Cumulative Incidence Of Recurrent Venous Thromboembolism Research Articles

Clinical Characteristics and Outcomes of Patients With Venous Thromboembolism Receiving Edoxaban in the Real World.

The effectiveness and safety of edoxaban for venous thromboembolism (VTE) in unselected real-world patients have not been fully evaluated.Methods and Results: In the Japanese nationwide administrative database, we identified 6,262 VTE patients in whom edoxaban was initiated; these patients were divided into 3 groups based on their index doses: 15 mg/day (n=235), 30 mg/day (n=4,532), and 60 mg/day (n=1,495). We evaluated patient characteristics, recurrent VTEs, and a composite endpoint of intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding. Patient characteristics among the 15-, 30-, and 60-mg edoxaban groups varied widely regarding several aspects, including age (mean 81.0, 76.2, and 65.0 years, respectively) and body weight (mean 49.5, 51.8, and 70.3 kg, respectively). At 180 days, the cumulative incidence of recurrent VTEs in the 15-, 30-, and 60-mg edoxaban groups was 4.4%, 2.6%, and 1.8%, respectively, whereas that of ICH or GI bleeding was 7.3%, 5.4%, and 3.3%, respectively. Subgroup analyses showed that the cumulative incidence of ICH or GI bleeding in patients in the 15-mg edoxaban group was 3.6% for patients aged ≥80 years, 8.4% for those with a body weight <60 kg, and 31.3% for those with renal dysfunction. Only a minority of patients with VTEs received a super low dose (15 mg) of edoxaban, and these patients may be at higher risk of bleeding as well as VTE recurrence.

Clinical characteristics and outcomes of super-low-dose edoxaban of 15 mg in patients with acute venous thromboembolism: insight from the COMMAND VTE Registry-2

Abstract Background/Introduction The current guidelines recommend specific durations of anticoagulation therapy depending on the risks of recurrent venous thromboembolism (VTE), and prolonged anticoagulation therapy is recommended for patients at not-low risk of recurrence. However, clinicians are sometimes reluctant to continue anticoagulation therapy for patients with high-bleeding risk. A recent study reported that super-low-dose edoxaban of 15 mg was useful in preventing thromboembolic events for elderly patients with atrial fibrillation who were considered as high-bleeding risk patients. However, super-low-dose edoxaban of 15 mg is currently off-label for VTE all over the world, which could be a potential option for patient with VTE at high-bleeding risk. Purpose The current study aimed to investigate clinical characteristics and outcomes of VTE patients with super-low-dose edoxaban of 15 mg, using a large-scale multicenter observational database of patients with VTE. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. After excluding 3193 patients without edoxaban as oral anticoagulation therapy, the current study population was consisted of 2004 patients with edoxaban, who were divided into 3 groups according to initial dosage of edoxaban; 60 mg/day (N=664, 33%) 30 mg/day (N=1309, 65%) and 15 mg/day (N=31, 1.5%). Results Patients with edoxaban of 15 mg/day were oldest (60 mg/day: 62.3 years, 30 mg/day: 72.9 years and 15 mg/day: 79.2 years, P&amp;lt;0.001), were most often women (44%, 73% and 84%, P&amp;lt;0.001), showed a lowest mean body weight (68.4, 51.9 and 48.7 kg, P&amp;lt;0.001). Pulmonary embolism as initial presentation was least frequent in patients with edoxaban of 15 mg/day (58%, 44% and 13%, P&amp;lt;0.001). Patients with edoxaban of 15 mg/day most frequently had chronic kidney disease (10%, 22% and 26%, P&amp;lt;0.001) and anemia (45%, 66% and 74%, P&amp;lt;0.001). The discontinuation rates of anticoagulation therapy were not significantly different among the 3 groups (54.4%, 56.5% and 64.8% at 3-year, Log rank P=0.38). The cumulative incidences of recurrent VTE were not significantly different among the 3 groups (6.0%, 6.6% and 0.0% at 3-year, Log rank P=0.31). Similarly, the cumulative incidences of major bleeding were not significantly different among the 3 groups (9.2%, 11.6% and 15.3% at 3-year, Log rank P=0.11). Conclusions In the current real-world large VTE registry, a very minority of VTE patients received edoxaban of 15 mg/day, including patients at high-bleeding risk such as old age, low body weight and chronic kidney disease, who did not show significant worse outcomes in terms of recurrent VTE.

