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Comparing the efficacy and safety of direct oral anticoagulants with vitamin K antagonist in cerebral venous thrombosis.
Lee, GKH, Chen, VH, Tan, CH, Leow, AST, Kong, WY, Sia, CH, Chew, NWS, Tu, TM, Chan, BPL, Yeo, LLL, et al
Journal of thrombosis and thrombolysis. 2020;(3):724-731
Abstract
Cerebral venous thrombosis (CVT) causes significant disability and mortality. Current guidelines for CVT management support the initial use of unfractionated heparin or low molecular weight heparin followed by longer-term oral vitamin K antagonist (VKA). There has been increasing, albeit limited, evidence for the use of direct oral anticoagulants (DOAC) as an alternative to VKA. We performed a systematic review and meta-analysis of studies that compared the safety and efficacy of DOACs to VKA in treating CVT. A comprehensive literature search was carried out in Medline, Embase and Cochrane Stroke Group Trials Register using a suitable keyword/MeSH term search strategy. All studies published in English comparing outcomes of patients with CVT treated with DOAC or VKA were included. In total, 6 studies (5 observational studies and 1 randomized clinical trial) comprising 412 patients (age range 16-83 years) were analyzed. DOAC was used in 151 patients, while 261 received VKA. The follow-up period was 3-11 months. The efficacy of DOACs was comparable with VKA in terms of partial or full thrombus recanalization (RR 1.02, 95% CI 0.89-1.16) and excellent functional recovery with modified Rankin scale < 2 (RR 1.02, 95% CI 0.93-1.13). Patients treated with DOAC developed lower major bleeding events when compared to VKA, although this did not reach statistical significance (RR 0.44, 95% CI 0.12-1.59). We provide preliminary evidence to support DOAC as effective and safe alternatives to VKA in CVT treatment. We await the results of upcoming randomized trials to further support our results and validate the use of DOAC.
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Systematic review of hepatic arterial infusion chemotherapy versus sorafenib in patients with hepatocellular carcinoma with portal vein tumor thrombosis.
Liu, M, Shi, J, Mou, T, Wang, Y, Wu, Z, Shen, A
Journal of gastroenterology and hepatology. 2020;(8):1277-1287
Abstract
BACKGROUND AND AIM The prognosis of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is very poor. This study aimed to evaluate hepatic arterial infusion chemotherapy (HAIC) versus sorafenib (SORF) in the treatment of HCC with PVTT. METHODS Studies were identified online in Embase and MEDLINE before October 31, 2019. The end-points were overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and safety. RESULTS Six studies with 417 cases were included in this systematic review. Meta-analyses demonstrated that HAIC is superior to SORF with respect to OS (hazard ratio [HR]: 0.50, 95% confidence interval: 0.38-0.66, P < 0.001) and PFS (HR: 0.47, 95% confidence interval: 0.31-0.73, P = 0.001) irrespective of research territoriality and study quality. Our systematic review also demonstrated that HAIC is superior to SORF with respect to DCR. Subgroup analysis demonstrated that the advantage is more obvious in the treatment of types III-IV PVTT with respect to OS (HR: 0.29, P < 0.001) and PFS(HR: 0.39, P < 0.001). HAIC caused more grades 3-4 neutropenia (HR: 10.71), anemia (HR: 7.55), leukopenia (HR: 10.38), and thrombocytopenia (HR: 13.09) than SORF. However, HAIC caused fewer cases of grades 3-4 aspartate aminotransferase rising (HR: 0.21), diarrhea (HR: 0.14), and hand-foot syndrome (HR: 0.14) than SORF. CONCLUSIONS This systematic review demonstrated that HAIC is superior to SORF in HCC with PVTT with respect to OS, PFS, and DCR, especially in HCC with types III-IV PVTT. HAIC caused more myelosuppression, whereas SORF is associated with diarrhea and hand-foot syndrome. Further randomized controlled trials are warranted.
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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.
Ferro, JM, Dentali, F, Coutinho, JM, Kobayashi, A, Caria, J, Desch, M, Fraessdorf, M, Huisman, H, Diener, HC
International journal of stroke : official journal of the International Stroke Society. 2018;(7):766-770
Abstract
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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Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study.
