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DOI: 10.1055/s-0040-1713683
Effectiveness and Safety of Apixaban for Treatment of Venous Thromboembolism in Daily Practice
Address for correspondence
Publikationsverlauf
24. März 2020
25. Mai 2020
Publikationsdatum:
24. Juni 2020 (online)
Abstract
Introduction Phase 3 trials have shown comparable efficacy of direct oral anticoagulants (DOACs) and vitamin K antagonists in patients with acute venous thromboembolism (VTE), with less major bleeding events in patients randomized to DOAC treatment. With DOACs being increasingly used in clinical practice, evaluation of the DOACs in daily practice-based conditions is needed to confirm their safety and effectiveness. The aim of this study is to evaluate the effectiveness and safety of apixaban in VTE patients in daily practice.
Methods In this retrospective cohort study, consecutive patients diagnosed with VTE in two Dutch hospitals (Leiden University Medical Center, Leiden and Haga Teaching Hospital, The Hague) were identified based on administrative codes. We assessed recurrent VTE, major bleeding and mortality during a 3-month follow-up period in those treated with apixaban.
Results Of 671 consecutive VTE patients treated with apixaban, 371 presented with acute pulmonary embolism (PE) and 300 patients with deep-vein thrombosis. During 3 months treatment, 2 patients had a recurrent VTE (0.3%; 95% confidence interval [CI]: 0.08–1.1), 12 patients had major bleeding (1.8%; 95% CI: 1.0–3.2), and 11 patients died (1.6%; 95% CI: 0.9–2.9), of which one patient with recurrent PE and one because of a intracerebral bleeding.
Conclusion In this daily practice-based cohort, apixaban yielded a low incidence of recurrent VTE, comparable to the phase 3 AMPLIFY study patients. The incidence of major bleeding was higher than in the AMPLIFY-study patients, reflecting the importance of daily practice evaluation and the fact that results from phase III clinical studies cannot be directly extrapolated toward daily practice.
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Introduction
Direct oral anticoagulants (DOACs) inhibit either thrombin (dabigatran) or activated factor X (apixaban, edoxaban, and rivaroxaban). Over the last years, DOACS are increasingly being used to prevent ischemic stroke in patients with atrial fibrillation and to treat acute venous thromboembolism (VTE). According to international treatment guidelines, the use of DOACS is being preferred over vitamin-K antagonists (VKA) for these two indications.[1] [2] [3] [4] In VTE treatment, phase 3 studies have shown comparable efficacy of DOACs and VKA, with a better bleeding profile.[5] [6] [7] [8] [9] [10] Furthermore, at prolonged treatment after the initial 6 months, DOACs have proven to be superior to placebo or aspirin for secondary VTE prevention.[11] [12]
Importantly, as phase 3 trials dictate to have strict in- and exclusion criteria both efficacy and bleeding rates may be underestimated because patients at higher risk of bleeding are usually excluded. With DOACs being increasingly used in clinical practice, evaluation of the DOACs using practice-based data sources is needed to better delineate their effectiveness and safety. Such data focusing on safety of apixaban for treatment of VTE are scarce.
In this study, we evaluated the efficacy and safety of apixaban in patients with VTE treated in two hospitals in the Netherlands.
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Methods
Design and Patients
In this retrospective cohort follow-up study, consecutive patients diagnosed with VTE between January 2016 and December 2018 in two Dutch hospitals (Leiden University Medical Center, Leiden and Haga Teaching Hospital, The Hague) were identified via the hospitals' administrative system. Patients were eligible for inclusion if they were 18 years or older and had established acute symptomatic or incidental pulmonary embolism (PE) involving subsegmental or more proximal pulmonary arteries confirmed by computed tomography pulmonary angiography (CTPA), or symptomatic or incidental deep-vein thrombosis (DVT) of the lower or upper extremities, involving the popliteal, femoral, iliac, subclavian, axillary or brachial vein or the inferior vena cava, diagnosed by compression ultrasound or CT venography, or by a positive signal on magnetic resonance direct thrombus imaging (DTI) indicative of fresh thrombus in the proximal veins of the leg.[13] [14] [15]
Patients were included in this study when the physician had the intention to start with apixaban treatment. In the Leiden University Medical Center, the treatment protocol recommended patients to be treated with apixaban 10 mg twice daily for 1 week after which apixaban 5 mg twice a day was initiated. In the Haga Teaching Hospital, the treatment protocol recommended patients to be initially treated with approximately 1 week of therapeutic weight based low-molecular-weight heparin (LMWH) after which apixaban 5 mg twice daily was given. Protocol deviations in both hospitals were common, truly reflecting practice-based medicine. Thus, the decision which of the two treatment regimens was initiated, depended on the discretion of the treating physician.
