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BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Edoxaban is a non-vitamin K dependent oral anticoagulant (NOAC) licensed for stroke prevention in atrial fibrillation (SPAF). Outcome data on clinical effectiveness and safety in routine care are increasing.In the prospective, non-interventional DRESDEN NOAC REGISTRY a network of 230 physicians enrolled5000 NOAC patients who received prospective central follow. All reported outcome events (stroke/transient ischemic attack/systemic embolism; ISTH bleeding; death) were adjudicated using standard definitions.Between 2016 and 2021, 1258 SPAF patients receiving edoxaban were followed for 927.1 ± 562.2 days with a mean edoxaban exposure of 790.3 ± 577.2 days. Edoxaban was discontinued by 274 patients (10.1/100 patient-years; 95% CI 8.9-11.3). The combined endpoint of stroke/TIA/systemic embolism occurred at a rate of 1.7/100 patient-years (95% CI 1.3-2.3) in the intention-to-treat analysis and at 1.3/100 patient-years (95% CI 0.9-1.9) in the on-treatment analysis (censored 3 days after last edoxaban intake). On-treatment rates of ISTH major bleeding were comparable for patients receiving edoxaban 30 mg OD (3.6/100 patient-years; 95% CI 2.2-5.5) or 60 mg OD (2.5/100 patient-years; 95% CI 1.8-3.2). A total of 151 patients (12.0%) died (4.7/100 patient-years; 95% CI 4.0-5.5), with non-stroke cardiovascular events (n = 50), infection/sepsis (n = 40) and terminal malignant disease (n = 31) being the leading causes of death.Overall rates of effectiveness and safety outcomes were in line with latest real-world data (such as ETNA-AF registry) and confirm findings of the phase-III ENGAGE-AF trial. Non-thrombotic cardiovascular events and infectious diseases were the leading causes of death, whereas fatal stroke and fatal bleeding were rare.

Introduction Following successful phase-III trials, direct oral anticoagulants such as rivaroxaban have largely replaced warfarin for stroke prevention in atrial fibrillation (SPAF). However, data from randomized trials should be confirmed in unselected cohorts. Materials and methods Prospective registries can provide such data but often limit follow-up to short periods only. Extending our previously reported follow-up of 2.2 years in 1204 SPAF patients receiving rivaroxaban in the non-interventional DRESDEN NOAC REGISTRY, we now provide prospectively collected 5 years data (mean follow-up 5.5 ± 2.3 years) for this cohort. Results Between 1 October 2011 and 31 December 2019, the combined endpoint of stroke/transient ischemic attack/systemic embolism occurred at a rate of 2.3/100 patient-years in the intention-to-treat analysis (95% confidence interval [CI] 1.9–2.7) and at 1.6/100 patient-years in the on-treatment analysis (events within 3 days after last drug intake). On-treatment rates for major or clinically relevant non-major bleeding were 3.1 and 19.6/100 patient-years, respectively. Rivaroxaban treatment discontinuation occurred in a total of 574 patients during follow-up (11.0/100 patient-years in Kaplan–Meier analysis) and 426 patient died (all-cause mortality 6.3/100 pt. years; mean time from enrolment 3.6 ± 2.1 years), of which the causes of death were reported as arterial or venous embolism for 32 patients (21 occurring after treatment discontinuation and 11 during active treatment) and as bleeding for 24 patients. Conclusions Our data provide reassuring long-term outcome data for an elderly, co-morbid SPAF population, especially with regard to the low rate of fatal thromboembolic and bleeding complications.

Background Depending on test assays and the time of last DOAC intake, direct thrombin inhibitors (DTI) and direct FXa inhibitors (DXI) may or may not affect prothrombin time (PT), international normalized ratio (INR) or activated thromboplastin time (aPTT) but the clinical impact is unknown. Methods Using data from the Dresden NOAC Registry, we evaluated the impact of DOAC on first PT, INR or aPTT tests during emergency hospitalizations of DTI/DXI patients and the assay performance across 50 coagulation laboratories. Results In 724 emergency admissions (77 DTI; 647 DXI), 490 cases (67.7%) had a reported last DOAC intake within 12 h before blood sampling. INR and PT were elevated above the upper limit of normal (ULN) in >65% of all cases and aPTT was elevated in 45%. On the other hand, >30% of all cases had normal values of INR, PR and aPTT despite a DOAC intake within the last 12 h. Assay performance for detecting or ruling out therapeutic DOAC levels was highly variable and, overall, insufficient to guide clinical decisions. DOAC specific testing was performed in Conclusion Many DOAC recipients present with elevated PT, INR or aPTT during emergency admissions but false negative values within 12 h of last intake as well as elevated values beyond 24 h after last DOAC intake are common. Both scenarios may result in clinical misinterpretation and, potentially, in patient harm, also because DOAC specific testing is rarely performed in emergency settings.