Small-Area Analysis of Treatment and Clinical Outcomes in Patients with Venous Thromboembolism in Denmark: A Nationwide Cohort Study.

To investigate geographical variation in initiation and extended treatment with anticoagulants and clinical outcomes among patients hospitalized with first-time venous thromboembolism (VTE) in Denmark between 2007 and 2018. Using nationwide health care registries, we identified all patients with a first-time VTE hospital diagnosis supported by imaging data from 2007 to 2018. Patients were grouped according to residential region (5) and municipality (98) at the time of VTE diagnosis. Cumulative incidence of initiation of and extended (beyond 365 days) anticoagulation treatment as well as clinical outcomes, including recurrent VTE, major bleeding, and all-cause death, were assessed. Sex- and age-adjusted relative risks (RRs) of the outcomes were computed when comparing across individual regions and municipalities. Overall geographic variation was quantified by computing the median RR. We identified 66,840 patients with a first-time VTE hospitalization. A difference in initiation of anticoagulation treatment of more than 20 percentage points between regions was observed (range: 51.9-72.4%, median RR: 1.09, 95% confidence interval [CI]: 1.04-1.13). Variation was also observed for extended treatment (range: 34.2-46.9%, median RR: 1.08, 95% CI: 1.02-1.14). The cumulative incidence of recurrent VTE ranged from 3.6 to 5.3% at 1 year (median RR: 1.08, 95% CI: 1.01-1.15). The difference remained after 5 years, and variation was also observed for major bleeding (median RR: 1.09, 95% CI: 1.03-1.15), whereas it appeared smaller for all-cause mortality (median RR: 1.03, 95% CI: 1.01-1.05). Substantial geographical variation in anticoagulation treatment and clinical outcomes occurs in Denmark. These findings indicate a need for initiatives to ensure uniform high-quality care for all VTE patients.

The Ottawa Score Performs Poorly to Identify Cancer Patients at High Risk of Recurrent Venous Thromboembolism: Insights from the TROPIQUE Study and Updated Meta-Analysis.

The Ottawa score (OS) for predicting the risk of recurrent venous thromboembolism (VTE) in cancer patients with VTE may help to guide anticoagulant treatment decisions that will optimize benefit-risk ratios. However, data on its reliability are conflicting. We applied the OS to all cancer patients with VTE enrolled in the prospective multicenter TROPIQUE study who received low-molecular-weight heparin over a 6-month period. Of 409 patients, 171 (41.8%) had a high-risk OS. The 6-month cumulative incidence of recurrent VTE was 7.8% (95%CI 4.2–14.8) in the high-risk OS group versus 4.8% (95%CI 2.6–8.9) in the low-risk OS group (SHR 1.47; 95%CI 0.24–8.55). The Area Under the Receiver Operating Characteristic curve (AUROC) of the OS in identifying patients who developed recurrent VTE was 0.53 (95%CI 0.38–0.65), and its accuracy was 57.9%. Among individual variables included in the OS, only prior VTE was significantly associated with the 6-month risk of recurrent VTE (SHR 4.39; 95% CI 1.13–17.04). When pooling data from all studies evaluating this score for predicting VTE recurrence in cancer patients (7 studies, 3413 patients), the OS estimated pooled AUROC was 0.59 (95%CI 0.56–0.62), and its accuracy was 55.7%. The present findings do not support the use of the OS to assess the risk of recurrent VTE in cancer patients.

Long-term use of tinzaparin for the treatment of cancer-associated thrombosis in clinical practice: Insights from the prospective TROPIQUE study.

