Abd-Allah, Foad

AlRukn, Suhail Abdulla

Awan, Safia

Farooq, Salman

Khan, Maria

Malik, Abdul

Memon, Mohammed Ibrahim

Nishat, Sadia

Rajput, Haris Majid

Shahid, Rizwana

Shoaib, Raja Farhat

Wasay, Mohammad

English

eCommons@AKU

eCommons@AKU Section of Neurology Department of Medicine 5-2019 New oral anticoagulants versus warfarin for cerebral venous thrombosis: A multi-center, observational study Mohammad Wasay Aga Khan University, mohammad.wasay@aku.edu Maria Khan Rashid Hospital, Dubai, United Arab Emirates Haris Majid Rajput Pakistan Institute of Medical Sciences, Islamabad, Pakistan Salman Farooq Aga Khan University, Karachi, salman.farooq@aku.edu Mohammed Ibrahim Memon King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia See next page for additional authors Follow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_med_neurol  Part of the Neurology Commons Recommended Citation Wasay, M., Khan, M., Rajput, H. M., Farooq, S., Memon, M. I., AlRukn, S. A., Malik, A., Abd-Allah, F., Shoaib, R. F., Shahid, R., Nishat, S., Awan, S. (2019). New oral anticoagulants versus warfarin for cerebral venous thrombosis: A multi-center, observational study. Journal of Stroke, 21(2), 220-223. Available at: https://ecommons.aku.edu/pakistan_fhs_mc_med_neurol/194 Authors Mohammad Wasay, Maria Khan, Haris Majid Rajput, Salman Farooq, Mohammed Ibrahim Memon, Suhail Abdulla AlRukn, Abdul Malik, Foad Abd-Allah, Raja Farhat Shoaib, Rizwana Shahid, Sadia Nishat, and Safia Awan This letter to the editor is available at eCommons@AKU: https://ecommons.aku.edu/pakistan_fhs_mc_med_neurol/194 Copyright © 2019  Korean Stroke SocietyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.pISSN: 2287-6391 • eISSN: 2287-6405Letter to the EditorJournal of Stroke 2019;21(2):220-223https://doi.org/10.5853/jos.2019.00150220 http://j-stroke.orgDear Sir:The incidence of cerebral venous thrombosis (CVT) is on the rise, partly due to an improvement in the diagnostic techniques.1 However, the therapeutic options have not changed much in the past three decades. Heparin followed by vitamin K antagonist (VKA), Warfarin is still the mainstay of treatment,2-4 although the limitations of VKA therapy including risk of major bleeding, need for constant monitoring, and drug and dietary interactions are all well recognized.5,6New direct oral anticoagulants (NOACs), which are target spe-cific for factor Xa (rivaroxaban, apixaban, edoxaban) or thrombin (dabigatran), were developed to overcome some of these limita-tions. These drugs have already shown to be safer then VKA for recurrent venous thromboembolism and embolism prevention in atrial fibrillation, with fewer intracranial and extracranial hemor-rhages, fewer fatal hemorrhages and no increase in the risk of gastrointestinal hemorrhages.7 Based on this safety data, and the efficacy results from venous thromboembolism studies, there is a growing tendency for neurologists to consider them for treat-ment of CVT. A few case series have been published supporting the safety and efficacy of these drugs in CVT cases.8-11 More re-cently, the results of one randomized controlled trial (randomized controlled trial of the safety and efficacy of dabigatran etexilate vs. dose-adjusted warfarin in patients with cerebral venous thrombosis [RESPECT CVT]) were presented at World Stroke Con-gress in 2018.12 The trial randomized 120 patients to either dabi-gatran or warfarin and showed no recurrence of venous throm-botic events and a small number of major bleedings in both arms.Before the results of RESPECT CVT were made available, we conducted a multicenter prospective, observational study to evaluate the safety of NOACs compared to warfarin in patients with CVT. Data was collected from October 2016 to October 2018. Nine centers in four countries Pakistan, Saudi Arabia, Egypt, and the United Arab Emirates participated in the study. All nine centers are tertiary care hospitals with full time neurologists and availability of diagnostic modalities for the diagnosis of CVT.We included consecutive patients aged 18 years or more, who presented with clinical features of CVT, confirmed with venogra-phy (either computed tomography [CT] or magnetic resonance [MR]). Those with traumatic or septic CVT were excluded.  