Ageno, W, Mantovani, LG, Haas, S, Kreutz, R, Monje, D, Schneider, J, van Eickels, M, Gebel, M, Zell, E, Turpie, AG
The Lancet. Haematology. 2016;(1):e12-21
Abstract
BACKGROUND The efficacy and safety of the anticoagulant rivaroxaban for the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism has been shown in phase 3 trials. However, data about rivaroxaban use in routine clinical practice are needed. METHODS XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was a multicentre, international, prospective, non-interventional study of patients with deep-vein thrombosis, done in hospitals and community care centres in 21 countries. The study investigated the safety and effectiveness of rivaroxaban compared with standard anticoagulation therapy (initial treatment with unfractionated heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist) for at least 3 months. Eligible patients were adults (aged ≥18 years) with an objectively confirmed diagnosis of deep-vein thrombosis, and an indication to receive anticoagulation treatment for at least 3 months. Following approval of rivaroxaban for the pulmonary embolism indication, patients with deep-vein thrombosis and concomitant pulmonary embolism were also eligible; however, those with isolated pulmonary embolism were not included. Type, dose, and duration of therapy for each patient were at the physician's discretion. The primary effectiveness and safety outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. Propensity score-adjusted analyses were done to account for potential imbalances between groups. This study is registered with ClinicalTrials.gov, number NCT01619007. FINDINGS Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled. The safety population (all patients who received at least one dose of the anticoagulant of interest) comprised 2619 patients in the rivaroxaban group and 2149 in the standard anticoagulant therapy group. Patients in the rivaroxaban group were younger and fewer had active cancer or concomitant pulmonary embolism than those in the standard anticoagulation group. In the propensity score-adjusted population, the frequency of major bleeding was 0·8% (19/2505) in the rivaroxaban group and 2·1% (43/2010) in the standard anticoagulation group, with a propensity score-adjusted hazard ratio (HR) of 0·77 (95% CI 0·40-1·50); p=0·44. The frequency of recurrent venous thromboembolism was 1·4% (36/2505) in the rivaroxaban group and 2·3% (47/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·91 [95% CI 0·54-1·54], p=0·72). The all-cause mortality frequency was 0·4% (11/2505) in the rivaroxaban group and 3·4% (69/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·51 [95% CI 0·24-1·07], p=0·074). The incidence of treatment-emergent adverse events in the safety population was similar between the two groups (944 [36·0%] of 2619 in the rivaroxaban group vs 805 [37·5%] of 2149 in the standard anticoagulation group). INTERPRETATION In routine clinical practice, rivaroxaban-treated patients had a lower risk profile at baseline than those treated with standard anticoagulation. Propensity score-adjusted results confirm that rivaroxaban is a safe and effective alternative to standard anticoagulation therapy in a broad range of patients. Rates of major bleeding and recurrent venous thromboembolism were low in rivaroxaban-treated patients and consistent with phase 3 findings. FUNDING Bayer HealthCare Pharmaceuticals and Janssen Research & Development, LLC.
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[Edoxaban is safer than vitamin K antagonists].
Einecke, D
MMW Fortschritte der Medizin. 2013;(16):20
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Oral rivaroxaban for symptomatic venous thromboembolism.
, , Bauersachs, R, Berkowitz, SD, Brenner, B, Buller, HR, Decousus, H, Gallus, AS, Lensing, AW, Misselwitz, F, Prins, MH, et al
The New England journal of medicine. 2010;(26):2499-510
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Abstract
BACKGROUND Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).
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[New oral anticoagulants: better than vitamin K antagonists?].
Völler, H, Alban, S, Westermann, D
Der Internist. 2010;(12):1571-81
Abstract
Many years of practical use and intensive scientific research have allowed vitamin K antagonists to become a cornerstone of treatment of internal diseases. Nevertheless, limitations in pharmacokinetics and -dynamics of vitamin K antagonists and the availability of new drugs in regard to a targeted anticoagulation therapy ask for a new review of the situation. Proof of effectiveness for the perioperative prophylaxis of venous thrombosis after hip and knee replacement has already been achieved for the direct thrombin inhibitor dabigatran etexilate as well as for the factor Xa inhibitors rivaroxaban und apixaban compared to low molecular weight heparins. These new drugs are now also investigated in patients with internal diseases. For the long-term application (6 or 12 months) concerning the treatment of venous thrombosis and/or stroke prophylaxis in patients with atrial fibrillation data is already available for the direct thrombin inhibitor dabigatran etexilate. Depending on its dosage its effectiveness in comparison with vitamin K antagonists is equal or even better without disadvantages in safety. However, vitamin K antagonists will remain the standard oral anticoagulation until open questions regarding e.g. insufficient therapy adherence (with termination rates up to 20%) or problems with drug interactions of the new competitive products have been completely answered.
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Ximelagatran.
Choudhury, A, Goyal, D, Lip, GY
Drugs of today (Barcelona, Spain : 1998). 2006;(1):3-19
Abstract
Despite the significant advances over the last 50 years with regard to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in at-risk patients, except those with acute coronary syndromes, in which antiplatelets are preferred. Ximelagatran, a prodrug of melagatran, is an orally administered direct thrombin inhibitor whose therapeutic potential has been investigated in venous thromboembolism, acute coronary syndromes and prevention of stroke in atrial fibrillation. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to the oral vitamin K antagonist warfarin and low molecular weight heparin for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Double-blind trials have also revealed the efficacy of ximelagatran in the secondary prevention of venous thromboembolism and shown the agent to be as effective as enoxaparin/warfarin in treating patients with acute deep vein thrombosis. Adverse effects with ximelagatran include elevations in alanine transaminase (ALT), which may require monitoring, and bleeding complications. Bleeding complications appear to be less than or at least comparable to those occurring with standard anticoagulant treatments like warfarin or low molecular weight heparin. In addition to its favorable efficacy and safety profile in comparison with standard anticoagulant therapy, the convenience of its oral, fixed-dose administration without the need for anticoagulation monitoring might help encourage a wider use of appropriate anticoagulation using ximelagatran across the population at risk, reducing the incidence of thromboembolic events.
