Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists

SummaryThe study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i. e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0 %) of 4130 patients receiving rivaroxaban and in 72 (1.7 %) of 4116 receiving enoxaparin/VKAs, with 44 % of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti-inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Clinical impact of major bleeding in patients with venous thromboembolism treated with factor Xa inhibitors or vitamin K antagonists

Thrombosis and Haemostasis ◽

10.1160/th16-12-0946 ◽

2017 ◽

Vol 117 (10) ◽

pp. 1944-1951 ◽

Cited By ~ 20

Author(s):

Elise Eerenberg ◽

Alexander Cohen ◽

Saskia Middeldorp ◽

Gary Raskob ◽

Harry Büller ◽

...

Keyword(s):

Venous Thromboembolism ◽

Vitamin K ◽

Major Bleeding ◽

Clinical Presentation ◽

Vitamin K Antagonists ◽

Factor Xa ◽

Bleeding Events ◽

Different Types ◽

Fxa Inhibitor ◽

Major Bleeding Events

SummaryFactor Xa (fXa)-inhibitors are as effective and safer than vitamin-K–antagonists (VKA) in the treatment of venous thromboembolism (VTE). We previously classified the severity of clinical presentation and course of all major bleeding events from the EINSTEIN, AMPLIFY and HOKUSAI-VTE trials separately. The current aim was to combine these findings in order to increase precision, assess a class effect and analyse presentation and course for different types of bleeding, i. e. intracranial, gastro-intestinal, and other. We classified the clinical presentation and course of all major bleeding events using pre-defined criteria. Both classifications comprised four categories; one being the mildest, and four the most severe. Odds ratios (OR) were calculated for all events classified as category three or four between fXa-inhibitors and VKA recipients. Also, ORs were computed for different types of bleeding. Major bleeding occurred in 111 fXa-inhibitor recipients and in 187 LMWH/VKA recipients. The clinical presentation was classified as category three or four in 35% and 48% of the major bleeds in fXa inhibitor and VKA recipients, respectively (OR 0.59, 95% CI 0.36–0.97). For intracranial, gastro-intestinal and other bleeding a trend towards a less severe presentation was observed for patients treated with fXa inhibitors. Clinical course was classified as severe in 22% of the fXa inhibitor and 25% of the VKA associated bleeds (OR 0.83, 95% CI 0.47–1.46). In conclusion, FXa inhibitor associated major bleeding events had a significantly less severe presentation and a similar course compared to VKA. This finding was consistent for different types of bleeding.

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Clinical impact and course of major bleeding with edoxaban versus vitamin K antagonists

Thrombosis and Haemostasis ◽

10.1160/th15-11-0892 ◽

2016 ◽

Vol 116 (07) ◽

pp. 155-161 ◽

Cited By ~ 11

Author(s):

Marjolein Brekelmans ◽

Suzanne Bleker ◽

Rupert Bauersachs ◽

Zoltan Boda ◽

Harry Büller ◽

...

Keyword(s):

Vitamin K ◽

Major Bleeding ◽

Clinical Presentation ◽

Clinical Course ◽

Vitamin K Antagonists ◽

Bleeding Events ◽

Vein Thrombosis ◽

Recurrent Deep Vein Thrombosis ◽

Major Bleeding Events ◽

Deep Vein

SummaryEdoxaban is a once-daily direct oral anticoagulant (DOAC). The Hokusai-VTE study revealed that, after initial treatment with heparin, edoxaban was non-inferior to and safer than vitamin K antagonists (VKA) in the prevention of recurrent deep-vein thrombosis and pulmonary embolism. This is the first report on the clinical relevance and management of bleeding events with edoxaban. All major bleeding events were classified blindly by three study-independent adjudicators. Predefined criteria were used to classify severity of clinical presentation and, separately, the clinical course and outcome into four categories. Major bleeding occurred in 56 patients treated with edoxaban and 65 patients treated with VKA. The severest categories (3 or 4) of the clinical presentation were assigned to 46 % of the major bleeding episodes in edoxaban recipients versus 58 % of the major bleeds in VKA recipients (odds ratio [OR] 0.62, 95 % confidence interval [CI] 0.30–1.27, p = 0.19). Clinical course was classified as severe (category 3 or 4) in 23 % of the edoxaban and 29 % of the VKA associated bleeds (OR 0.73, 95 % CI 0.32–1.66, p = 0.46). In conclusion, edoxaban associated major bleeding events have a comparable clinical presentation and course to major bleeds with VKA in patients treated for venous thromboembolism in the Hokusai-VTE study. These results may assure physicians that it is safe to prescribe this medication. If a major bleeding during edoxaban treatment occurs, its clinical presentation and clinical course are not worse than in VKA-treated patients.

