Rationale, design, and protocol of a randomized controlled trial of the safety and efficacy of dabigatran etexilate versus dose-adjusted warfarin in patients with cerebral venous thrombosis

Rationale To prevent recurrent venous thrombotic events after acute cerebral venous or dural sinus thrombosis, guidelines recommend long-term oral anticoagulation with vitamin K antagonists. Non-vitamin K oral anticoagulant experience in cerebral venous or dural sinus thrombosis is limited to case reports and series. Aim To compare dabigatran with dose-adjusted warfarin in patients with cerebral venous or dural sinus thrombosis for the prevention of recurrent venous thrombotic event. Sample size One hundred and twenty patients. Methods and design This study is a phase III, prospective, randomized, parallel-group, open-label, multicenter, exploratory trial with blinded endpoint adjudication. Patients with acute cerebral venous or dural sinus thrombosis after 5–15 days of treatment with parenteral heparin are randomized to either dabigatran etexilate 150 mg twice daily or dose-adjusted (international normalized ratio 2–3) warfarin (≤24 weeks). Study outcome The primary endpoint is a composite of patients with new venous thrombotic event (recurring cerebral venous or dural sinus thrombosis, deep venous thrombosis of any limb, pulmonary embolism, and major bleeding (International Society on Thrombosis and Hemostasis definition)) during the treatment period. Statistics will be descriptive (number and frequencies). Study timelines Inclusion started in December 2016. Final results are expected by the end of 2018. Discussion This exploratory trial is the first to compare vitamin K with non-vitamin K antagonists in cerebral venous or dural sinus thrombosis. It will provide evidence to guide physicians and patients in choosing oral anticoagulants to prevent venous thrombotic event after acute cerebral venous or dural sinus thrombosis. ClinicalTrials.gov number: NCT02913326.

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RE-COVERY DVT/PE: Rationale and design of a prospective observational study of acute venous thromboembolism with a focus on dabigatran etexilate

Thrombosis and Haemostasis ◽

10.1160/th16-07-0566 ◽

2017 ◽

Vol 117 (02) ◽

pp. 415-421 ◽

Cited By ~ 6

Author(s):

Walter Ageno ◽

Ivan B. Casella ◽

Chee Kok Han ◽

Gary E. Raskob ◽

Sebastian Schellong ◽

...

Keyword(s):

Venous Thromboembolism ◽

Vitamin K ◽

Large Scale ◽

Vitamin K Antagonists ◽

Phase 1 ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Phase Iii ◽

Real World Data ◽

Phase Iii Studies

SummaryThe therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i. e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VTE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VTE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase III studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice.

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DOACs vs Vitamin K Antagonists: a Comparison of Phase III Clinical Trials and a Prescriber Support Tool

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2019.289 ◽

2019 ◽

Vol 7 (7) ◽

pp. 1226-1232 ◽

Cited By ~ 1

Author(s):

Alina-Maria Pirlog ◽

Cristian Daniel Pirlog ◽

Marius Adrian Maghiar

Keyword(s):

Clinical Trials ◽

Vitamin K ◽

Primary Outcome ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Phase Iii ◽

Support Tool ◽

Phase Iii Clinical Trials

AIM: The purpose of this article was to systematically review the literature assessing the efficacy and safety of phase III clinical trials for each direct oral anticoagulant versus vitamin K antagonists and to design a ’’go-to’’ table for the prescriber. MATERIAL AND METHODS: A systematic review of specialist literature was conducted to identify RCTs which compared direct oral anticoagulants (DOACs) with standard warfarin treatment. Medline, Em-base, and the Cochrane databases were searched from January 2005- January 2019. The inclusion criteria were randomised controlled trials of oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF). Four publications were phase III randomised control trials (RCTs) included in the final analysis. RESULTS: Regarding the primary outcome in RELY the results were 1.69% per 100-year patients (p/y) for Warfarin compared to 1.11% p/y dabigatran etexilate 150mg BD (twice daily). In ROCKET AF the rates of the primary outcome were 2.2% p/y for warfarin compared to 1.7% p/y for rivaroxaban 20 mg OD (once daily). In ARISTOTLE trial the rates of the primary outcome were 1.60% p/y for warfarin compared to 1.27% p/y for apixaban 5 mg BD. In ENGAGE AF TIMI, the rates of the primary outcome were 1.50% p/y for warfarin compared to 1.18% p/y for edoxaban 60mg BD. CONCLUSION: DOACs showed to be either noninferior or superior to warfarin with regards to the primary outcome with better safety patterns. Our ’’go-to’’ table provides a supportive tool for physicians in preventing medical errors when managing patients on oral anticoagulants.

