of dabigatran to warfarin, over 2000 patients would need to be enrolled. |
| Maqsood 20209 SC, RCT Treatment for 3 to 12 months; follow-up for 12 months | N=45 patients aged 18 to 60 years with thrombosis of the dural sinus and/or cerebral veins who were stable after initial therapy with heparin Mean age: 26 years in the rivaroxaban group and 25.3 years in the warfarin group | Rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg once daily for 3 to 12 months (n=21) Warfarin dose-adjusted to maintain an INR between 2.0 and 3.0 for 3 to 12 months (n=24) Randomization took place 5 to 12 days after initiating acute treatment with UFH or LMWH Time in therapeutic range for warfarin not reported | Primary: Partial or complete recanalization (assessed by magnetic resonance venography) at 3 months: 71% in both treatment groups (p=0.377) Partial or complete recanalization (assessed by magnetic resonance venography) at 6 months: 86% vs. 83% for rivaroxaban vs. warfarin (p=0.598) Partial or complete recanalization (assessed by magnetic resonance venography) at 12 months: 100% in both treatment groups (p=0.754) Secondary: NIHSS score of 0 (excellent outcome) at 3 months: 95% vs. 88% for rivaroxaban vs. warfarin (p=0.368) NIHSS score of 0 (excellent outcome) at 6 and 12 months: 95% vs. 96% for rivaroxaban vs. warfarin (p=0.924) No recurrence of thromboembolism was observed in either group Safety: No major bleeding events were reported in either group Clinically relevant nonmajor bleeding occurred in 2 patients (8%) receiving warfarin and 0 patients receiving rivaroxaban Bleeding events of any severity occurred in 10% of rivaroxaban-treated patients and 25% of warfarin-treated patients (p=0.161) | No significant differences in safety or efficacy were observed between rivaroxaban and warfarin. However, this trial is limited by its small size and the lack of true randomization (patients were assigned to treatment groups based on whether they presented to the hospital on an odd or even numbered date). |
| Cohort Studies (>100 patients) | ||||
| Yaghi 202210 ACTION-CVT MC, international retrospective observational study Study period: January 1, 2015 to December 31, 2020 Median follow-up: 345 days | N=845 adults with CVT treated with oral anticoagulation Mean age: 44.8 years | Treatment with a DOAC only (n=279) Treatment with warfarin only (n=438) Treatment with both a DOAC and warfarin at different times during the study (n=128) Among patients who used DOACs, 13.5% used dabigatran, 18.2% used rivaroxaban, 66.6% used apixaban, and 1.7% used other or multiple DOACs Median duration of anticoagulation was 194 days among DOAC-treated patients and 202.5 days among warfarin-treated patients No data on time in range for warfarin-treated patients | Primary: Recurrent VTE or CVT: 5.26 per 100 patient-years in the DOAC group vs. 5.87 per 100 patient-years in the warfarin group (unweighted/unadjusted HR, 0.86; 95% CI, 0.47 to 1.56; p=0.61) Findings were similar in IPTW unadjusted and adjusted analyses as well as the propensity score-matched analysis Secondary: Partial or complete recanalization: 86% vs. 84.1% among patients treated with DOACs and warfarin, respectively (unweighted/unadjusted OR, 1.16; 95% CI, 0.70 to 1.94; p=0.56); results were similar in IPTW and propensity score matched analyses Safety: Major bleeding: 2.44 per 100 patient-years in the DOAC group vs. 4.70 per 100 patient-years in the warfarin group (unweighted/unadjusted HR, 0.47; 95% CI, 0.21 to 1.04; p=0.06); the between-group difference in major bleeding rates was significant in IPTW unadjusted and adjusted analyses (favoring DOACs), but not in a propensity score-matched analysis Mortality: 1.81 per 100 patient-years in the DOAC group vs. 1.90 per 100 patient-years in the warfarin group (unweighted/unadjusted HR, 1.02; 95% CI, 0.36 to 2.84; p=0.97); results were similar in IPTW and propensity score matched analyses | DOAC treatment was associated with a lower risk of major bleeding compared to warfarin and similar risks of recurrent VTE, death, and CVT recanalization. DOACs may be a reasonable alternative to warfarin for CVT treatment; however, this study is limited by its retrospective, observational design. |