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Risk Factors for Major Bleeding during Prolonged Anticoagulation Therapy in Patients with Venous Thromboembolism: From the COMMAND VTE Registry

Thrombosis and Haemostasis ◽

10.1055/s-0039-1692425 ◽

2019 ◽

Vol 119 (09) ◽

pp. 1498-1507 ◽

Cited By ~ 8

Author(s):

Kitae Kim ◽

Yugo Yamashita ◽

Takeshi Morimoto ◽

Takeshi Kitai ◽

Takafumi Yamane ◽

...

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Acute Phase ◽

Major Bleeding ◽

Anticoagulation Therapy ◽

Bleeding Events ◽

Increased Risk ◽

Major Bleeding Events ◽

Active Cancer

Background There are limited data assessing the risk for bleeding on anticoagulation therapy beyond the acute phase in patients with venous thromboembolism (VTE). The present study aimed to identify risk factors for major bleeding during prolonged anticoagulation therapy in VTE patients. Patients and Methods The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTE. The current study population consisted of 2,728 patients who received anticoagulation therapy beyond the acute phase, after excluding those patients with major bleeding events (n = 48), death (n = 66), or loss to follow-up (n = 32) during the initial parenteral anticoagulation period within 10 days after diagnosis, and those without anticoagulation therapy beyond 10 days after diagnosis (n = 153). Results During the median follow-up period of 555 days, major bleeding occurred in 189 patients (70 patients within 3 months; 119 patients beyond 3 months) with fatal bleeding in 24 patients (13%). The cumulative incidence of major bleeding was 2.7% at 3 months, 5.2% at 1 year, and 11.8% at 5 years. Active cancer (hazard ratio [HR], 3.06, 95% confidence interval [CI], 2.23–4.18), previous major bleeding (HR, 2.38, 95% CI, 1.51–3.59), anemia (HR, 1.75, 95% CI, 1.27–2.43), thrombocytopenia (HR, 2.11, 95% CI, 1.27–3.33), and age ≥75 years (HR, 1.64, 95% CI, 1.22–2.20) were independently associated with an increased risk for major bleeding by the multivariable Cox regression model. Conclusion Major bleeding events were not uncommon during prolonged anticoagulation therapy in real-world VTE patients. Active cancer, previous major bleeding, anemia, thrombocytopenia, and old age were the independent risk factors for major bleeding.

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Prediction of major and clinically relevant bleeding in patients with VTE treated with edoxaban or vitamin K antagonists

Thrombosis and Haemostasis ◽

10.1160/th16-11-0830 ◽

2017 ◽

Vol 117 (04) ◽

pp. 784-793 ◽

Cited By ~ 15

Author(s):

Gary Raskob ◽

Harry Büller ◽

Michael Grosso ◽

George Zhang ◽

Shannon Winters ◽

...

Keyword(s):

Risk Factors ◽

Major Bleeding ◽

Risk Model ◽

Vitamin K Antagonists ◽

Significant Risk ◽

Study Drug ◽

Duration Of Treatment ◽

Bleeding Events ◽

C Statistic ◽

Increased Risk

SummaryBetter understanding of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism (VTE) may help physicians when deciding on intensity and duration of treatment. The primary aim of this study was to identify risk factors for major and clinically relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE. We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study. Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model. We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation. Major bleeding occurred in 56/4118 (1.4 %) patients given edoxaban and in 66/4122 (1.6 %) patients given warfarin. Clinically relevant bleeding occurred in 349 (8.5 %) and 423 (10.3 %), respectively. Significant risk factors for major bleeding during edoxaban treatment were female sex, concomitant antiplatelet therapy, haemoglobin ≤10 g/dl, history of arterial hypertension, and systolic blood pressure >160 mmHg. The discrimination of the model was high (C-statistic: 0.71) for major bleeding, lower for clinically relevant bleeding (C-statistic: 0.62) and when the model was applied to patients receiving warfarin (C-statistic 0.60). In conclusion, we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE. A risk model based on these factors predicted an increased risk of bleeding with good discrimination.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Thromboembolic and major bleeding events in relation to perioperative bridging of vitamin K antagonists in 649 fast-track total hip and knee arthroplasties

Acta Orthopaedica ◽

10.1080/17453674.2016.1245998 ◽

2016 ◽

Vol 88 (1) ◽

pp. 55-61 ◽

Cited By ~ 2

Author(s):

Christoffer C Jørgensen ◽

Henrik Kehlet ◽

Keyword(s):