Real word data on the efficacy and safety of long-term use of tinzaparin for the treatment of cancer-associated thrombosis (CAT) are scarce. We performed a post-hoc analysis of all cancer patients included in the prospective multicenter observational TROPIQUE study who received long-term treatment with tinzaparin for a first venous thromboembolism (VTE) event. We evaluated the patterns of anticoagulant prescription, the adherence to clinical practice guidelines (CPGs) for the treatment of CAT, and the clinical outcomes within a 6-month follow-up. In total, 301 patients were included in this post-hoc analysis. At study entry, their mean age was 64.6±11.9years and 143 (47.5%) patients were men. The most frequent cancer type was gastrointestinal (23.9%), followed by breast (17.9%) and lung (15.3%) cancer. At time of VTE diagnosis, 164 (57.8%) patients had metastatic disease and 245 (81.42%) were receiving chemotherapy. Based on the aggregation of all study pre-defined criteria, tinzaparin prescription was fully compliant with CPGs in 219 (72.8%) patients. The mean effective treatment duration with tinzaparin was 6.07±0.17months. At 6-month follow-up, the cumulative incidence of recurrent VTE was 5.4% (95% CI: 3.2-9.2%) and the cumulative incidence of major bleeding was 5.8% (95% CI: 3.6-9.6%). Clinical outcomes tended to differ across different types of cancer. Death from any cause occurred in 102 (33.9%) patients, mainly related to cancer progression. This post-hoc analysis of TROPIQUE confirms the favorable benefit-risk ratio of tinzaparin for the long-term treatment of CAT.

Effectiveness and safety of DOACs for the prevention of recurrent VTE: a prospective cohort study

Abstract Background In the direct oral anticoagulants (DOACs) era, extended anticoagulation after 6–12 months of treatment is an attractive strategy in patients with venous thromboembolism (VTE). Real-life data on the clinical benefit of DOAC over time is lacking. Purpose The aim of this study is to assess the effectiveness and safety of DOACs in patients with acute VTE treated for variable periods. Methods Data on patients with an objective diagnosis of acute VTE treated with DOACs were included in prospective cohort study. Study outcomes were recurrent VTE and major bleeding (ISTH definition). Results Overall, 934 patients were included (mean age 67.0±16.0, male gender 51.4%). Three-hundred and forty-six patients had a deep vein thrombosis (37.0%), 98 (10.5%) had isolated pulmonary embolism and 490 (52.5%) had both. One-hundred and sixty-nine patients (18.1%) had an active cancer, 59 (6.3%) a history of cancer and 365 patients (39.1%) an unprovoked VTE. During DOAC treatment (mean 21.6 months), 7 recurrent VTEs and 25 major bleedings occurred. In 546 and in 98 patients, DOAC was continued with full and reduced doses, respectively. In 290 patients (43.8% unprovoked, 13.8% active cancer, 42.4% associated with non-cancer risk factor), anticoagulants were withdrawn (average treatment duration 8.8 months) and 22 recurrent VTEs occurred over a follow-up off-treatment period of 31.9 months. In these patients, 2 episodes of major bleeding were observed. Overall, 201 patients died; fatal PE occurred in 4 and fatal bleeding in 1 patient. Time course for recurrent VTE according to 2019 ESC risk for recurrence is reported in the Figure. Conclusions In this cohort study, DOACs showed a good risk to benefit profile in the extended phase after an acute VTE event. Funding Acknowledgement Type of funding sources: None. Figure 1. Cumulative incidence of recurrent VTE

Risk factors of recurrence in patients with cancer-associated venous thromboembolism: from the COMMAND VTE Registry

Abstract Background/Introduction Cancer is a strong risk factor for the development of venous thromboembolism (VTE) including pulmonary embolism (PE) and deep vein thrombosis (DVT). Patients with VTE have a long-term risk of recurrence, which can be prevented by anticoagulation therapy. Prolonged anticoagulation therapy is recommended for patients with cancer-associated VTE, although the risk of recurrence might depend on the individual patient. Purpose We aimed to identify the risk factors of recurrence in patients with cancer-associated VTE. Methods The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3027 consecutive patients with acute symptomatic VTE among 29 Japanese centers between January 2010 and August 2014. The present study population consisted of 695 cancer-associated VTE patients. The primary outcome measure in the present study was recurrent VTE, which was defined as PE and/or DVT with symptoms accompanied by confirmation of a new thrombus or exacerbation of the thrombus by objective imaging examinations or autopsy. Discontinuation of anticoagulation was defined as a withdrawal of anticoagulation therapy lasting &amp;gt;14 days for any reason. We selected clinically relevant variables and variables with P values &amp;lt;0.1 in a univariate analysis as potential risk factors, and constructed a multivariable Cox proportional hazard model for recurrent VTE incorporating the anticoagulation therapy status as a time-updated covariate. Results Among the 695 study patients, recurrent VTE occurred in 78 patients, of whom 54 (69%) occurred within 6 months. The cumulative incidence of recurrent VTE was 7.7% at 3-months, 8.9% at 6-months, 11.8% at 1-year, and 17.7% at 5-years. The cumulative incidence of discontinuation of anticoagulation therapy was 18.0% at 3-months, 29.5% at 6-months, 43.4% at 1-year, and 66.5% at 5-years. The cumulative 5-year incidence of recurrent VTE was most frequent in patients with uterus/ovary cancer (26.0%), followed by those with lung cancer (24.7%). The multivariable Cox proportional hazard model revealed that chronic kidney disease (HR, 2.27; 95% CI, 1.36–3.77, P=0.002), a high D-dimer level at the time of VTE diagnosis (HR, 2.85; 95% CI, 1.71–4.74, P&amp;lt;0.001), advanced cancer (HR, 1.69; 95% CI, 1.05–2.72, P=0.03) and discontinuation of anticoagulation therapy (HR, 2.66; 95% CI, 1.53–4.63, P&amp;lt;0.001) were independently associated with an increased risk of recurrent VTE. No cancer site was independently associated with an increased risk for recurrent VTE when adjusting for the above mentioned risk factors in the multivariable Cox proportional hazard model, although the risk of recurrent VTE numerically differed according to the cancer site. Conclusions Among patients with cancer-associated VTE, chronic kidney disease, a high D-dimer level at the time of VTE diagnosis, advanced cancer, and discontinuation of anticoagulation therapy were independent risk factors of recurrence. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation Figure 1Figure 2