| Powell 202111 SC retrospective observational study Study period: January 1, 2014 to December 21, 2018 Median time frame to follow-up visit: 45 days | N=119 patients aged 18 to 89 years with confirmed CVT who received therapeutic anticoagulation for at least 3 months Mean age: 44.5 years in the warfarin group, 37.7 years in the enoxaparin group, and 48.1 years in the DOAC group | Warfarin (n=89; median duration of therapy, 13.99 months) Enoxaparin (n=11; median duration of therapy, 9.36 months) DOAC (rivaroxaban [n=12] or apixaban [n=7]; median duration of therapy, 11.03 months) All patients received UFH or enoxaparin for acute treatment prior to initiating long-term therapy with one of the agents above No data on time in range for warfarin-treated patients | Primary: Recurrent thrombotic event while on anticoagulation: 11.2%, 0%, and 10.5% for patients treated with warfarin, enoxaparin, and DOAC, respectively (p=0.7635) Secondary: Rehospitalization for increased intracranial pressure: 2.2%, 0%, and 5.3% for patients treated with warfarin, enoxaparin, and DOAC, respectively (p=0.5889) Modified Rankin scale scores decreased by 57.5%, 50%, and 72.7% from admission to follow-up in the warfarin, enoxaparin, and DOAC groups, respectively (p-value not provided) Safety: Major bleeding events: 2.2%, 9.1%, and 0% for patients treated with warfarin, enoxaparin, and DOAC, respectively (p=0.3135) Minor bleeding events: 6.7%, 9.1%, and 5.3% for patients treated with warfarin, enoxaparin, and DOAC, respectively (p=0.8331) | DOACs may be a reasonable treatment option for CVT, although this study was limited by its retrospective design and small sample size. |
| Dong 202112 SC, prospective cohort study Study period: January 1, 2006 to December 31, 2013 Follow-up duration: 6 months post-discharge | N=157 adults with CVT who received oral anticoagulation for at least 3 to 6 months | Standard anticoagulant therapy with subcutaneous enoxaparin 1 mg/kg twice daily for 5 to 15 days followed by warfarin titrated to achieve a goal INR between 2.0 and 3.0 (n=95) Anticoagulant therapy with IV UFH followed by apixaban 5 mg twice daily (n=62) No data on time in range for warfarin-treated patients | Compared to standard anticoagulant therapy, more patients receiving apixaban were “basically cured” (defined as a 91% to 100% reduction in the patient’s functional impairment score and grade 0 disability): 41.94% and 9.47% were “basically cured” in the apixaban and standard anticoagulation groups, respectively (p<0.001) More patients in the standard anticoagulation group reported no significant change/improvement in functional impairment score (10.53% vs. 1.61%; p=0.032) AEs, including intracranial hemorrhage, gastrointestinal bleeding, and venous thrombosis, were not significantly different between groups | Apixaban, following an initial period of treatment with UFH, is effective and safe in CVT; however, this study is limited by its observational nature and small sample size. |
| Wasay 201913 MC, prospective observational study Study period: October 2016 to October 2018 Median follow-up: 8 months | N=111 adults with CVT Mean age: 39.2 years | Warfarin titrated to achieve a goal INR between 2.0 and 3.0 (n=66) DOAC (rivaroxaban [n=36] or dabigatran [n=9]) Oral anticoagulation was started within a median of 1 week of diagnosis | Modified Rankin scale scores were not significantly different between groups at time of discharge or at 6 months At 6 months, modified Rankin scale scores were 0 in 44% of patients who received DOACs and 36% of patients who received warfarin (p=0.3) Bleeding events occurred in 2 patients receiving DOACs and 4 patients receiving warfarin | DOACs may be a safe and effective alternative to warfarin for the treatment of CVT; however, this study is limited by its small sample size and observational nature. |
