Clinical outcomes of prolonged anticoagulation with rivaroxaban after unprovoked venous thromboembolism.
ABSTRACT: Randomized trial data demonstrate the gain of extended duration anticoagulation in patients with venous thromboembolic events (VTE); however, real-world data are limited.Assess the risk of recurrent VTE and major bleeding in a real-world setting of patients who experienced unprovoked VTE and received extended treatment with rivaroxaban.US claims databases (February 2011-April 2015) were used in this retrospective study. The study population included adult patients initiated on rivaroxaban within 7 days after their first unprovoked VTE (ie, deep vein thrombosis, pulmonary embolism) and received ?3 months continuous rivaroxaban treatment (index date: end of 3-month treatment). Patients who were treated beyond 3 months formed the continued cohort and the remainder formed the discontinued cohort (ie, discontinued at 3 months). Adjusted Kaplan-Meier rates for recurrent VTE and major bleeding events were compared between cohorts with confounders being controlled through a propensity score weighting approach.Patients in the continued cohort (N = 3763) had significantly lower rates of recurrent VTE than those who discontinued (N = 1051): 0.57% vs 1.19% (P = .042), 1.07% vs 2.10% (P = .017), and 1.45% vs 2.60% (P = .023) at 3, 6, and 12 months, respectively. No significant differences in the rate of major bleeding were observed between cohorts. A sensitivity analysis among unprovoked VTE patients receiving rivaroxaban for ?6 months showed similar results.Continued rivaroxaban treatment beyond an initial 3- or 6-month treatment period significantly lowered the risk of recurrent VTE without a significant increase of major bleeding, compared to treatment discontinued at 3 or 6 months.
Project description:Venous thromboembolism (VTE)-BLEED, a decision tool for predicting major bleeding during chronic anticoagulation for VTE has not yet been validated in practice-based conditions. We calculated the prognostic indices of VTE-BLEED for major bleeding after day 30 and day 90, as well as for recurrent VTE and all-cause mortality, in 4457 patients enrolled in the international, prospective XALIA study. The median at-risk time was 190 days (interquartile range 106-360). The crude hazard ratio (HR) for major bleeding after day 30 was 2·6 [95% confidence interval (CI) 1·3-5·2] and the treatment-adjusted HR was 2·3 (95% CI 1·1-4·5) for VTE-BLEED high (versus low) risk patients: the corresponding values for major bleeding after day 90 were 3·8 (95% CI 1·6-9·3) and 3·2 (95% CI 1·3-7·7), respectively. The predictive value of VTE-BLEED was similar in selected patients with unprovoked VTE or those treated with rivaroxaban. High VTE-BLEED score was associated with higher incidence of all-cause mortality (treatment-adjusted HR 11, 95% CI 4·8-23), but not evidently with recurrent VTE (treatment-adjusted HR 1·5; 95% CI 0·85-2·7). These results confirm the predictive value of VTE-BLEED in practice-based data in patients treated with rivaroxaban or conventional anticoagulation, supporting the hypothesis that VTE-BLEED may be useful for making management decisions on the duration of anticoagulant therapy.
Project description:Background ?Overall, 30 to 50% of lower-limb deep-vein thrombosis (DVT) cases are isolated distal DVT (IDDVT). The recurrent venous thromboembolism (VTE) risk is unclear, leaving uncertainty over optimal IDDVT treatment. We present data on patients with IDDVT and proximal DVT (PDVT) from the prospective, noninterventional XALIA study of rivaroxaban for acute and extended VTE treatment. Methods ?Patients aged ?18 years scheduled to receive ?3 months' anticoagulation with rivaroxaban or standard anticoagulation were eligible, with follow-up for ?12 months. We describe baseline characteristics, management strategies, and incidence proportions of VTE recurrence, major bleeding, and all-cause mortality in patients with IDDVT or PDVT, with or without distal vein involvement. Findings ?Overall, 1,004 patients with IDDVT and 3,098 with PDVT were enrolled; 641 (63.8%) and 1,683 (54.3%) received rivaroxaban, respectively. Patients with IDDVT were younger and had lower incidences of renal impairment, cancer, and unprovoked VTE than those with PDVT. On-treatment recurrence incidences for IDDVT versus PDVT were 1.0 versus 2.4% (adjusted hazard ratio [HR]: 0.56; 95% confidence interval [CI]: 0.29-1.08), and incidences posttreatment cessation were 1.1 versus 2.1% (adjusted HR: 0.65; 95% CI: 0.32-1.35), respectively. On-treatment major bleeding incidences were 0.9 versus 1.4% and mortality was 0.8 versus 2.2%, respectively. Median treatment duration in patients with IDDVT was shorter than in those with PDVT (102 vs. 192 days, respectively). Interpretation ?Patients with IDDVT had fewer comorbidities and were more frequently treated with rivaroxaban than those with PDVT. On-treatment and posttreatment recurrences were less frequent in patients with IDDVT. Trial registration number: ?NCT01619007.