Severity of pulmonary embolism at initial diagnosis and long-term clinical outcomes: From the COMMAND VTE Registry

BackgroundThere is a paucity of data on the long-term clinical outcomes according to the severity of pulmonary embolism (PE) at initial diagnosis. MethodsThe COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE). After excluding 1312 patients without PE, the current study population consisted of 1715 patients with PE, who were divided into 3 groups according to the clinical severity; massive PE, sub-massive PE and low-risk PE. ResultsThere were 179 patients (10%) with massive PE, 742 patients (43%) with sub-massive PE, and 794 patients (46%) with low-risk PE. By the landmark analysis at 3 months, the cumulative incidences of recurrent VTE were similar among the 3 groups both within and beyond 3 months (Massive PE: 2.9%, Sub-massive PE: 4.2%, and Low-risk PE: 3.3%, P = 0.61, and 4.3%, 8.8%, and 7.8% at 5 years, P = 0.47, respectively). After adjusting confounders, the risk of massive PE relative to low-risk PE for recurrent VTE beyond 3 months remained insignificant (adjusted HR 0.54, 95% CI: 0.13–1.51, P = 0.27). Patients with massive PE at initial diagnosis more often presented as severe recurrent PE events than those with sub-massive and low-risk PE. ConclusionsIn the current real-world large registry, the long-term risk of overall recurrent VTE in patients with massive PE at initial diagnosis did not significantly differ from those with sub-massive and low-risk PE beyond 3 months, although patients with massive PE at initial diagnosis more frequently developed recurrent VTE as PE with severe clinical presentation.

Effectiveness and Safety of Rivaroxaban in Patients with Cancer-Associated Venous Thromboembolism

