Bleeding and Thrombotic Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants in Patients with Prior Venous Thromboembolic Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2614-2614
Author(s):  
Joseph Shaw ◽  
Carine de Wit ◽  
Gregoire Le Gal ◽  
Marc Carrier
Keyword(s):  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Risk ◽  
Thromboembolic Complication ◽  
Invasive Procedures ◽  
Bleeding Rate ◽  
Major Bleeding Rate ◽  
Venous Thromboembolic ◽  
Overall Mortality

Abstract Introduction: The use of Direct Oral Anticoagulants (DOACs) for the prevention and treatment of Venous Thromboembolic Disease (VTE) is increasingly common. Patients on longstanding anticoagulation for the prevention of VTE frequently undergo invasive procedures that necessitate interruption of anticoagulation in order to avoid excessive bleeding during the procedure. There is little evidence surrounding the safety of perioperative DOAC interruption in patients with VTE. Methods: This study represents a retrospective analysis of adult patients on DOAC therapy for prior VTE, who underwent temporary interruption of anticoagulation therapy for inpatient or outpatient invasive procedures. The timing to hold and resume DOAC anticoagulation was based on the estimated half-life of the DOAC, as well as the bleeding risk of the procedure (Standard vs High). Our primary outcomes included the 30-day thromboembolic complication rate, as well as the 30-day major bleeding rate (ISTH non-surgical and surgical major bleeding criteria). Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and overall mortality. Results: To date, a total of 87 patients have been included in the analysis, 68% of which were male. The mean age of the cohort was 58.3 years. All patients were on DOAC anticoagulation for acute treatment or secondary prevention of recurrent VTE. A large majority of patients (94%) were anticoagulated with rivaroxaban. Procedures were performed on an inpatient or outpatient basis in 24 and 63 patients, respectively. Forty six patients underwent procedures with standard bleeding risk. Mean time to anticoagulation discontinuation for standard and high bleeding risk procedures was 41.3 (SD = 20.8) and 49.3 (SD = 17.7) hours, respectively. The 30-day thromboembolic complication rate was 1.2% (95% CI: 0.2 to 6.2%), whereas the 30-day major bleeding rate was 0% (95% CI: 0 to 4.2%). The rate of CRNMB was 3.5% (95% CI: 1.2 to 9.7%). Overall mortality was 0% (95% CI: 0 to 4.2%). Conclusion: The perioperative interruption of direct oral anticoagulation for invasive procedures in patients with prior VTE appears to be associated with a relatively low risk of major bleeding, as well as recurrent VTE. Prospective studies are needed to evaluate the benefits and risks of perioperative interruption of direct oral anticoagulation in patients with prior VTE. Disclosures Carrier: BMS: Research Funding; Leo Pharma: Research Funding.

scholarly journals Bleeding Risk in Non-Valvular Atrial Fibrillation Patients Receiving Direct Oral Anticoagulants and Warfarin: A Systematic Review and Meta-Analysis of Observational Studies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3672-3672 ◽  
Author(s):  
Yimin Pearl Wang ◽  
Rohan Kehar ◽  
Alla Iansavitchene ◽  
Alejandro Lazo-Langner
Keyword(s):  
Major Bleeding ◽  
Lower Risk ◽  
Observational Studies ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Risk Of Bleeding ◽  
Significant Difference