Patients who completed at least 3 months of anticoagulant therapy or met a study end-point in that period were included in this current analysis. Follow-up data were retrieved from the patient chart. Due to the retrospective study design, the need for informed consent was waived by the institutional review boards of both hospitals.
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Aims and Outcomes
The primary aim of this study was to evaluate the efficacy and safety of apixaban in VTE patients in daily practice. The primary efficacy outcome was recurrent VTE and all-cause mortality during a 3-month follow-up period after index VTE. The primary safety outcome was the 3-month incidence of major bleeding.
Secondary outcomes in this study were (1) the reported side effects of apixaban as noted by the treating physician in the patient chart and (2) the primary outcomes in the first week of treatment.
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Definitions
Recurrent VTE was defined as a new intraluminal filling defect on computed tomographic pulmonary angiography, confirmation of a new PE at autopsy, or a new intraluminal filling defect on computed tomographic angiography in other venous beds. Recurrent lower extremity DVT was defined as new noncompressibility by ultrasonography or as an increase in vein diameter under maximal compression, as measured in the abnormal venous segment, indicating an increase in thrombus diameter (≥ 4 mm), or by a positive signal on magnetic resonance DTI indicative of fresh thrombus in the proximal veins of the leg.[13] [14] [15]
Major bleeding was defined according to the International Society of Thrombosis and Haemostasis (ISTH) criteria as any bleeding resulting in death, symptomatic bleeding in a critical organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular and pericardial bleeding and muscle bleeding resulting in compartment syndrome) or symptomatic bleeding resulting in a decrease in the hemoglobin concentration of at least 2 g/dL or resulting in the transfusion of at least two packs of red blood cells.[16]
In case of death, information was obtained from the hospital records. VTE-related mortality was defined as death within 7 days of PE diagnosis, PE confirmed as cause of death during autopsy, or sudden unexpected death with no other explanation. All events were adjudicated by two independent experts who were unaware of the initial management decision. Any disagreement between the two independent experts was resolved by a third expert.
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Statistical Analysis
For the presentation of the baseline characteristics, categorical data are presented as percentages or as proportion and continuous variables as means with standard deviation (SD). The main outcomes of the study are expressed by frequency and proportion with corresponding 95% confidence interval (95% CI). All adverse events were included in the primary analysis. The secondary outcome-reported side effect is provided as frequencies and proportion. SPSS version 25.0.0 (SPSS, IBM, Armonk, NY) was used to perform all analyses.
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Results
Study Patients
Between January 2016 and December 2018, 671 consecutive patients were diagnosed with VTE and treated with apixaban, of whom 300 (45%) had DVT and 371 (55%) had PE with or without DVT. The baseline demographic and clinical characteristics of all 671 patients are summarized in [Table 1]. Their mean age was 60 years (SD: 16), 48% was female and 6.3% had active malignancy at time of diagnosis. The median weight in this cohort was 85 kg (SD: 18.6) with 84 patients (13%) having a weight above 100kg. Renal insufficiency (creatinine clearance < 50 mL/min) was present in 60 patients (8.9%). Thirteen patients had severe renal insufficiency, a creatinine clearance estimated glomerular filtration rate < 30 mL/min (1.9%). The vast majority of the patients (74%) were treated as outpatient after initial index VTE; this was 93% for those with DVT and 58% for those with PE with or without DVT. For the patients treated initially in hospital, the median admission duration was 5.0 days (interquartile range 7).
Abbreviation: COPD, chronic obstructive pulmonary disease; DVT, deep-vein thrombosis; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism.