Base-line characteristics including demographics, Glasgow Coma Scale, clinical features, imaging findings, and anticoagulant at discharge were recorded. Choice of oral anticoagulation was left New Oral Anticoagulants versus Warfarin for Cerebral Venous Thrombosis: A Multi-Center, Observational StudyMohammad Wasay,a Maria Khan,b Haris Majid Rajput,c Salman Farooq,a Mohammed Ibrahim Memon,d Suhail Abdulla AlRukn,b Abdul Malik,e Foad Abd-Allah,f Raja Farhat Shoaib,g Rizwana Shahid,h  Sadia Nishat,i Safia Awanj aDepartment of Neurology, Aga Khan University, Karachi, PakistanbDepartment of Neurology, Rashid Hospital, Dubai, United Arab Emirates cDepartment of Neurology, Pakistan Institute of Medical Sciences, Islamabad, PakistandDepartment of Neurology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia eDepartment of Medicine, Liaquat College of Medicine and Dentistry, Karachi, Pakistan fDepartment of Neurology, Cairo University, Cairo, EgyptgDepartment of Neurology, Shifa International University and Hospital, Islamabad, PakistanhDepartment of Neurology, Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi ArabiaiDepartment of Neurology, Sindh Institute of Urology and Transplantation, Karachi, PakistanjDepartment of Medicine, Aga Khan University, Karachi, PakistanVol. 21 / No. 2 / May 2019https://doi.org/10.5853/jos.2019.00150 http://j-stroke.org 221Table 1. NOACs vs. warfarin for cerebral venous thrombosis (n=111)Variable All patients (n=111) NOACs (n=45, 41%) Warfarin (n=66, 59%) P Age (yr) 39.3±14.9 36.5±14.7  41.3±14.8 0.10Female sex 64 (57.7) 27 (60) 37 (56.1) 0.68Predisposing factorsPregnancy/puerperium 15 (23.1) 8 (28.6) 7 (18.9) 0.36Hematological disorders 74 (66.7) 28 (62.2) 46 (69.7) 0.41Malignancy 6 (5.4) 0 (0) 6 (10.5) 0.03Systemic infections 36 (32.4) 15 (33.3) 21 (31.8) 0.86Drugs/OCP 11 (9.9) 4 (9) 7 (11) 0.32Other medical conditions 7 (6.3) 6 (13.3) 1 (1.5) 0.01Clinical findingsBaseline GCS (available in 89 cases) 0.7313–15 64 (71) 28 (74) 36 (70)9–12 17 (19) 7 (18) 10 (20)≤8 8 (10) 3 (8) 5 (10)Seizures 37 (33.3) 14 (31) 23 (34.8) 0.68Paresis 49 (44) 22 (48) 27 (52) 0.32Aphasia 7 (6.3) 5 (11) 2 (3.0) 0.08Headache 84 (75.7) 42 (93) 42 (63.6) <0.001Papilledema 4 (3.6) 1 (2) 3 (4) 0.18Imaging findingsIntracerebral hemorrhage 45 (40.5) 25 (55.6) 20 (30.3) 0.01Venous infarction 54 (48.6) 25 (55.6) 29 (43.9) 0.22Midline shift 10 (9.0) 4 (8.9) 6 (9.1) 0.97Hydrocephalus 1 (0.9) 0 (0) 1 (1.5) 0.40SSS thrombus 56 (50.5) 26 (57.8) 30 (45.5) 0.20TS thrombus 60 (54.1) 30 (66.7) 30 (45.5) 0.02Straight sinus/DCVT/cortical vein 28 (25.2) 11 (24.4) 17 (25.8) 0.87Sigmoid sinus/jugular vein 62 (55.9) 29 (64.4) 33 (50) 0.13TreatmentHeparin/LMWH 79 (71) 36 (80) 43 (65) 0.06Surgery 12 (10.8) 5 (12.5) 7 (11.7) 0.90Start of oral anticoagulation in days 6 (3–11) 7 (3–12) 5 (3–10)mRS at discharge 111 45 66 0.520 23 (21) 11 (25) 12 (18)1 29 (26) 11 (23) 18 (28)2 28 (25) 12 (27) 16 (23)3 15 (14) 4 (9) 11 (17)4 10 (10) 5 (10) 5 (8)5 2 (2) 1 (2) 1 (2)6 4 (4) 1 (2) 3 (5)Wasay et al.  