Introduction: The standard oral anticoagulant therapy administered to non-valvular AF patients has typically been Vitamin K Antagonists (VKA) particularly warfarin. In recent years, Direct Oral Anticoagulants (DOACs) including Direct Thrombin Inhibitors (DTI) and Direct Factor Xa inhibitors (FXa inhibitors) have become an alternative to warfarin. Randomized trials comparing warfarin and DOACs showed comparable effectiveness without significant additional major bleeding risk. However, bleeding events in RCTs may differ from those in daily use due to the routine exclusion of patients with a higher risk of bleeding from many studies. We aimed to assess bleeding risk between DOACs and warfarin in AF patients in observational studies and we also sought to determine differences between patients that were experienced or naïve to oral anticoagulants. Methods: A systematic literature search was conducted in the OVID MEDLINE® and EMBASE® electronic databases. Observational studies and randomized control trials (RCT) from 1990 to January 2019 were retrieved and examined by two independent reviewers. A pooled effect hazard ratio (HR) was calculated using a random effects model using the generic inverse variance method. Subgroup analyses according to previous exposure to anticoagulants, study type, funding type and DOAC type were conducted. The primary outcome was major bleeding risk. The secondary outcome was clinically relevant non-major bleeding. All studies must have used an established or validated definition of major bleeding. Results: The initial literature search identified 3359 potentially eligible citations. After primary screening, 150 articles were eligible for full text review and there were 35 studies including 2,356,201 patients that met the inclusion criteria. Overall, patients on DOACs were less likely to experience a bleeding event compared to warfarin (HR 0.78, 95%CI 0.71, 0.85, P<0.001). The results were consistent when analyzing patients receiving DTIs or FXa inhibitors (DTI: HR 0.76, 95% CI 0.67,0.87; FXa inhibitors: HR 0.79, 95% CI 0.69,0.89). However, among patients receiving factor Xa inhibitors, there was a significant difference in the risk of bleeding according to individual drug. Among patients receiving rivaroxaban the risk of bleeding was similar to warfarin (HR 0.98, 95%CI 0.91,1.06, p=0.60) whereas in those receiving apixaban there was a 40% reduction in the risk of bleeding compared to warfarin (HR 0.60, 95%CI 0.50,0.71, p<0.001) (Figure 1). Three studies reported information according to previous anticoagulant exposure. The overall pooled hazard ratio was 0.68 (95% CI 0.55, 0.82 p<0.001) in favor of patients on DOACs. In the subgroup analysis of previous anticoagulant use, the risk of bleeding was lower for DOACs compared to warfarin in both the experienced population (HR 0.70, 95%CI 0.51, 0.96) and the naïve population (HR 0.64, 95% CI 0.47,0.87). However, heterogeneity was moderate to high among both subgroups. Conclusion: This review and meta-analysis of observational studies including over 2.3 million patients showed that overall DOACs have a lower risk of major bleeding and clinically relevant non-major bleeding compared to warfarin. Most importantly, although the pooled effect estimate did not differ between DTIs and FXa inhibitors, among patients receiving FXa inhibitors there was a significant difference between individual agents. Patients on apixaban had a significantly lower risk of bleeding compared to warfarin in contrast to patients on rivaroxaban who had a similar risk. Disclosures No relevant conflicts of interest to declare.

P690Incidence of events between vitamin K antagonists and direct oral anticoagulants in patients with cancer

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Pardo Sanz ◽  
L M Rincon ◽  
G De Lara ◽  
A Tamayo ◽  
L C Belarte ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vitamin K ◽  
Major Bleeding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Risk ◽  
Systemic Embolism ◽  
Bleeding Events ◽  
Patients With Cancer

Abstract Background Balance between embolic and bleeding risk is challenging in patients with cancer. There is a lack of specific recommendations for the use of antithrombotic therapy in oncologic patients with atrial fibrillation (AF). We aimed to evaluate the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) within patients with breast cancer. We also compared the embolic and bleeding risk, the preventive management and the incidence of events between patients with and without cancer. Methods It is an ambispective observational multicentric study that analysed patients with non-valvular AF treated in Oncology and Cardiology Departments in Spain in the period 2011–2018. A total of 1237 female patients with AF were enrolled: 637 with breast cancer and 599 without cancer. The incidence of thromboembolic and major bleeding events according to the antithrombotic strategy with VKAs or DOACs was evaluated in the cohort of 637 patients with cancer. Analysis were conducted using SPSS software V.22.0 and R V.3.5.1, with a two-tailed significance value of 0.05. Results Mean follow-up was 3.1 years. Both groups were similar in age, CHA2DS2-VASc and HASB-LED scores. There was no evidence that the incidence of ischemic stroke/systemic embolism differed between patients with cancer treated with AVK and DOAC after CHA2DS2-VASc adjustment: HR 0.91 (95% CI, 0.42–1.99). In addition, no significant differences in the incidence of major bleeding events were found between DOACs and VKA after adjustment for HAS-BLED score: HR 1.53 (95% CI, 0.93–2.53) (Figure 3). Gastrointestinal bleeding was the main source of haemorrhages in both groups (45% of bleedings among patients treated with DOACs and, 37% in VKAs group). Metastatic disease or active chemotherapy were studied as potential covariates but none of them posed any relevant change in the result. Kaplan-Meier analysis Conclusions Cancer patients treated with DOACs did not differ versus those treated with VKAs with regards to stroke or systemic embolism in a model adjusted for CHA2DS2-VASc. Neither significant differences were found for bleeding events in a model adjusted for baseline HASBLED.