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Outcomes
During 3 months follow-up, two patients experienced a recurrent VTE (0.30%; 95% CI: 0.08–1.1; [Table 2]). A 71-year-old patient had progressive iliac vein thrombosis, 3 days after diagnosis of a DVT of the femoral vein and start of apixaban in the presence of a myelodysplastic syndrome. Another 49-year-old patient was diagnosed with symptomatic segmental PE, 1 month after initial DVT diagnosis, in the presence of a progressive stage IV nonsmall cell lung carcinoma.
Number |
Incidence |
95% CI |
|
---|---|---|---|
1. Overall mortality |
11 |
1.6 |
0.9–2.9 |
2. Major bleeding |
12 |
1.8 |
1.0–3.2 |
3. Recurrent VTE |
2 |
0.30 |
0.08–1.1 |
Abbreviations: VTE, venous thromboembolism, 95% CI, 95% confidence interval.
A total of 12 patients (1.8%; 95% CI: 1.0–3.2) experienced major bleeding. The details of the major bleeding, its management, and outcome are provided in [Table 3]. Of the 12 major bleedings, three occurred during the first week, including two major bleedings during LMWH therapy. One possible intracranial bleeding under LMWH was fatal; another major bleeding occurred in the presence of thrombocytopenia (platelet count 23 × 10*9/L); three patients (25%) had a malignancy.
Abbreviations: CT, computed tomography; DLBCL, diffuse large B cell lymphoma; F, female; IU, international units; LMWH, light-molecular-weight heparin; M, male.
Note: Time to adverse event: time from initial events (and subsequent start of anticoagulant therapy) until occurrence of major bleeding.
Eleven patients (1.6%; 95% CI: 0.9–2.9) died during the 3 months follow-up ([Table 4]). One patient on apixaban died of the index PE within 24 hours of the initial PE diagnosis. Seven patients (64%) had active malignancy at time of death and all died after initiation of palliative care at home or hospice because of metastasized end-stage disease. One patient died due to a possible intracerebral bleed; apixaban was already stopped and LMWH had been started.
Abbreviations: CT, computed tomography; ER, emergency room; F, female; LMWH, light-molecular-weight heparin; M, male; NSCLC, nonsmall cell lung carcinoma; PE, pulmonary embolism.
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Secondary Outcomes
The most frequent reported side effects of apixaban were headache (2.5%) and abdominal discomfort (2.4%). The following less frequent side effects were reported by the treating physician: nausea (0.9%), rash/hypersensitivity (0.4%), itching (0.8%), hair loss (0.3%), paraesthesia (0.3%), and dizziness (0.3%; [Table 5]) causing switch to an alternative anticoagulant in 13% of all 53 patients with side effects. All adverse events within the first week of anticoagulant treatment strategies are provided in [Table 6].
Abbreviations LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.
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Discussion
In this practice-based study, we observed a lower rate of recurrent VTE (0.3% during 3 months) in patients treated with apixaban than that observed in the phase 3 AMPLIFY clinical trial (2.3% during 6 months). In contrast, the incidence of major bleeding (1.8% during 3 months) was higher than in the apixaban-treated patients in the AMPLIFY study (0.6% during 6-month follow-up).
The low rate of recurrent VTE could be explained by the difference in the follow-up duration in the phase 3 AMPLIFY clinical trial, which was twice as long. Moreover, a considerable percentage of recurrent VTE was adjudicated as death for which PE could not be ruled out. We therefore think VTE recurrence rates in both studies are likely comparable. Overall, the baseline characteristics in our cohort were comparable to those of the AMPLIFY study except that the proportion of patients included with a DVT was higher in the AMPLIFY study compared with 45% in this cohort. Moreover, more than half (52%) of our patients started apixaban without prior anticoagulant treatment, while this rate was 13% in the AMPLIFY study patients. Notably, the proportion of patients with initial LMWH treatment decreased over time, as experience and knowledge with apixaban treatment increased during the observation period.