The recent approval of direct-acting oral anticoagulants (DOAC) for long-term anticoagulation in atrial fibrillation and venous thromboembolism resulted in a rapid implementation of these new drugs into daily care. Although DOAC dosing is similar for women and men and, overall, results in comparable outcomes, sex specific issues need to be considered. This review will discuss DOAC topics specifically related to women's health, including the risks and benefits of DOAC treatment for women, the issue of abnormal uterine bleeding from DOAC and the risk and management of DOAC exposure in pregnancy.

Edoxaban is licensed in many countries around the world, following successful phase-III trials in stroke prevention in atrial fibrillation (SPAF) and treatment of venous thromboembolism (VTE), but at present, little is known about edoxaban-related bleeding complications in daily care. Using data from a prospective, non-interventional oral anticoagulation registry, we analysed rates, management and outcome of edoxaban-related bleeding. Between 1 October 2011 and 28 February 2019, 996 patients were enrolled in the edoxaban cohort and a total of 891 bleeding events were observed (53.2% ISTH minor, 41.9% clinically relevant non-major and 4.9% major bleeding events). In case of major bleeding, surgical or interventional treatment was performed in 25.0% and prothrombin complex concentrate was given in 2 cases. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1/100 patient-years (95% CI 2.2-4.2). In the as-exposed analysis, case-fatality rates of edoxaban-associated bleeding leading to hospitalizations were 7.5% and 9.0% at days 30 and 90 post bleeding, respectively. Taken together, our data indicate that, in real life, rates of edoxaban-related major bleeding in line with rates observed in phase III trials and that bleeding pattern, management and outcome of these events are not different from those reported for other direct factor Xa inhibitors. Clinical Trial Notation: Dresden NOAC Registry - ClinicalTrials.gov Identifier NCT01588119.

Introduction For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), rivaroxaban is given in fixed doses without routine coagulation monitoring. Patients and methods To determine whether monitoring would enhance its benefit-risk profile, we examined whether peak and trough prothrombin time (PT) values measured in 3797 rivaroxaban-treated patients included in the EINSTEIN DVT and PE studies correlated with subsequent recurrent VTE and major bleeding. In addition, we examined the stability of PT values over time and the impact of clinical variables on PT values. Results The mean peak PT values at months 3 and 6 or 12 were 21.9 ± 5 and 21.7 ± 6.0 s, respectively, while the mean trough PT values at months 2 and 6 were 15.1 ± 5.1 and 15.3 ± 2.9 s, respectively. Although peak and through PT values were higher in females, and with older age, frailty, active cancer, low body weight, impaired renal function and use of moderate to strong inhibitors of CYP3A4 and/or P-glycoprotein, and were lower in patients taking strong CYP 3A4 inducers, the differences were small and results were overlapping. Neither peak nor trough PT values correlated with recurrent VTE or major bleeding. Conclusions PT monitoring is unlikely to improve the benefit-risk profile of rivaroxaban in patients with DVT or PE. The study was registered at www.clinicaltrials.gov as # NCT00440193 (EINSTEIN-DVT) and # NCT00439777 (EINSTEIN-PE).

Screening for primary hypercoagulable states (PHSs) in venous thromboembolism (VTE) patients was not mandated in the EINSTEIN trials; and therefore, few patients with a known PHS were available for analysis. We sought to assess the effectiveness and safety of rivaroxaban versus warfarin for treatment of VTE in patients with a known PHS.Using MarketScan claims data from 1/2012-9/2015, we identified adults with a primary diagnosis of VTE during a hospitalization/emergency department visit (the index event), with ≥180-days of continuous insurance coverage prior to the index event, a documented diagnosis for a PHS and newly-initiated as an outpatient on rivaroxaban or warfarin within 30-days of the index VTE. Rivaroxaban and warfarin users were 1:1 propensity-score matched. Balance between cohorts was evaluated by inspecting standardized differences for baseline covariates (0.1 considered well-balanced). Patients were followed up to 12-months from the index event or until occurrence of an endpoint, switch/discontinuation of index oral anticoagulation or insurance disenrollment. Rates of recurrent VTE and major bleeding were compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs).We matched 403 rivaroxaban and 403 warfarin patients with VTE and a known PHS. All baseline covariates had a standardized difference 0.1. Rivaroxaban use was associated with a non-significant reduction in recurrent VTE (HR = 0.70, 95%CI = 0.33-1.49) and major bleeding (HR = 0.55, 95%CI = 0.16-1.86) versus warfarin.In routine practice, the effectiveness and safety of rivaroxaban versus warfarin in VTE patients with a known PHS appears to be similar to that observed in the EINSTEIN trial program.