Bleeding with Apixaban and Dalteparin in Patients with Cancer-Associated Venous Thromboembolism: Results from the Caravaggio Study

2020 ◽  
Author(s):  
Walter Ageno ◽  
Maria Cristina Vedovati ◽  
Ander Cohen ◽  
Menno Huisman ◽  
Rupert Bauersachs ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Gastrointestinal Cancer ◽  
Clinical Presentation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Risk ◽  
Analysis Data ◽  
Bleeding Events ◽  
Open Label ◽  
Safe Alternative

Abstract Background Direct oral anticoagulants are recommended for the treatment of cancer-associated thrombosis (CAT) as an alternative to low-molecular-weight heparin (LMWH), but an increased bleeding risk in patients with gastrointestinal cancer was reported. The Caravaggio study compared apixaban and dalteparin for the treatment of patients with CAT. Here we describe sites of bleeding, associated cancer sites, clinical presentation, and course of major bleeding in patients included in the Caravaggio study. Methods The Caravaggio study was a multinational, randomized, open-label, noninferiority study. Bleeding events and the severity of major bleedings were adjudicated by a committee unaware of treatment allocation using predefined criteria; for the purpose of this analysis, data were analyzed in the safety population. Results Major bleeding occurred in 22 of 576 patients on apixaban (3.8%) and in 23 of 579 patients on dalteparin (4.0%). The sites of major bleeding and their distribution according to the type of cancer were similar between the two treatment groups. Major bleeding occurred in nine patients with gastrointestinal cancer in each treatment group. The clinical presentation of major bleeding was severe or fatal in 6 patients on apixaban and in 5 patients on dalteparin, while the clinical course was severe in 5 patients on apixaban and in 7 patients on dalteparin. Conclusion Apixaban is a safe alternative to LMWH for the treatment in patients with CAT. No excess in gastrointestinal bleeding was observed in patients who received apixaban, including those with gastrointestinal cancer.

scholarly journals Thrombotic and Bleeding Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants and Vitamin K Antagonists in Patients with Non-Valvular Atrial Fibrillation - a Comparative Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1234-1234
Author(s):  
Joseph R. Shaw ◽  
Tinghua Zhang ◽  
Gregoire Le Gal ◽  
James Douketis ◽  
Marc Carrier
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Risk ◽  
Advisory Board ◽  
Bleeding Events ◽  
Chads2 Score ◽  
High Bleeding Risk