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Mobilization versus immobilization in the treatment of acute proximal deep venous thrombosis: a prospective, randomized, open, multicentre trial.
Jünger, M, Diehm, C, Störiko, H, Hach-Wunderle, V, Heidrich, H, Karasch, T, Ochs, HR, Ranft, J, Sannwald, GA, Strölin, A, et al
Current medical research and opinion. 2006;(3):593-602
Abstract
OBJECTIVE The aim of prescribing strict bed rest for acute deep venous thrombosis is to reduce the risk of pulmonary embolism and pain in the legs, as well as swelling. This study was performed in order to compare outcome of mobilization against 5 days of strict bed rest in patients with acute proximal deep venous thrombosis (DVT). METHODS 103 in-patients with proximal DVT or patients admitted to the hospital because of proximal DVT were recruited to a randomized study. All patients were treated in hospital and given a lower leg and thigh compression bandage as well as therapeutic doses of the low molecular weight heparin, dalteparin-sodium (Fragmin). RESULTS Seven of 52 patients (13.5%) in the mobile group versus 14 of 50 patients (28.0%) in the immobile group suffered at least one of the outcomes defined under the combined primary endpoint (clinically relevant pulmonary embolisms, pulmonary embolisms detectable by scintigraphy or computer tomography, progression of thrombosis or new thrombosis, nosocomial infections and/or serious adverse events) (p = 0.088), whereby serious adverse events occurred once in the mobile group and three times in the immobile group. New pulmonary embolisms over the course were seen in 10 of 50 patients (20%) with a perfusion disorder at baseline scintigraphy, while such was ascertained only in one of 52 patients (1.9%) without a perfusion disorder at baseline scintigraphy. Leg pain was reduced from 54.1 (+/-30.4) to 20.7 (+/-19.2) in the mobilized group and from 41.0 (+/-26.8) to 14.0 (+/-11.1) in the immobilized patients. Leg pain was assessed using the visual analogue scale (0 = no pain, 100 = maximum pain). More immobilized patients complained of increasing back pain (23% versus 6%) and disturbed micturition (10% versus 2%) as well as defecation (13% versus 6%) on day 5. More patients in the mobile group reported increased stress from the thrombosis and its treatment (15% versus 6%). CONCLUSIONS No benefit of prescribing bed rest in patients with deep venous thrombosis could be detected in this study. Based on data available, strict bed rest for at least 5 days is not justified if adequate therapy with low molecular weight heparin and adequate compression is assured. It remains open whether patients with initial signs of pulmonary embolism might profit from a brief immobilization.
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A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
Wells, PS, Anderson, DR, Rodger, MA, Forgie, MA, Florack, P, Touchie, D, Morrow, B, Gray, L, O'Rourke, K, Wells, G, et al
Archives of internal medicine. 2005;(7):733-8
Abstract
BACKGROUND Low-molecular-weight heparins (LMWHs) are now standard therapy for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). No published trials have compared LMWHs, and few studies have examined outpatient therapy for PE. Only tinzaparin sodium has demonstrated superiority to unfractionated heparin in a clinical trial. METHODS We compared 2 LMWH products, tinzaparin and dalteparin sodium, for the treatment of acute DVT and PE in a randomized, controlled clinical trial of consecutive outpatients presenting to a venous thromboembolism service at 4 tertiary-care hospitals. Patients were treated with subcutaneous tinzaparin sodium, 175 IU/kg every 24 hours, or subcutaneous dalteparin sodium, 200 IU/kg every 24 hours, for at least 5 days. Warfarin sodium therapy was started simultaneously and continued for 90 days. The primary end point was efficacy (recurrence of venous thromboembolism); safety (bleeding) was a composite end point. RESULTS Two hundred fifty-four patients received tinzaparin (39 with PE and 215 with DVT) and 251 received dalteparin (51 with PE and 200 with DVT). Most patients had an active malignancy or idiopathic DVT/PE. The outcome events occurred in 11 (4.4%; 95% confidence interval [CI], 2.2%-7.7%) and 15 patients (5.9%; 95% CI, 3.3%-9.5%) in the dalteparin and tinzaparin groups, respectively, including 9 and 10 recurrences, respectively, and 2 and 5 major hemorrhages, respectively (P = .44). The 95% CI on the difference of -1.5% was -5.3% to 2.4%. CONCLUSIONS Tinzaparin and dalteparin are safe and effective for the outpatient treatment of DVT or PE. Our finding of no differences between the LMWHs based on major clinical end points means that practical issues can be the deciding factor on which drug to use.