The most notable difference of this analysis compared with the AMPLIFY study was the incidence of major bleeding. Taking a closer look at the patients who experienced a major bleeding episode elucidates the difference between our practice-based study and the phase 3 AMPLIFY study. First of all, two patients suffered from a hematooncological disease, with one being shortly after a hematopoietic stem cell transplantation, at time of bleeding. Overall, three out of 12 patients (25%) who experienced major bleeding had an active malignancy. Treatment of cancer-associated VTE is not only challenging due to a higher risk of recurrent VTE and mortality but also because of higher incidences of major bleeding.[17] The added value of DOAC therapy in patients with cancer-associated thrombosis has already been established with the publication of the SELECT-D3 and Hokusai VTE cancer trials, with consideration for the risk of bleeding in certain tumor types (e.g., gastrointestinal, urogenital).[18] [19] International guidelines currently advise to consider the use of DOACs in cancer-associated thrombosis with caveats for these gastrointestinal and urogenital tumors.[4] In this respect, the fact that DOACs were sometimes prescribed in patients with cancer-associated VTE in this cohort reflects anticoagulant therapy in current daily practice. Second, in two patients bleeding occurred shortly after intervention; one patient already had a subdural fluid collection and one patient experienced bleeding within a week after prior treatment of thrombolytic therapy. These patients would have been excluded in phase 3 trials as they dictate strict in- and exclusion criteria.
We observed two heavy menstrual bleedings in this cohort. Treatment with factor Xa inhibitors is indeed associated with an increased risk of abnormal uterine bleeding, particularly heavy menstrual bleeding in premenopausal women when compared with treatment with VKA.[20] [21] [22] [23] [24] The observation that these women were admitted because of heavy menstrual bleeding, although it was not specifically monitored in this cohort, underlines the relevance of monitoring and counseling the risk of heavy menstrual bleeding in premenopausal women after initiating DOAC therapy.
Interestingly, in the management of major bleeding, prothrombin complex concentrate (PCC) was only used twice in patients with gastrointestinal bleeding, while all other patients with major bleeding were treated conservatively by only stopping the apixaban. This observation that most major bleeding events were managed conservatively, without the use of PCC, was also observed in the Dresden NOAC registry (PCC administered in 6.7% of all major bleeding events).[25]
Overall, the rate of major bleeding in our cohort is comparable to rates of other practice-based cohorts in current literature. A systematic review including five large observational cohorts showed a 0.6 to 3.6% 3 months major bleeding rate in patients treated with apixaban for acute VTE.[26] Same proportions of major bleeding associated with DOAC therapy (3.3% during a mean follow-up of 85 days) were observed in a large practice-based multicenter, population study, although most DOAC users in this study used rivaroxaban.[27]
The main limitation is the presence of selection bias as we do not know in how many patients (and why) another anticoagulant strategy than apixaban was chosen. Of note, apixaban was the first choice in anticoagulant therapy in both hospital protocols for VTE management. Therefore, we consider our results representative for daily practice since patients from both an academic and a nonacademic teaching hospital were studied and we observed rates of adverse events and mortality comparable to the published literature. Two of the major bleedings occurred on LMWH treatment in the first week of anticoagulant treatment, while the treating physician continued with apixaban treatment after the initial LMWH course. According to the intention to treat principle, we included those adverse events in the final analysis, which may have led to an overestimation of the apixaban associated rate of major bleeding. Strengths include the completeness of follow-up and the lack of exclusion criteria compared with clinical trials. Moreover, all outcomes were adjudicated by independent experts and we could provide detailed data on management and outcome for each adverse event.
In conclusion, apixaban yielded a low incidence of recurrent VTE in our large practice-based patient cohort. The incidence of major bleeding was, however, higher than in the AMPLIFY study, reflecting the importance of daily practice evaluation and the fact that results from phase III clinical studies cannot be directly extrapolated toward daily practice.
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Conflict of Interest
F.A.K. reports research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart Foundation, and the Netherlands Thrombosis Foundation. J.E. reports research grants from CSL Behring, the Landsteiner Foundation for Blood Transfusion Research, and Netherlands Thrombosis Foundation. M.V.H. reports grants from ZonMW Dutch Healthcare Fund, grants and consultancy fees from Boehringer Ingelheim, grants and personal fees from Pfizer-BMS, grants and consultancy fees from Bayer Health Care, grants from Aspen, and grants and personal fees from Daiichi-Sankyo, outside the submitted work. The other authors report no conflict of interest.