Abstract Background: Atrial fibrillation (AF) is a common disorder that will affect up to 5.6 million patients in the U.S. by 2050. Both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs), typically warfarin, are used for stroke prevention in AF and such patients frequently undergo invasive procedures requiring anticoagulant interruption. Temporary interruption of anticoagulants can be associated with significant morbidity and mortality in the form of thromboembolic and bleeding complications. DOACs have a short half-life and fast onset of action, thereby facilitating their perioperative management as compared to VKAs. Despite important differences in perioperative management and pharmacokinetics between DOACs and VKAs, there is a paucity of data comparing perioperative outcomes in DOAC and VKA-treated patients. Methods: We undertook a single-center, retrospective chart review that compared consecutive DOAC- or warfarin-treated patients with AF who underwent perioperative anticoagulant interruption for invasive procedures between January 2017 and March 2018. Perioperative warfarin interruption was done as per CHEST guidelines (Douketis et al. Chest 141,2 Suppl). Perioperative bridging with low-molecular-weight heparin was only used for patients with CHADS2 scores of 5-6 or in patients with stroke within the past 6 months. Perioperative interruption of DOACs was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Primary outcomes included the 30-day post-operative thromboembolic and major bleeding rates. Secondary outcomes included the 30-day clinically relevant non-major bleeding (CRNMB) andl mortality rates. Major bleeding and CRNMB were defined according to ISTH definitions. Procedural bleeding risk was defined as per Schulman et al (Circulation 2015; 132(3)). Outcome events were independently adjudicated by two investigators. Outcomes from patients on DOACs and VKAs were compared. Demographic data was analyzed on a per-patient basis, p-values were calculated using independent T-Test, Chi-Square/Fisher's Exact Test where appropriate. Outcome data was analyzed on a per-interruption basis. P-values for unadjusted and adjusted comparisons were calculated using generalized estimating equations (GEE) to account for correlation between multiple procedures on the same patients. Results: 325 DOAC patients and 199 warfarin patients underwent 351 and 221 periprocedural interruptions, respectively. Warfarin patients had a significantly higher mean age, CHADS2 score, and proportion with renal dysfunction (Table 1). There was no statistically significant difference in 30-day post-operative rates of thromboembolism, CRNMB, and overall mortality, but warfarin patients had a significantly higher rate of major bleeding (Table 2). This latter result remained statistically significant following multivariate logistic regression correction for age, CHADS2 score and level of renal dysfunction. All bleeding events occurred post-procedure, with major bleeding events occurring from post-operative day 1 to post-operative day 25. None of the warfarin patients with major bleeding received perioperative bridging; the mean international normalized ratio (INR) at the time of major bleeding was 3.3. Most major bleeding events (7/8) in the VKA arm were surgical, with a single non-surgical major-bleed (spontaneous ICH on post-operative day 15 following urological surgery). Conclusions: The perioperative interruption of warfarin was associated with a higher 30-day rate of major bleeding as compared with DOAC interruption. Re-initiation of warfarin should be done judiciously following high bleeding risk procedures, and close INR monitoring may be warranted. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:Janssen: Consultancy; Pfizer: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; Portola: Other: Advisory Board; The Medicines Company: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Biotie: Other: Advisory Board; Bayer: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; BMS: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board. Carrier:Bayer: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

Validation of Bleeding Risk Prediction Scores for Patients With Major Bleeding on Direct Oral Anticoagulants

2020 ◽  
Vol 54 (12) ◽  
pp. 1175-1184 ◽  
Author(s):  
Stephanie Tchen ◽  
Nicole Ryba ◽  
Vishal Patel ◽  
Joseph Cavanaugh ◽  
Jesse B. Sullivan
Keyword(s):  
Diagnostic Accuracy ◽  
Risk Prediction ◽  
Major Bleeding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Significant Risk ◽  
Bleeding Risk ◽  
International Normalized Ratio ◽  
Primary Objective

Background: Direct oral anticoagulants (DOACs) offer many benefits over vitamin K antagonists (VKAs) but still carry a significant risk of major bleeding. Bleeding risk prediction scores such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, and Drugs/Alcohol (HAS-BLED), Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk, and Stroke (HEMORR2HAGES), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), Registro Informatizado Enfermedad TromboEmbólica (RIETE), and CHEST scores were validated or evaluated for use with VKAs and parenteral anticoagulants, but evidence for use with DOACs is lacking. Objective: This study aims to evaluate bleeding risk prediction scores for DOAC patients presenting with major bleeding. Methods: A retrospective analysis of patients presenting from 2015 to 2018 was performed. Patients were separated into bleed and nonbleed groups. The primary objective was to assess the diagnostic accuracy of the bleeding risk prediction scores utilizing the receiver operating characteristic (ROC) curve. Results: A total of 126 patients were included in the analyses. The areas under the curve (AUC) for the ROC curves of the HAS-BLED, HEMORR2HAGES, ATRIA, RIETE, and CHEST scores were 0.645, 0.675, 0.580, 0.638, and 0.667, respectively. Conclusion and Relevance: The HAS-BLED, HEMORR2HAGES, RIETE, and CHEST scores were found to have sufficient diagnostic accuracy for predicting risk of major bleeding in our study population; however, no score was identified as having an AUC greater than 0.7. Caution may be considered when utilizing these scores for patients on DOACs.