| Abbreviations: AE=adverse event; CI=confidence interval; CVT=cerebral venous thrombosis; DOAC=direct oral anticoagulant; HR=hazard ratio; INR=international normalized ratio; IPTW=inverse probability of treatment weighted; IV=intravenous; LMWH=low-molecular weight heparin; MC=multicenter; NIHSS=National Institute of Health Stroke Scale; OL=open label; OR=odds ratio; RCT=randomized controlled trial; SC=single center; UFH=unfractionated heparin; VTE=venous thromboembolism. |
||||
Conclusion
Although data on the use of DOACs in patients with CVT remains limited, existing studies seem to suggest that DOACs may be at least as effective as warfarin for this indication, with possible safety advantages that require confirmation in larger RCTs and observational studies. Several ongoing studies are seeking to evaluate the use of DOACs in CVT: the SECRET RCT (NCT03178864) and the RWCVT RCT (NCT04569279) will compare rivaroxaban to standard anticoagulation with warfarin/heparin for the treatment of CVT, and the DOAC-CVT prospective observational cohort study (NCT04660747) will compare outcomes with warfarin and multiple DOACs.14
References
- Cohen O, Pegoraro S, Ageno W. Cerebral venous thrombosis. Minerva Med. 2021;112(6):755-766. doi:10.23736/s0026-4806.21.07353-5
- Alimohammadi A, Kim DJ, Field TS. Updates in cerebral venous thrombosis. Curr Cardiol Rep. 2022;24(1):43-50. doi:10.1007/s11886-021-01622-z
- Saposnik G, Barinagarrementeria F, Brown RD, Jr., et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(4):1158-1192. doi:10.1161/STR.0b013e31820a8364
- Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055
- Ferro JM, Bousser MG, Canhão P, et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis – endorsed by the European Academy of Neurology. Eur J Neurol. 2017;24(10):1203-1213. doi:10.1111/ene.13381
- Riva N, Galea F, Buhagiar I, Gatt A, Calleja-Agius J. Efficacy and safety of the direct oral anti-coagulants in patients with cerebral vein thrombosis: a systematic review and meta-analysis. Br J Haematol. Published online March 31, 2022. doi:10.1111/bjh.18177
- Ferro JM, Bendszus M, Jansen O, et al. Recanalization after cerebral venous thrombosis. A randomized controlled trial of the safety and efficacy of dabigatran etexilate versus dose-adjusted warfarin in patients with cerebral venous and dural sinus thrombosis. Int J Stroke. 2022;17(2):189-197. doi:10.1177/17474930211006303
- Ferro JM, Coutinho JM, Dentali F, et al. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol. 2019;76(12):1457-1465. doi:10.1001/jamaneurol.2019.2764
- Maqsood M, Imran Hasan Khan M, Yameen M, Aziz Ahmed K, Hussain N, Hussain S. Use of oral rivaroxaban in cerebral venous thrombosis. J Drug Assess. 2020;10(1):1-6. doi:10.1080/21556660.2020.1838769
- Yaghi S, Shu L, Bakradze E, et al. Direct oral anticoagulants versus warfarin in the treatment of cerebral venous thrombosis (ACTION-CVT): a multicenter international study. Stroke. 2022;53(3):728-738. doi:10.1161/strokeaha.121.037541
- Powell M, Tremolet de Villers K, Schwarz K, Case D, Trujillo T. A single-center retrospective evaluation of the use of oral factor Xa inhibitors in patients with cerebral venous thrombosis. Ann Pharmacother. 2021;55(3):286-293. doi:10.1177/1060028020952749
- Dong X, Liu X, Liu Y, Jiang L, Zhang H, Liu B. Clinical efficacy of conventional heparin anticoagulation combined with apixaban in the treatment of patients with cerebral venous thrombosis and its effect on serum d-dimer and FIB expression. Comput Math Methods Med. 2021;2021:4979210. doi:10.1155/2021/4979210
- Wasay M, Khan M, Rajput HM, et al. New oral anticoagulants versus warfarin for cerebral venous thrombosis: a multi-center, observational study. J Stroke. 2019;21(2):220-223. doi:10.5853/jos.2019.00150
- Clinicaltrials.gov. U.S. National Library of Medicine. Accessed May 23, 2022. https://clinicaltrials.gov/
Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
June 2022
The information presented is current as of May 12, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.