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Dural Arteriovenous Fistulae After Cerebral Venous Thrombosis

Stroke ◽

10.1161/strokeaha.120.031235 ◽

2020 ◽

Vol 51 (11) ◽

pp. 3344-3347

Author(s):

José M. Ferro ◽

Jonathan M. Coutinho ◽

Olav Jansen ◽

Martin Bendszus ◽

Francesco Dentali ◽

...

Keyword(s):

Venous Thrombosis ◽

Cerebral Venous Thrombosis ◽

Mr Angiography ◽

Sinus Thrombosis ◽

Controlled Trial ◽

Dabigatran Etexilate ◽

Dural Sinus ◽

Arteriovenous Fistulae ◽

3 Dimensional

Background and Purpose: This analysis examined the frequency of dural arteriovenous fistulae (dAVF) after cerebral venous thrombosis (CVT) in patients included in a randomized controlled trial comparing dabigatran etexilate with dose-adjusted warfarin (RE-SPECT CVT [A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis]), who had systematic follow-up magnetic resonance (MR) imaging. Methods: RE-SPECT CVT was a Phase 3, prospective, randomized, parallel-group, open-label, multicenter, exploratory trial with blinded end point adjudication. We allocated patients with acute CVT to dabigatran 150 mg twice daily or dose-adjusted warfarin, for 24 weeks and obtained a standardized MR protocol including time-of-flight MR angiography, 3-dimensional phase-contrast venography, and 3-dimensional contrast-enhanced MR venography at the end of the treatment period. A blinded adjudication committee assessed the presence of dAVF in a predefined substudy of the trial. Results: We analyzed development of dAVF in 112 of 120 randomized patients; 57 allocated to dabigatran and 55 to warfarin. For 3 (2.7%) of these 112 patients, quality of follow-up imaging was insufficient to evaluate dAVF. A dAVF (Borden I) was found in 1 patient (0.9%) allocated to warfarin; however, this dAVF was already present at baseline. The patient did not present with hemorrhage at baseline or during the trial and was asymptomatic at follow-up. Conclusions: Despite systematic imaging, we found no new dAVF 6 months after CVT. Routine follow-up cerebral MR angiography aiming to detect new dAVF 6 months after CVT has a very low yield. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02913326.

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Successful Intravascular Ultrasound Thrombolysis of Dural Sinus Thrombosis with Pre-Existing Subarachnoid and Intraparenchymal Hemorrhages

Interventional Neuroradiology ◽

10.1177/159101991001600414 ◽

2010 ◽

Vol 16 (4) ◽

pp. 455-458 ◽

Cited By ~ 3

Author(s):

M.E. Atherton ◽

W.C. Culp ◽

A.T. Brown ◽

E. Erdem

Keyword(s):

Venous Thrombosis ◽

Intravascular Ultrasound ◽

Cerebral Venous Thrombosis ◽

Sinus Thrombosis ◽

Dural Sinus ◽

Dural Sinus Thrombosis ◽

Direct Infusion ◽

Tissue Plasminogen ◽

Thrombolytic Effect ◽

Subarachnoid Hemorrhages

A case of cerebral venous thrombosis with intraparenchymal and subarachnoid hemorrhages was initially treated unsuccessfully with mechanical and pharmacologic thrombolysis using intrathrombus tissue plasminogen activator (tPA) and angioplasty, and later successfully treated with an intravascular ultrasound tPA infusion catheter. This new microcatheter allowed direct infusion of tPA while using local therapeutic intravascular ultrasound to increase the thrombolytic effect. Flow was quickly restored. Our patient recovered from coma to discharge home without worsening of existing hemorrhages.

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Anticoagulant Therapy in Atrial Fibrillation – Time for a Change?