P4753Impact of renal function on bleeding risk in patients with non-valvular atrial fibrillation treated with direct oral anticoagulants: Subanalysis of the DIRECT registry

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Hirata ◽  
Y Sotomi ◽  
T Kobayashi ◽  
R Amiya ◽  
A Hirayama ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Renal Function ◽  
Renal Dysfunction ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Risk ◽  
Rank Test ◽  
Log Rank Test ◽  
Kaplan Meier

Abstract Background Renal dysfunction is one of the high bleeding risk factors in patients with atrial fibrillation as presented in the HAS-BLED score. The impact of renal function on bleeding risk is, however, still to be investigated in the era of direct oral anticoagulants (DOAC). Methods We conducted a single-center prospective observational registry of NVAF patients with DOACs: the DIRECT registry (UMINehz745.112933283). All patients with NVAF (N=2216) who were users of dabigatran (N=648), rivaroxaban (N=538), apixaban (N=599), or edoxaban (N=431) from 2011 to 2017 were enrolled (71.6±10.8 years, mean follow-up duration: 407.2±388.3 days). In the present substudy, all patients were stratified by renal function. Creatinine clearance (CCr) was estimated with the Cockcroft-Gault equations with available creatinine at baseline. Patients were divided into 4 groups based on CCr. (CCr>80, CCr50–80, CCr30–50, and CCr<30). The primary endpoint was major bleeding according to the ISTH criteria. Clinical endpoints were compared between the groups (Kaplan-Meier analysis, Log-rank test). The influence of DOAC type in patients with renal dysfunction was also assessed for the primary endpoints of major bleeding. Results Kaplan-Meier estimated 2-year major bleeding rate significantly increased as renal function decreased (CCr>80 2.5%, CCr50–80 4.2%, CCr30–50 4.2%, CCr<30 7.8%, Log-rank test p<0.001). However, in patients with apixaban (low CCr 59.6±25.9ml), major bleeding does not appear to increase as renal function decreased.(CCr >80 9.2%, CCr 50–80 8.0%, CCr 30–50 10.3%, CCr<30 7.3%, Log-rank test p=0.97). Kaplan-Meier Analysis Conclusions Renal dysfunction increased bleeding risks in NVAS patients with DOACs. Apixaban might be safely used for patients with renal dysfunction.

scholarly journals Clinical outcomes in patients with atrial fibrillation and frailty: insights from the ENGAGE AF-TIMI 48 trial

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Chris Wilkinson ◽  
Jianhua Wu ◽  
Samuel D. Searle ◽  
Oliver Todd ◽  
Marlous Hall ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Outcomes ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Frailty Index ◽  
Bleeding Risk ◽  
Similar Efficacy ◽  
Systemic Embolism ◽  
Increased Risk

Abstract Background Atrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. This study aims to report clinical outcomes of patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial by frailty status. Methods Post hoc analysis of 20,867 participants in the ENGAGE AF-TIMI 48 trial, representing 98.8% of those randomised. This double-blinded double-dummy trial compared two once-daily regimens of edoxaban (a DOAC) with warfarin. Participants were categorised as fit, living with pre-frailty, mild-moderate, or severe frailty according to a standardised index, based upon the cumulative deficit model. The primary efficacy endpoint was stroke or systemic embolism and the safety endpoint was major bleeding. Results A fifth (19.6%) of the study population had frailty (fit: n = 4459, pre-frailty: n = 12,326, mild-moderate frailty: n = 3722, severe frailty: n = 360). On average over the follow-up period, the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 95% CI 1.19–1.58) and major bleeding by 42% (adjusted HR 1.42, 1.27–1.59) for each 0.1 increase in the frailty index (four additional health deficits). Edoxaban was associated with similar efficacy to warfarin in every frailty category, and a lower risk of bleeding than warfarin in all but those living with severe frailty. Conclusions Edoxaban was similarly efficacious to warfarin across the frailty spectrum and was associated with lower rates of bleeding except in those with severe frailty. Overall, with increasing frailty, there was an increase in stroke and bleeding risk. There is a need for high-quality, frailty-specific population randomised control trials to guide therapy in this vulnerable population. Trial registration ClinicalTrials.gov NCT00781391. First registered on 28 October 2008

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