Background: Venous thromboembolism (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication of both cancer and its treatment.Unlike low-molecular weight heparins (LMWHs) which represent the current standard-of-care for cancer-associated venous thromboembolism (CAT) management, rivaroxaban can be administered orally, avoiding the need for uncomfortable injections. While not guideline-recommended as first-line therapy for CAT, rivaroxaban has been used in routine clinical practice for this purpose.Objective: To estimate the cumulative incidence of recurrent VTE, major bleeding and mortality in patients with CAT treated with rivaroxaban as outpatients in routine clinical practice.Methods: Within US Truven MarketScan administrative claims data from 1/2012 to 6/2015, we identified adult patients with active cancer using National Cancer Institute-Surveillance, Epidemiology and End Results Program (NCI-SEER) coding who had ≥1 primary hospitalization or emergency department visit discharge diagnosis code for DVT and/or PE (the index event) and received a prescription of rivaroxaban as their first outpatient anticoagulant within 30-days of the index VTE. Eligible patients were required to have a minimum of 180-days continuous medical and prescription benefits prior to the index VTE (baseline period). Patients with a prior claim for VTE or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% confidence intervals (CIs) of recurrent VTE, major bleeding (identified per the Cunningham algorithm) and mortality (defined as in-hospital mortality or need for hospice care without subsequent claims) at 180-days assuming competing risks.Results: A total of 949 active cancer patients were initiated on rivaroxaban following their index VTE. The mean ± standard deviation (SD) time from index VTE to first outpatient rivaroxaban fill was 4.4±5.8 days. Mean±SD age of identified patients was 62.5±12.8 years, 45.6% were men and PE (with or without DVT) was present in 43.6% of patients. Time from the diagnosis of active cancer to index CAT was ≤90-days in 30.0%, 91-180 days for 18.9% and 181-days of greater for 54.3% of patients. Cancer sites for this rivaroxaban-treated cohort were as follows: 25.5% breast, 21.0% genitourinary (including prostate), 13.2% hematologic, 13.2% colorectal, 11.5% lung, 7.4% gynecologic, 5.8% pancreas, 4.1% stomach/esophagus and 39.5% other. Metastatic disease was present in 42.6% of patients. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding and 105 deaths. The 180-day cumulative incidence estimate was 4.0% (95%CI 2.8-5.4%) for recurrent VTE; 2.7% (95%CI=1.7−4.0%) for major bleeding and 11.3% (95%CI=9.2-13.6%) for mortality (Figure).Conclusion: Event rates observed in this rivaroxaban treated cohort were consistent with those observed in prior studies of LMWH- and rivaroxaban-managed CAT patients. Our data may provide some reassurance to clinicians regarding the effectiveness and safety of rivaroxaban in treating CAT patients in routine outpatient practice. [Display omitted] DisclosuresBeyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria, Research Funding. Spyropoulos:Boehringer Ingelheim: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Portola: Membership on an entity's Board of Directors or advisory committees. Coleman:Boehringer Ingelheim: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bayer AG: Consultancy, Honoraria, Research Funding.

Failure of the Ottawa Score to Predict the Risk of Recurrent Venous Thromboembolism in Cancer Patients: The Prospective PREDICARE Cohort Study.

Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients. In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score. A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65). In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.

The Cumulative Incidence and Risk Factors of Recurrent Venous Thromboembolism in the Elderly.

BackgroundIncidence and outcomes of recurrent venous thromboembolism (VTE) in the elderly are still not fully elucidated. The purpose of this study was to determine the incidence and identify the risk factors of VTE recurrence in this population.MethodsA prospective cohort study of a one-year follow-up of 277 patients aged ≥65 years with primary VTE was performed at King Abdulaziz Medical City, a tertiary care teaching hospital in Riyadh, Saudi Arabia. Demographic data, risk factors, and the consequences of VTE (recurrence, bleeding, and mortality) were recorded.ResultsOf the 277 VTE patients, 39 (14%) were diagnosed with recurrent VTE over a median follow-up period of 12 months. The cumulative incidence of recurrent VTE was 12.75 per hundred patient-year (95% CI, 8.24–17.36). In multivariate Cox regression, malignancy (hazard ratio [HR], 2.87, 95% CI, 1.32–6.24, p=0.008) and surgery (HR 2.78, 95% CI, 1.36–5.67, p=0.005) were identified as independent risk factors for recurrent VTE. Metformin had a significant independent protection effect (HR, 0.16, 95% CI, 0.08–0.33, p<0.001). During follow-up, two patients in the recurrent VTE group and five patients in the group with no recurrent VTE, all of whom were minor bleeding cases, reported no major bleeding. Seven (18%) patients in the recurrent VTE group and nine (4%) patients in the group with no recurrent VTE died (p<0.001).ConclusionThe findings of this study show that elderly patients with initial VTE have a recurrent rate (14%), with a cumulative incidence rate of 12.75 per hundred patient-year. Malignancy and surgery were the most important clinical risk factors to impact significantly the development of recurrent VTE in our elderly population. Metformin may have a protective effect against recurrent VTE in the elderly population, and a larger study is needed to validate our findings.