Background: The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6 months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively).Methods: To determine the effect of these methodological differences on outcomes, the patients enrolled in EINSTEIN-DVT/PE were divided into 2 cohorts; the 5253 patients that matched the exclusion criteria for AMPLIFY and were treated for at least 6 months (cohort 1) and the 2368 patients who would have been ineligible for AMPLIFY (cohort 2).Results: Compared with patients in cohort 2, those in cohort 1 were older and more often male and there were more with unprovoked VTE, prior VTE, cancer and known thrombophilia. In cohort 1, rivaroxaban would have significantly reduced recurrent VTE (relative risk [RR], 0.64; 95% confidence interval [CI], 0.43-0.95) and major bleeding (RR, 0.50; 95% CI, 0.30-0.82) compared with conventional therapy, whereas the two treatments would have had similar effects on recurrent VTE (RR, 1.08; 95% CI, 0.65-1.79) and major bleeding (RR, 1.03; 95% CI, 0.48-2.18) in cohort 2.Conclusions: This analysis illustrates the influence of patient selection and treatments duration on outcome results and highlights the limitations of cross-trial comparisons. (C) 2016 Elsevier Ltd. All rights reserved.

Introduction In a management study, a diagnostic algorithm consisting of a clinical decision rule, D-dimer, and ultrasonography was shown to safely exclude upper extremity deep vein thrombosis (UEDVT). Efficiency may be lower in high-risk subgroups: those with a central venous catheter or pacemaker, inpatients, cancer, and elderly patients. Methods Data of 406 patients with suspected UEDVT enrolled in a prospective management study were used for the present analysis. The aim was to evaluate the efficiency of the algorithm in subgroups, defined as the proportion of patients in whom imaging could be safely withheld based on the combination of a decision rule result indicating “UEDVT unlikely” and a normal D-dimer result. Results The strategy excluded UEDVT in 87 of 406 patients (21%); ultrasonography was withheld in these patients and none developed UEDVT during 3 months of follow-up. In contrast, ultrasonography could be withheld in only 4 of 92 patients with a catheter or pacemaker (4.3%; 95% CI: 1.7% to 11%) and in 4 of 83 inpatients (4.8%; 95% CI: 1.9% to 12%). The efficiency was 11% in patients with cancer and 13% in those older than 75 years. Conclusion Although the combination of a decision rule and D-dimer testing is safe in excluding UEDVT in the overall population of patients with suspected UEDVT, its efficiency appears limited in some subgroups, in particular those with a central venous catheter or pacemaker, and inpatients.

Background In phase III trials, rivaroxaban demonstrated non-inferiority over enoxaparin/warfarin to prevent recurrent venous thromboembolism (VTE), with a reduction of major bleeding. However, compared to provoked VTE, the risk-benefit ratio of rivaroxaban may be different for patients with unprovoked VTE. Methods In a retrospective claims data analysis using US MarketScan claims from 1/2012 to 12/2016, we included adults with a primary diagnosis of VTE newly-initiated on rivaroxaban or warfarin within 30-days of the incident VTE and with ≥12-months of continuous insurance benefits prior to the VTE (baseline). Patients with provoked VTE, a claim for anticoagulation during baseline or who redeemed prescriptions for ≥1 oral anticoagulant were excluded. Our primary outcomes were recurrent VTE and major bleeding at 6-months using an intention-to-treat (ITT) analysis. Three-month ITT and 12-month on-treatment (30-day permissible gap) analyses were also performed. Inverse probability-of-treatment weights based on propensity-scores and Cox regression were used to compare outcomes. Findings We identified 10,489 rivaroxaban users and 26,364 warfarin users with incident unprovoked VTE. At 6-months, rivaroxaban was associated with a hazard ratio (HR) of 0.60 (95% confidence interval [CI] = 0.54–0.67) for recurrent VTE (number-needed-to-treat: 59; 95%CI 49–76) and a HR = 0.80 (95% CI = 0.66–0.98) for major bleeding versus warfarin. Our findings remained consistent in the 3- and 12-month analyses. Interpretation Consistent with the results from the EINSTEIN phase-III trials, findings of our routine practice study suggest that, in patients with unprovoked VTE, rivaroxaban has the potential to reduce both the risk of major bleeding and recurrent VTE compared to warfarin.