New Oral Anticoagulants in Cerebral Venous Thrombosishttps://doi.org/10.5853/jos.2019.00150222 http://j-stroke.orgto the discretion of the treating physician. Recruited patients were followed up prospectively for outcomes assessment which was done by the treating physician in outpatient clinic setup. Treating physicians took verbal consent from the patients or their surrogates for contributing their data to the study. Ethics approval was taken from the Institutional Review Board of each participating center. Data was entered and analyzed on SPSS version 21 (IBM Co., Armonk, NY, USA).  A total of 111 patients were included (45 were on NOACs and 66 on warfarin). Diagnosis was confirmed by magnetic resonance imaging (MRI)/magnetic resonance venography (MRV) in 96, CT venogram in 10 and both MRV and CT veno-gram in five patients. Out of 45 patients on NOACs, 36 were given rivaroxaban and nine were given dabigatran. Warfarin was adjusted to achieve an international normalized ratio (INR) of 2 to 3. The mean age of the participants was 39.3±14.9 years and 57% were females and the two groups were comparable (Table 1). Hematological disorders followed by systemic infections were the most common etiological factors for CVT in both the NOAC and warfarin groups. Ma-lignancy was a more common predisposing factor in the war-farin group, with six out of 66 patients suffering from the condition. No patient in the NOAC arm had malignancy. Whereas the two groups did not differ significantly in terms of clinical features, patients in the NOAC group presented more frequently with headache (93% vs. 63%) and were significant-ly more likely than warfarin group to have intracerebral hem-orrhage on initial imaging, reflecting the comfort of treating physician with NOACs. There were no other significant differ-ences in the clinical and imaging features of the two groups. Patients in both groups were started on oral anticoagulation (warfarin with target INR 2 to 3; rivaroxaban 15 to 20 mg; dabigatrin 75 to 150 mg twice a day) within median of one week of diagnosis. At discharge as well as at 6 months follow-up, the functional outcomes as measured by modified Rankin Scale, were not significantly different between the two groups. Four patients died during hospital stay, one in the NOAC arm and three in the warfarin arm. The hospital course was compli-cated by extracranial hemorrhage in two patients, both of whom were in the warfarin group. Two additional patients were dead at 6 months follow-up, one in each group.Follow-up ranged from minimum 6 to 13 months (median, 8). All patients underwent neurological examination at follow-up. Follow-up evaluation included history of headaches, sei-zures, any signs of bleeding, side effects and compliance of medications, evaluation of modified Rankin Scale score and any imaging. At 6 months follow-up (95/107 discharged pa-tients, 89%), clinical neurological worsening was reported in one patient (warfarin group), and no patient required switching from one to the other group. In addition, no patient required discontinuation of therapy by the physician. Only 12 patients (five in NOAC group, seven in warfarin group) had follow-up MRI/MRV (one patient for neurologic worsening, mostly for persistent headache and non-improvement) during 6 months follow-up. Of these, four in the NOAC arm and four in the war-farin arm had complete and the rest had partial recanalization.Six patients reported systemic bleeding at follow-up, two in the NOAC arm and four in the warfarin arm. As per Interna-tional Society on Thrombosis and Haemostasis (ISTH) classifi-cation, one patient had major, one non-major clinically rele-vant, and four had minor hemorrhages. Only one patient in the NOAC arm required blood transfusion and a single patient in the warfarin group had intracranial hemorrhage that required intervention. No recurrent thrombotic events were seen in any of the patients.This open label, comparative study reports on the largest co-Table 1. ContinuedVariable All patients (n=111) NOACs (n=45, 41%) Warfarin (n=66, 59%) P