Anticoagulation after intracranial hemorrhage in brain tumors: Risk of recurrent hemorrhage and venous thromboembolism

BackgroundIntracranial hemorrhage (ICH) is a common and often devastating outcome in patients with brain tumors. Despite this, there is little evidence to guide anticoagulation management following an initial ICH event. ObjectivesTo analyze the risk of recurrent hemorrhagic and thrombotic outcomes after an initial ICH event in patients with brain tumors and prior venous thromboembolism (VTE). Patients and MethodsA retrospective cohort study was performed. Radiographic images obtained after initial ICH were reviewed for the primary outcomes of recurrent ICH and VTE. Results and ConclusionsA total of 79 patients with brain tumors who developed ICH on anticoagulation for VTE were analyzed. Fifty‐four patients (68.4%) restarted anticoagulation following ICH. The cumulative incidence of recurrent ICH at 1 year was 6.1% (95% confidence interval [CI], 1.5‐15.3) following reinitiation of anticoagulation. Following a major ICH (defined as an ICH >10 mL in size, causing symptoms, or requiring intervention), the rate of recurrent ICH upon reexposure to anticoagulation was 14.5% (95% CI, 2.1‐38.35), whereas the rate of recurrent ICH following smaller ICH was 2.6% (95% CI, 0.2%‐12.0%). Mortality following a recurrent ICH on anticoagulation was 67% at 30 days. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to patients who did not restart anticoagulation (8.1% vs 35.3%; P = .003). We conclude that resumption of anticoagulation is lowest among patients with metastatic brain tumors with small initial ICH. Following an initial major ICH, resumption of anticoagulation was associated with a high rate of recurrent ICH.

Predictive ability of modified Ottawa score for recurrence in patients with cancer-associated venous thromboembolism: From the COMMAND VTE Registry

IntroductionThe external validation of the modified Ottawa score to predict the risk of recurrence in patients with cancer-associated venous thromboembolism (VTE) has not yet been firmly established. The present study aimed to evaluate the utility and limitations of the modified Ottawa score in the risk stratification of recurrent VTE in patients with cancer-associated VTE. Materials and methodsThe COMMAND VTE Registry is a multicenter retrospective registry enrolling 3027 consecutive patients with acute symptomatic VTE among 29 Japanese centers. The present study population consisted of 614 cancer-associated VTE patients, who were divided into 3 groups; High-risk group: 202 patients (33%) with a modified Ottawa score ≥ 1, Intermediate-risk group: 269 patients (44%) with a score = 0, and Low-risk group: 143 patients (23%) with a score ≤ −1. ResultsRecurrent VTE occurred in 39 patients on anticoagulation therapy within 6 months. The cumulative incidence of recurrent VTE substantially increased in the higher risk categories by the modified Ottawa score (high-risk group: 13.6% [95%CI, 8.9%–20.2%], intermediate-risk group: 5.9% [95%CI, 3.5%–9.8%], and low-risk group: 3.0% [95%CI, 1.1%–7.8%], P = .02). The discriminating power of the score was modest with a C-statistic of 0.63. Each score component of the score had a different impact on recurrent events with a variable effect size. ConclusionsThe risks of recurrence in patients with cancer-associated VTE substantially increased in the higher risk categories by using the modified Ottawa score, but the discriminating power of the score for recurrence was modest with a variable impact of each score component on recurrent events.

Recurrent Intracranial Hemorrhage and Venous Thromboembolism Following Initial Intracranial Hemorrhage in Patients with Brain Tumors on Anticoagulation