Project description:INTRODUCTION:Rivaroxaban, a factor Xa inhibitor used as a direct oral anticoagulant, is beneficial over warfarin in terms of food-drug interactions and the need for therapeutic monitoring in patients with acute venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. Because there is little data regarding VTE treatment in Japan, a real-world survey of Japanese patients being treated with rivaroxaban for VTE is needed. METHODS AND ANALYSIS:The Japanese Registry of Rivaroxaban Effectiveness & Safety for the Prevention of Recurrence in Patients with Deep Vein Thrombosis and Pulmonary Embolism has been established to investigate the clinical outcomes of rivaroxaban for the initial treatment and prevention of symptomatic recurrent VTE in Japanese patients with acute symptomatic/asymptomatic VTE. 150 institutions in Japan will enrol patients in the study; the target enrolment is 1000. All patients will be followed up two times a year for at least 18 months and up to 3 years after their enrolment. The primary outcome is symptomatic recurrent VTE occurring during the study period. The principal safety outcome is clinically relevant bleeding (ie, major bleeding or clinically relevant non-major bleeding) occurring during treatment. A clinical events committee will adjudicate all outcomes. ETHICS AND DISSEMINATION:The study protocol has been approved by the Nihon University Itabashi Hospital, Clinical Research Ethics Committee and all local institutional ethics committees of the participating hospitals. Findings of the study will be presented in scientific sessions and will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER:NCT03091621,UMIN000025072; Pre-results.
Project description:BACKGROUND/AIMS:Limited data are available regarding the efficacy of rivaroxaban for the treatment of cancer-associated venous thromboembolism (VTE). The aim of this study was to evaluate the effectiveness and safety of rivaroxaban for the treatment of VTE in active cancer patients. METHODS:In this prospective, multicenter, open-label trial (NCT01989845), we enrolled patients with active cancer and objectively diagnosed lower-extremity deep vein thrombosis, pulmonary embolism (PE), or both from November 2013 to June 2016. Active cancer was defined as a histologically confirmed malignancy, which was diagnosed or treated within the previous 6 months, or as a recurrent/ metastatic cancer. Patients received oral rivaroxaban 15 mg twice daily for first 3 weeks, followed by 20 mg once daily for 6 months. The primary outcome was the symptomatic recurrent VTE and the secondary outcomes included any recurrent VTE, major or clinically relevant non-major (CRNM) bleeding events, and overall mortality. All study outcomes were validated by blinded central adjudication. RESULTS:Of 124 patients enrolled, 110 (88.7%) had solid cancer, 93 (75.0%) had metastatic disease, and 110 (88.7%) were receiving chemotherapy or radiotherapy. During the 6-month study period, seven patients experienced symptomatic recurrent VTE (cumulative incidence, 5.9%), and two patients experienced incidental recurrent PE (cumulative incidence of any recurrent VTE, 7.6%). Major bleeding events occurred in six patients (cumulative incidence, 5.3%) and CRNM bleeding events in 11 patients (cumulative incidence, 10.2%). Twenty-eight patients (overall mortality, 24.0%) died. CONCLUSION:Rivaroxaban is effective and safe for the treatment of VTE in patients with active cancer.
Project description:Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4?% (95?% CI?=?1.4-7.4?%), major bleeding was 2.2?% (95?% CI?=?0-4.2?%) and all-cause mortality 17.6?% (95?% CI?=?11.7-23.0?%). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH.
Project description:Anticoagulation is used to treat venous thromboembolism (VTE) in cancer patients, but may be associated with an increased risk of bleeding. VTE recurrence and major bleeding were assessed in cancer patients treated for VTE with the most currently prescribed anticoagulants in clinical practice. Newly diagnosed cancer patients (first VTE 1/1/2013-05/31/2015) who initiated rivaroxaban, low-molecular-weight heparin (LMWH), or warfarin were identified from Humana claims data and observed until end of eligibility or end of data availability. VTE recurrence was a hospitalization with a primary diagnosis of VTE ?7 days after first VTE. Major bleeding events on treatment were identified using validated criteria. Cohorts were compared using Kaplan-Meier rates at 6 and 12 months and Cox proportional hazards models. Cohorts were adjusted for their differences at baseline. A total of 2428 patients (rivaroxaban: 707; LMWH: 660; warfarin: 1061) met inclusion criteria. Patient characteristics were well balanced after weighting. There was a trend for lower VTE recurrence rates in rivaroxaban users compared to LMWH users at 6 months (13.2% vs. 17.1%; P?=?.060) and significantly lower at 12 months (16.5% vs. 22.2%; P?=?.030) [HR: 0.72, 95% CI: (0.52-0.95); P?=?.024]. VTE recurrence rates were also lower for rivaroxaban than warfarin users at 6 months (13.2% vs. 17.5%; P?=?.014) and 12 months (15.7% vs. 19.9%; P?=?.017) [HR: 0.74, 95% CI: (0.56-0.96); P?=?.028]. Major bleeding rates were similar across cohorts. This real-world analysis suggests cancer patients with VTE treated with rivaroxaban had significantly lower risk of recurrent VTE and similar risk of bleeding compared to those treated with LMWH or warfarin.