Increasing D-dimer (DD) levels after discontinuation of vitamin K antagonist (VKA) therapy indicate an increased risk of recurrence of venous thromboembolism (VTE). However, after discontinuation of d irect-acting n on-VKA o ral a nti c oagulants (DOACs or NOACs) the extent of coagulation activation and its clinical impact is unknown. Blood samples were collected from consenting patients with proximal VTE at the end of anticoagulation treatment with apixaban (n = 37), dabigatran (n = 17), rivaroxaban (n = 9) or VKA (n = 184) and 4 weeks later. DD, prothrombin fragments F1 + 2 (F1 + 2) and thrombin–antithrombin complexes (TAT) were measured. All patients underwent follow-up at 12 months to establish recurrent VTE or death from any cause. Irrespective of the treatment, DD and F1 + 2 but not TAT demonstrated a similar increase between baseline and week 4. At 12 months, 18 patients (7.3%) had recurrent VTE and two (0.8%) had died. For all patients and subgroups of VKA and DOAC, positive likelihood ratios were numerically higher for baseline values but only TAT values at 4 weeks were found to be related to a small increase of outcome event likelihood (2.6; 95%CI 1.23-5.50), which was driven by VKA patients (3.1; 95%CI 1.32-7.30) and not by DOAC patients (2.27; 95%CI 0.52-9.95). For all parameters, negative likelihood ratios were not predictive. In logistic regression analysis, only ΔTAT (optimal cut-off > 178% from baseline demonstrated a significant risk increase for VTE/death (odds ratio 3.76; 95% confidence interval 1.46-9.68; p = 0.006). In conclusion, the concept of testing coagulation activation parameters may also be transferred to VTE patients at the end of DOAC therapy. For patients with an increase of TAT levels within 4 weeks after treatment discontinuation (> 178% from baseline) is associated with an increased risk for VTE recurrence or death at 12 months.

Venous thromboembolism (VTE) remains a substantial clinical and health-economic burden worldwide and effective anticoagulant treatment is necessary immediately after VTE is suspected to reduce short- and long-term VTE related morbidity and mortality. For decades, low molecular weight heparin (LMWH), fondaparinux and Vitamin K antagonists (VKAs) have been the standard of anticoagulant therapy for VTE patients but these treatment options had clinically relevant drawbacks and limitations. The introduction of non-VKA oral anticoagulants (NOACs) that specifically inhibit either thrombin or factor Xa have resolved many of these drawbacks because these new compounds exhibit a rapid onset and offset of action, fewer food and drug interactions and a predictable anticoagulant effect. All NOACs have successfully completed their respective phase-III trial programs consisting of many large randomized controlled trials, leading to approval for acute VTE treatment around the world. Nevertheless, their introduction into daily care practice is challenging and a careful evaluation of the effectiveness and safety of NOACs in less selected cohorts outside carefully monitored clinical trials is essential. This review introduces the different types of real-world evidence (RWE) and explores the available data for VTE treatment with NOACs, based on a literature search using the key words "venous thromboembolism" or "VTE" in combination with "NOAC", "DOAC", "apixaban", "dabigatran", "edoxaban" and "rivaroxaban" on June 30; 2017, followed by data extraction from studies that reported real-world outcome data for VTE treatment with NOACs, although available evidence is almost exclusively limited to rivaroxaban.

Venous thromboembolism (VTE) is a common complication associated with increased mortality in cancer patients. Adequate treatment of thrombotic complications increases survival in these patients although additional complications such as thrombus progression with pulmonary embolism and bleeding events are common. The incidence of types of cancer as well as malignancy-associated VTE varies between genders. This article focuses on cancers more common in male patients and reviews the risk of VTE with special regard to types of cancer and anticancer therapy.