Essentials
• In VTE treatment, phase 3 studies have shown comparable efficacy of DOACs and VKA, with a better bleeding profile.
• Both efficacy and bleeding rates may be underestimated in phase 3 trials because patients at higher risk of bleeding are usually excluded.
• In this practice-based cohort, the incidence of major bleeding was higher than in the AMPLIFY study patients.
• Results from phase III clinical studies cannot be directly extrapolated toward daily practice.
Authors' Contributions
S.V.H. contributed to concept and design of the study, analyzed and interpreted the data, and drafted the manuscript. M.V.H. contributed to concept and design of the study, analyzed and interpreted the data, reviewed the manuscript, and provided important intellectual content. J.C.J.E. reviewed the manuscript and provided important intellectual content. J.F. reviewed the manuscript and provided important intellectual content. W.J.E.S. analyzed and interpreted the data and provided important intellectual content. A.T.A.M. reviewed the manuscript and provided important intellectual content. F.A.K. reviewed the manuscript, contributed to concept and design of the study, and analyzed and interpreted the data.
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References
- 1 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
- 2 Kirchhof P, Benussi S, Kotecha D. , et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37 (38) 2893-2962
- 3 January CT, Wann LS, Calkins H. , et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140 (02) e125-e151
- 4 Konstantinides SV, Meyer G. The 2019 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2019; 40 (42) 3453-3455
- 5 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
- 6 Büller HR, Prins MH, Lensin AW. , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
- 7 Schulman S, Kakkar AK, Goldhaber SZ. , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
- 8 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
- 9 Huisman MV, Barco S, Cannegieter SC. , et al. Pulmonary embolism. Nat Rev Dis Primers 2018; 4: 18028
- 10 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (03) 320-328
- 11 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
- 12 Weitz JI, Lensing AWA, Prins MH. , et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
- 13 Huisman MV, Klok FA. Diagnostic management of acute deep vein thrombosis and pulmonary embolism. J Thromb Haemost 2013; 11 (03) 412-422
- 14 Klok FA, Tan M, Huisman MV. Letter by Klok et al Regarding Article, “18F-fluorodeoxyglucose positron emission tomography/computed tomography enables the detection of recurrent same-site deep vein thrombosis by illuminating recently formed, neutrophil-rich thrombus”. Circulation 2015; 131 (24) e530
- 15 Tan M, Mol GC, van Rooden CJ. , et al. Magnetic resonance direct thrombus imaging differentiates acute recurrent ipsilateral deep vein thrombosis from residual thrombosis. Blood 2014; 124 (04) 623-627
- 16 Schulman S, Kearon C. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
- 17 Prandoni P, Lensing AW, Piccioli A. , et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100 (10) 3484-3488
- 18 Young AM, Marshall A, Thirlwall J. , et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018; 36 (20) 2017-2023
- 19 Raskob GE, van Es N, Verhamme P. , et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
- 20 Scheres L, Brekelmans M, Ageno W. , et al. Abnormal vaginal bleeding in women of reproductive age treated with edoxaban or warfarin for venous thromboembolism: a post hoc analysis of the Hokusai-VTE study. BJOG 2018; 125 (12) 1581-1589
- 21 Beyer-Westendorf J, Michalski F, Tittl L, Hauswald-Dörschel S, Marten S. Vaginal bleeding and heavy menstrual bleeding during direct oral anti-Xa inhibitor therapy. Thromb Haemost 2016; 115 (06) 1234-1236
- 22 Ferreira M, Barsam S, Patel JP. , et al. Heavy menstrual bleeding on rivaroxaban. Br J Haematol 2016; 173 (02) 314-315
- 23 Klok FA, Barco S. Optimal management of hormonal contraceptives after an episode of venous thromboembolism. Thromb Res 2019; 181 (Suppl. 01) S1-S5
- 24 Klok FA, Schreiber K, Stach K. , et al. Oral contraception and menstrual bleeding during treatment of venous thromboembolism: expert opinion versus current practice: Combined results of a systematic review, expert panel opinion and an international survey. Thromb Res 2017; 153: 101-107