European Cardiology Review ◽

10.15420/ecr.2009.5.2.57 ◽

2009 ◽

Vol 5 (2) ◽

pp. 57

Author(s):

Raffaele De Caterina ◽

Giulia Renda ◽

◽

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Anticoagulation Therapy ◽

New Drugs ◽

Phase Iii ◽

Therapeutic Window ◽

Randomized Evaluation ◽

New Anticoagulants

Although to date warfarin and other vitamin K antagonists have clearly had the greatest efficacy among commonly available treatments in preventing stroke in atrial fibrillation, their use is associated with a substantial risk of major bleeding and is impractical because of their narrow therapeutic window, their interaction with drugs and foods and the need for frequent coagulation monitoring. Several new anticoagulants are undergoing phase III clinical trials in atrial fibrillation with the aim of demonstrating non-inferiority compared with vitamin K antagonists or superiority compared with aspirin in patients in whom vitamin K antagonists are contraindicated or not tolerated. In the recently released Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, the first such drug, dabigatran etexilate, was proved substantially equivalent to 2–3 international normalised ratio (INR)-adjusted warfarin at the dosage of 110mg twice a day (BID), with superior efficacy at a dosage of 150mg BID. With these new drugs, cardiologists and internists are witnessing a real revolution in the thromboprophylaxis in atrial fibrillation.

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Dural Sinus Thrombosis after Translabyrinthine Approach for Vestibular Schwannomas

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0034-1383972 ◽

2014 ◽

Vol 75 (S 02) ◽

Author(s):

Ashish Kumar ◽

F. Pirouzmand ◽

J. Chen

Keyword(s):

Sinus Thrombosis ◽

Vestibular Schwannomas ◽

Dural Sinus ◽

Dural Sinus Thrombosis ◽

Translabyrinthine Approach

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Idiopathic venous thrombosis

Hämostaseologie ◽

10.1055/s-0037-1616877 ◽

2006 ◽

Vol 26 (01) ◽

pp. 52-54 ◽

Cited By ~ 3

Author(s):

P. A. Kyrle

Keyword(s):

Chronic Disease ◽

Venous Thrombosis ◽

Vitamin K ◽

Clinical Benefit ◽

Plasma Levels ◽

Vitamin K Antagonists ◽

Antithrombin Deficiency ◽

Optimal Duration ◽

Risk Of Treatment

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

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Extensive Experience with Dural Sinus Thrombosis

Neurosurgery ◽

10.1227/01.neu.0000047815.21786.c1 ◽

2003 ◽

Vol 52 (3) ◽

pp. 534-544 ◽

Cited By ~ 84

Author(s):

Scott W. Soleau ◽

Richard Schmidt ◽

Steve Stevens ◽

Anne Osborn ◽

Joel D. MacDonald

Keyword(s):

Clinical Improvement ◽

Sinus Thrombosis ◽

Treatment Strategies ◽

Retrospective Chart Review ◽

Dural Sinus ◽

Hemorrhagic Complication ◽

Dural Sinus Thrombosis ◽

Extensive Experience ◽

Medical Observation ◽

Hemorrhagic Complications

Abstract OBJECTIVE Dural sinus thrombosis (DST) is an uncommon cause of stroke. The safest and most effective therapy for DST has not been conclusively identified. METHODS A retrospective chart review of data for 31 patients who were treated for DST at our institution between 1992 and 2001 was performed. Four treatment strategies were identified, i.e., 1) medical observation only, 2) systemic anticoagulation (AC) therapy with heparin, 3) endovascular chemical thrombolysis with urokinase or tissue plasminogen activator and concurrent systemic AC therapy, and 4) mechanical endovascular clot thrombolysis with concurrent systemic AC therapy. Complications and clinical outcomes were assessed for each group. RESULTS Patients treated solely with medical observation fared the worst; four of five patients experienced intracranial hemorrhagic complications, and only two of five exhibited clinical improvement. Patients who received systemic AC therapy experienced no hemorrhagic complications, even when pretreatment hemorrhage was present; 75% (six of eight patients) exhibited improvement with AC therapy alone. Chemical thrombolysis was very effective in restoring sinus patency (90% of patients); however, 30% of patients (3 of 10 patients) experienced hemorrhagic complications. Sixty percent of patients (6 of 10 patients) who underwent chemical thrombolysis exhibited clinical improvement. Patients who underwent mechanical thrombectomies demonstrated a low hemorrhagic complication rate, and most (88%) made good recoveries. CONCLUSION Therapy directed at the underlying clot in DST must begin without delay. Our results suggest that supportive medical management of DST, without therapy directed at the clot or clotting process, is not effective. Systemic AC therapy, even in the presence of intracerebral hemorrhage, seems to be safe. Heparin can be safely titrated to yield partial thromboplastin times of 60 to 70 seconds. Chemical clot thrombolysis is efficacious in opening occluded sinuses but may cause intracranial hemorrhage. We currently recommend either systemic AC therapy or systemic AC therapy in conjunction with mechanical clot thrombectomy as a safe effective treatment for DST.

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