Introduction Both venous thromboembolism (VTE) and intracranial hemorrhage (ICH) are common potentially life-threatening complications of primary and metastatic brain tumors. Despite emerging evidence regarding the safety of anticoagulation in patients with brain tumors, there is little evidence on appropriate management of VTE following an ICH. Potential management options after an ICH in patients with brain tumors include resumption of full or modified dose anticoagulation or cessation of anticoagulant therapy with or without placement of an inferior vena cava (IVC) filter. We evaluated rates of recurrent VTE and ICH following an initial ICH occurring on anticoagulant therapy. Methods A retrospective cohort study was performed using a hospital-based online medical record database (CQ2) which links ICD-9 and ICD-10 codes with prescription medication records. Cases were identified based on coding for primary brain tumors or brain metastases, after which charts were manually reviewed for a diagnosis of ICH. A blinded review of radiographic imaging was performed, and the initial ICH was categorized as either trace, measurable, or major. Measurable intracranial hemorrhages were those defined as greater than 1 mL in volume and major intracranial hemorrhages were defined as greater than 10 mL in volume, symptomatic, or requiring surgical intervention. The electronic medical record was reviewed to ascertain longitudinal anticoagulation status after the initial ICH. The primary endpoints of the study were recurrent ICH and venous thromboembolism (VTE) within 12 months from the initial ICH. Gray's test was used to compare the cumulative incidence of recurrent ICH and VTE between the groups, with death as a competing risk. Results A total of 79 patients with primary brain tumors or brain metastases and confirmed ICH were included in the study. Fifty-four patients (68.4%) restarted anticoagulation after ICH and 25 patients discontinued anticoagulation entirely. The cohorts were well-matched for tumor diagnosis, age, and comorbidities that portend an increased risk of ICH such as hypertension, chronic kidney disease, and concomitant aspirin use (Table 1). The cumulative incidence of recurrent ICH (95% CI) at one year was 6.1% (1.5 - 15.3) in the restart cohort compared to 4.2% (0.3 - 18.3) in patients who did not restart anticoagulation. Median time from anticoagulation restart to recurrent ICH was 36 days. A total of 16 of 31 patients with major ICH restarted anticoagulation and among these patients two developed subsequent ICH (cumulative incidence 14.5%, 95% CI 2.1 - 38.3). Among the 15 patients with a major ICH who did not restart anticoagulation, the cumulative incidence was 6.7% (0.3 - 27.5). Eleven of 15 patients with measurable ICH restarted anticoagulation and among these patients one subsequently developed ICH (cumulative incidence 0.1%, 95% CI 0.0 - 0.3). No recurrent ICH events were observed in 33 patients with trace initial hemorrhages regardless of restart status. All recurrent ICH events met criteria for classification as a major hemorrhage on the basis of clinical symptoms, and 30-day mortality after recurrent ICH was 100%. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to cohort of patients who did not restart anticoagulation (8.1 vs. 35.3, P=0.003, Figure 1). There were a total of five VTE events in the restart cohort, three deep vein thrombi (DVT) and two pulmonary emboli (PE). Two of the DVT were associated with an IVC filter. There were a total of nine VTE events in patients who did not restart anticoagulation, seven DVT and two PE. Five of the DVT were associated with an IVC filter. The two PE were both submassive events requiring ICU admission. Conclusions Recurrent VTE events are less frequent and less severe in patients who restart anticoagulation following ICH in patients with brain tumors on anticoagulation. Restarting anticoagulation after smaller ICH (trace or measurable) appears safe. However, approximately 1 in 7 patients with major initial ICH who restarted anticoagulation subsequently developed recurrent major ICH that was associated with a very high mortality rate. This raises serious questions as to the safety of restarting therapeutic anticoagulation following major hemorrhage in the setting of brain tumors. Disclosures Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Zwicker:Quercegen: Research Funding; Daiichi: Consultancy; Seattle Genetics: Consultancy; Parexel: Consultancy; Incyte: Research Funding; Bayer: Consultancy; Portola: Consultancy.

Risk Factors Associated with 6-Month Recurrent VTE Among Patients in Two Large Population-Based Surveillance Systems