- 25 Helmert S, Marten S, Mizera H. , et al. Effectiveness and safety of apixaban therapy in daily-care patients with atrial fibrillation: results from the Dresden NOAC registry. J Thromb Thrombolysis 2017; 44 (02) 169-178
- 26 Aryal MR, Gosain R, Donato A. , et al. Systematic review and meta-analysis of the efficacy and safety of apixaban compared to rivaroxaban in acute VTE in the real world. Blood Adv 2019; 3 (15) 2381-2387
- 27 Jun M, Lix LM, Durand M. , et al; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study. BMJ 2017; 359: j4323
Address for correspondence
-
References
- 1 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
- 2 Kirchhof P, Benussi S, Kotecha D. , et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37 (38) 2893-2962
- 3 January CT, Wann LS, Calkins H. , et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140 (02) e125-e151
- 4 Konstantinides SV, Meyer G. The 2019 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2019; 40 (42) 3453-3455
- 5 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
- 6 Büller HR, Prins MH, Lensin AW. , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
- 7 Schulman S, Kakkar AK, Goldhaber SZ. , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
- 8 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
- 9 Huisman MV, Barco S, Cannegieter SC. , et al. Pulmonary embolism. Nat Rev Dis Primers 2018; 4: 18028
- 10 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (03) 320-328
- 11 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
- 12 Weitz JI, Lensing AWA, Prins MH. , et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
- 13 Huisman MV, Klok FA. Diagnostic management of acute deep vein thrombosis and pulmonary embolism. J Thromb Haemost 2013; 11 (03) 412-422
- 14 Klok FA, Tan M, Huisman MV. Letter by Klok et al Regarding Article, “18F-fluorodeoxyglucose positron emission tomography/computed tomography enables the detection of recurrent same-site deep vein thrombosis by illuminating recently formed, neutrophil-rich thrombus”. Circulation 2015; 131 (24) e530
- 15 Tan M, Mol GC, van Rooden CJ. , et al. Magnetic resonance direct thrombus imaging differentiates acute recurrent ipsilateral deep vein thrombosis from residual thrombosis. Blood 2014; 124 (04) 623-627
- 16 Schulman S, Kearon C. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
- 17 Prandoni P, Lensing AW, Piccioli A. , et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100 (10) 3484-3488
- 18 Young AM, Marshall A, Thirlwall J. , et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018; 36 (20) 2017-2023
- 19 Raskob GE, van Es N, Verhamme P. , et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
- 20 Scheres L, Brekelmans M, Ageno W. , et al. Abnormal vaginal bleeding in women of reproductive age treated with edoxaban or warfarin for venous thromboembolism: a post hoc analysis of the Hokusai-VTE study. BJOG 2018; 125 (12) 1581-1589
- 21 Beyer-Westendorf J, Michalski F, Tittl L, Hauswald-Dörschel S, Marten S. Vaginal bleeding and heavy menstrual bleeding during direct oral anti-Xa inhibitor therapy. Thromb Haemost 2016; 115 (06) 1234-1236
- 22 Ferreira M, Barsam S, Patel JP. , et al. Heavy menstrual bleeding on rivaroxaban. Br J Haematol 2016; 173 (02) 314-315
- 23 Klok FA, Barco S. Optimal management of hormonal contraceptives after an episode of venous thromboembolism. Thromb Res 2019; 181 (Suppl. 01) S1-S5
- 24 Klok FA, Schreiber K, Stach K. , et al. Oral contraception and menstrual bleeding during treatment of venous thromboembolism: expert opinion versus current practice: Combined results of a systematic review, expert panel opinion and an international survey. Thromb Res 2017; 153: 101-107
- 25 Helmert S, Marten S, Mizera H. , et al. Effectiveness and safety of apixaban therapy in daily-care patients with atrial fibrillation: results from the Dresden NOAC registry. J Thromb Thrombolysis 2017; 44 (02) 169-178
- 26 Aryal MR, Gosain R, Donato A. , et al. Systematic review and meta-analysis of the efficacy and safety of apixaban compared to rivaroxaban in acute VTE in the real world. Blood Adv 2019; 3 (15) 2381-2387
- 27 Jun M, Lix LM, Durand M. , et al; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study. BMJ 2017; 359: j4323