Vitamin K ◽

Major Bleeding ◽

Fast Track ◽

Vitamin K Antagonists ◽

Bleeding Events ◽

Total Hip ◽

Major Bleeding Events

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145 Major Bleeding Events in Patients on Vitamin K Antagonists and Direct Oral Anticoagulants Presenting to the Emergency Department

Annals of Emergency Medicine ◽

10.1016/j.annemergmed.2019.08.150 ◽

2019 ◽

Vol 74 (4) ◽

pp. S57-S58

Author(s):

G. Maloney

Keyword(s):

Emergency Department ◽

Vitamin K ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Events ◽

Major Bleeding Events

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Meta-analysis of major bleeding events on aspirin versus vitamin K antagonists in randomized trials

International Journal of Cardiology ◽

10.1016/j.ijcard.2016.12.055 ◽

2017 ◽

Vol 230 ◽

pp. 572-576 ◽

Cited By ~ 3

Author(s):

P. Ambrosi ◽

A. Daumas ◽

P. Villani ◽

R. Giorgi

Keyword(s):

Vitamin K ◽

Major Bleeding ◽

Randomized Trials ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Bleeding Events ◽

Major Bleeding Events

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Predictors for intra cranial haemorrhage in frail elderly patients with frequent falls using antithrombotic medication

European Heart Journal ◽

10.1093/eurheartj/ehab724.0549 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

L.A.R Zwart ◽

J.J Walgers ◽

R.L.C Vogels ◽

T Germans ◽

S Simsek ◽

...

Keyword(s):

Risk Factors ◽

Elderly Patients ◽

Major Bleeding ◽

Small Vessel Disease ◽

Vitamin K Antagonists ◽

Cerebral Small Vessel Disease ◽

Bleeding Events ◽

Vessel Disease ◽

Major Bleeding Events

Abstract Background Physicians can be reluctant to prescribe antithrombotic agents in frail elderly patients with frequent falls due to the fear for severe bleeding, mainly for intracranial haemorrhage (ICH). Presently, there is only a limited amount of inconclusive data available on the topic. Purpose Identification of risk factors for ICH within a cohort of geriatric patients with repeated falls. Methods All patients of 65 years of age and older with repeated falls at our day clinic were eligible. If an MRI of the brain was performed as part of the assessment, patients were included in this analysis. Baseline characteristics including medical, functional, and cognitive state were collected, a Frailty Index (FI) was calculated [1,2]. Cerebral small vessel disease was described and evaluated as proposed in a position paper in 2013 [3]. Follow-up data concerning major bleeding events were retrieved from the electronic medical files. Odds ratios (OR) with confidence intervals (CI) were calculated. Results 670 patients were eligible; an MRI was performed in 486 patients. The average age was 80 years, 50% was severely frail at the time of inclusion. 83 patients (17%) used OAC (mainly Vitamin K antagonists prescribed for atrial fibrillation), 165 patients (34%) used anti platelet agents (APA), 1 patient used both OAC and APA. In total, 29 major bleeding events (MB) occurred, of which 13 were ICH. Among patients using OAC, 8 MB occurred, of which 2 were ICH. The patient with both OAC and APA did not experience a bleeding event. Well known risk factors for ICH such as hypertension, diabetes mellitus and cognitive impairment were not predictive for ICH in this cohort, nor were the use APA (OR 0.86, 95% CI 0.26–2.84), or vitamin K antagonists (OR 0.88, 95% CI 0.19–4.05). However, a composite factor of using either APA or OAC, heightened the risk for MB (OR 3.24, 95% CI 1.35–7.74), but not for ICH (OR 0.83, 95% 0.27–2.49). Of cerebral small vessel disease, predictive factors for ICH were the presence of lacunes (OR 3.81, 95% CI 1.25–11.56), and relevant white matter hyperintensities (WMH) (defined as a Fazekas score of 2 or more) (OR 11.3, 95% CI 1.45–87.3). Furthermore, cognitive decline defined as an MMSE score of ≤26 heightened the risk of MB (OR 2.28, 95% CI 1.05–4.96). The low number of ICH did not allow for a multivariate analysis. Conclusion This analysis has several important findings. First, despite the long follow up of a cohort of severely frail patients that frequently fall, a low number of MB and ICH was observed. Second, well known risk factors for MB do not seem predictive of ICH in this cohort of very elderly patients. Finally, cognitive decline was predictive for MB, and WMH and lacunes were predictive for ICH. Adding cognitive screening and brain imaging to the diagnostic work up of patients with an indication for OAC could be of value when assessing the future risk for major bleeding events. FUNDunding Acknowledgement Type of funding sources: None.

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