Project description:After completing anticoagulation therapy for acute venous thromboembolism (VTE), patients with unprovoked VTE are at increased risk of recurrent thrombotic events. Recent studies suggest a risk of nearly 10% in the first year after stopping anticoagulants and 30% at 8 years. Therefore, it is important to consider extended anticoagulation for secondary prevention in these high-risk patients. While several oral anticoagulants are available for this purpose, there is limited information available regarding the optimal agent to minimize bleeding risks and maximize efficacy at VTE prevention. This review article summarizes the evidence available for Vitamin-K antagonists (VKAs) and direct oral anticoagulants (DOACs) for extended treatment of VTE. We also introduce the COVET trial, the first head-to-head comparison of VKAs to DOACs, rivaroxaban and apixaban, for extended management of unprovoked VTE.
Project description:Patients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended "life-long" anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a "weak provoking factor" there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event.A systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued.MEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles.Randomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy.Independent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent.Seven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11-0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69-3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40-1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm.VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients' risk for recurrent PE as well as the patients' values and preferences.
Project description:Introduction:VTE-BLEED is a validated score for identification of patients at increased risk of major bleeding during extended anticoagulation for venous thromboembolism (VTE). It is unknown whether VTE-BLEED high-risk patients also have an increased risk for recurrent VTE, which would limit the potential usefulness of the score. Methods:This was a post hoc analysis of the randomized, double-blind, placebo-controlled PADIS-PE trial that randomized patients with a first unprovoked pulmonary embolism (PE) initially treated during 6 months to receive an additional 18-month of warfarin vs. placebo. The primary outcome of this analysis was recurrent VTE during 2-year follow-up after anticoagulant discontinuation, that is, after the initial 6-month treatment in the placebo arm and after 24 months of anticoagulation in the active treatment arm. This rate, adjusted for study treatment allocation, was compared between patients in the high- vs. low-risk VTE-BLEED group. Results:In complete case analysis (n = 308; 82.4% of total population), 89 (28.9%) patients were classified as high risk; 44 VTE events occurred after anticoagulant discontinuation during 668 patient-years. The cumulative incidence of recurrent VTE was 16.4% (95% confidence interval [CI], 10.0%-26.1%; 14 events) and 14.6% (95% CI, 10.4%-20.3%; 30 events) in the high-risk and low-risk VTE-BLEED groups, respectively, for an adjusted hazard ratio of 1.16 (95% CI, 0.62-2.19). Conclusion:In this study, patients with unprovoked PE classified at high risk of major bleeding by VTE-BLEED did not have a higher incidence of recurrent VTE after cessation of anticoagulant therapy, supporting the potential yield of the score for making management decisions on the optimal duration of anticoagulant therapy.
Project description:Bleeding is the most feared and difficult to predict adverse event of anticoagulation. We sought to investigate whether calibrated automated thrombography (CAT) parameters are associated with minor bleeding (MB) in anticoagulated patients following venous thromboembolism (VTE). Enrolled were 132 patients on rivaroxaban, 145 on vitamin K antagonists (VKA) and 31 controls who stopped anticoagulation. Prior to the next dose of the anticoagulant, we measured CAT parameters, along with rivaroxaban concentration and INR. During a median follow-up of 10 months, we recorded minor and major bleedings. On rivaroxaban, 27 (20.5%) patients with MB had longer time to start thrombin generation, lower peak thrombin generation and lower endogenous thrombin potential compared with subjects without MB (all p < 0.001). All CAT parameters, except for peak thrombin generation (p = 0.049), were similar in VKA patients with (n = 25, 17.2%) vs. without MBs. By logistic regression, time to start thrombin generation (p = 0.007) and unprovoked VTE (p = 0.041) independently predicted MBs on rivaroxaban. Major bleedings were more frequent in patients with MBs (17.3% vs. 1.8%, p < 0.001). Abnormal CAT parameters characterize VTE patients prone to MBs on rivaroxaban, but not on VKA. Time to start thrombin generation measured about 24 h since the last rivaroxaban dose might help predict MBs.