mRS at 6 months 95 39 56 0.300 37 (39) 17 (44) 20 (36)1 23 (24) 8 (21) 15 (28)2 19 (20) 10 (26) 9 (16)3 9 (10) 2 (4) 7 (12)4 4 (4) 1 (2) 3 (5)5 3 (3) 1 (2) 2 (3)6 2 (0.02) 1 (0.03) 1 (0.02)Values are presented as mean±standard deviation, number (%), or median (interquartile range).NOAC, new direct oral anticoagulant; OCP, oral contraceptive pill; GCS, Glasgow Coma Scale; SSS, superior sagittal sinus; TS, transverse sinus; DCVT, deep ce-rebral vein thrombosis; LMWH, low molecular weight heparin; mRS, modified Rankin Scale.Vol. 21 / No. 2 / May 2019https://doi.org/10.5853/jos.2019.00150 http://j-stroke.org 223hort of CVT patients treated with new oral anticoagulants and shows that the use of NOACs (mainly rivaroxaban and dabiga-tran) appear to be safe and may be as effective as warfarin in patients with CVT. Limitations of our study include non-ran-domization, open label, lack of adequate radiological data at follow-up to assess recanalization and non-blinded and non-adjudicated outcome assessments. Despite these, our study findings provide external validity for the RESPECT CVT results in a real-world setting and supports the growing trend of NOAC use for this potentially devastating condition. References1. Luo Y, Tian X, Wang X. Diagnosis and treatment of cerebral ve-nous thrombosis: a review. Front Aging Neurosci 2018;10:2.2. Einhäupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, et al. Heparin treatment in sinus venous throm-bosis. Lancet 1991;338:597-600.3. Nagaraja D, Rao BSS, Taly AB, Subhash MN. Randomized controlled trial of heparin in puerperal cerebral venous/sinus thrombosis. NIMHANS J 1995;13:111-115.4. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999;30:484-488.5. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous throm-boembolism: a meta-analysis. Ann Intern Med 2003;139:893-900.6. Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, et al. Death and disability from warfarin-associated in-tracranial and extracranial hemorrhages. Am J Med 2007; 120:700-705.7. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The im-pact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014;124:2450-2458.8. Hon SF, Li HL, Cheng PW. Use of direct thrombin inhibitor for treatment of cerebral venous thrombosis. J Stroke Cerebro-vasc Dis 2012;21:915.e11-915.e15.9. Rao SK, Ibrahim M, Hanni CM, Suchdev K, Parker D, Raja-mani K, et al. Apixaban for the treatment of cerebral venous thrombosis: a case series. J Neurol Sci 2017;381:318-320.10. Anticoli S, Pezzella FR, Scifoni G, Ferrari C, Pozzessere C. Treatment of cerebral venous thrombosis with rivaroxaban. J Biomedical Sci 2016;5:3.11. Mendonça MD, Barbosa R, Cruz-e-Silva V, Calado S, Viana-Baptista M. Oral direct thrombin inhibitor as an alternative in the management of cerebral venous thrombosis: a series of 15 patients. Int J Stroke 2015;10:1115-1118.12. Ferro JM, Dentali F, Coutinho JM, Kobayashi A, Caria J, Desch M, et al. Rationale, design, and protocol of a randomized controlled trial of the safety and efficacy of dabigatran etex-ilate versus dose-adjusted warfarin in patients with cerebral venous thrombosis. Int J Stroke 2018;13:766-770Correspondence: Mohammad Wasay Department of Neurology, Aga Khan University, Stadium Road, Karachi 74800, PakistanTel: +92-21-4930051Fax: +92-21-34934294E-mail: mohammad.wasay@aku.eduReceived: January 15, 2019Revised: February 21, 2019Accepted: March 10, 2019The authors have no financial conflicts of interest.

New oral anticoagulants versus warfarin for cerebral venous thrombosis: A multi-center, observational study

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New oral anticoagulants versus warfarin for cerebral venous thrombosis: A multi-center, observational study

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