Introduction The incidence of recurrent venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is dependent on multiple patient demographic factors and medical co-morbidities, such as cancer and surgery. We sought to determine risk factors associated with 6-month cumulative incidence of recurrent VTE. Methods A detailed description of the population-based surveillance systems have been previously published (Wendelboe 2015 and Ortel 2019 pending publication). In brief, the Centers for Disease Control and Prevention collaborated with University of Oklahoma Health Science Center and Duke University to establish surveillance systems that utilized active and passive methods to obtain data on all VTE events that occurred within Oklahoma and Durham counties, respectively between April 2012 and March 2014. This is the first report combining data from the two surveillance systems. Eligibility for the current analysis included 1) patients 18 years or older at the time of index VTE 2) no reports of patient death between index VTE and recurrent VTE or within 6 months of index VTE 3) patient data from a hospital system or out-patient clinics associated with a hospital (i.e. individuals treated at non-hospital-based out-patient clinics were excluded due to missing treatment data) 4) and index VTE occurred at least 6 months prior to the end of the surveillance period or a 6-month follow-up data abstraction was performed by the site. Recurrent VTE was defined as 1) VTE (either DVT or PE) in a different location and diagnosed after the index VTE or 2) VTE in the same location and diagnosed greater than 90 days after index VTE. Results During the surveillance period 4,205 patients were diagnosed with an index VTE, of these 2,883 (68.6%) were eligible for analysis. The 6-month incidence of VTE recurrence was 5.8% (n=166). Recurrent VTE events were diagnosed within 3 to 179 days post index VTE. Compared to patients without recurrent VTE, patients with recurrent VTE were more likely to be younger (≤ 60 years of age) and black (Table 1). They were also more likely to have a DVT only as their index VTE, to have a provoked VTE, and to have had a VTE prior to their index VTE; they were less likely to present with symptoms at the time their index VTE was diagnosed. The majority of index DVTs were located in the veins of the lower extremities, however among patients with recurrent DVT there was an increased proportion of index DVTs diagnosed in the upper extremities, other locations, and in more than one location. These differences remained after multivariable adjustment (Table 2). Clinical characteristics of recurrent VTE events are summarized in Table 3. Recurrent VTEs were primarily DVT only (73.5%), located in the lower extremity (52.7%), symptomatic at presentation (73.4%), and were associated with transient provoking factors (50.6%) including hospitalization (41.6%). Several patients (n=25) were hospitalized from the date of their index VTE to the date of VTE recurrence. Use of pharmacologic prophylaxis was high at time of recurrence (33.1%) compared to use at index VTE (12.3%). Discussion Currently, there is no U.S. national VTE surveillance system. Our VTE surveillance results show significant differences in the risk of VTE recurrence according to both patient demographic factors and clinical features of the index VTE. Factors associated with higher recurrence risk include 60 years or younger, black race, and index VTE that was DVT only, asymptomatic, and associated with persistent or transient provoking factors. Fatal recurrent VTEs may not have been identified at time of death, potentially underestimating the VTE recurrence incidence and influence of risk factors. The proportions of recurrent VTE events reported here is similar to the proportions reported in previous cohort studies, indicating that these population-based surveillance systems captured most recurrent VTE events among patients seen within hospital systems for their index VTE. Disclosures Ortel: Instrumentation Laboratories: Consultancy. Raskob:Bayer Healthcare: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Tetherex: Consultancy; Novartis: Consultancy; Anthos: Consultancy; Janssen R&amp;D, LLC: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; BMS: Consultancy, Honoraria; Portola: Consultancy; Eli Lilly: Consultancy.

The Ottawa score performs poorly in cancer patients with incidental pulmonary embolism

BackgroundThe Ottawa score was previously developed to predict recurrent venous thromboembolism (VTE) in cancer patients with VTE. The performance of this score in patients with incidental VTE is currently unclear. AimTo evaluate the performance of the Ottawa risk score in cancer patients with incidental pulmonary embolism included in an international, prospective, observational cohort study. MethodsThe score was used to classify patients as high (≥1), intermediate (0), or low risk (≤−1). The discriminative performance of the score was estimated by calculating the cumulative incidence of recurrent VTE for all groups, the time-dependent c-statistic, and the sub-distribution hazard ratio (SHR), using a competing risk approach. ResultsOf the 691 patients for which the Ottawa score could be calculated, 25 (3.6%) had recurrent VTE during 6-month follow-up and 38 (5.5%) during 12-month follow-up. The c-statistics of the continuous score at 6 and 12 months were 0.45 (95% CI, 0.36–0.54) and 0.51 (95% CI, 0.46–0.59), respectively. The 6-month cumulative incidences of recurrent VTE for those at low, intermediate, and high risk were 3.9% (95% CI, 1.5–8.4), 3.6% (95% CI, 1.9–6.2), and 3.6% (95% CI, 1.8–6.5), respectively. A sensitivity analysis restricted to the on-treatment period yielded similar results. None of the Ottawa risk score items were significantly associated with recurrent VTE. ConclusionIn cancer patients with incidental pulmonary embolism, the Ottawa risk score has a poor predictive value for recurrent VTE, which does not support the use of the score in this patient population.

Evaluation of the predictive value of the bleeding prediction score VTE‐BLEED for recurrent venous thromboembolism

IntroductionVTE‐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. MethodsThis 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. ResultsIn 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). ConclusionIn 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.

Risk and Risk Factors Associated With Recurrent Venous Thromboembolism Following Surgery in Patients With History of Venous Thromboembolism

The size of the risk of recurrent venous thromboembolism (VTE) after surgery in patients with a history of VTE is not well known. To estimate the risk of and to identify the factors associated with recurrent VTE in patients undergoing surgery who have a history of VTE. This population-based, follow-up cohort study includes patients with VTE who participated in the Multiple Environment and Genetic Assessment (MEGA) study. Original data were collected from March 1999 to April 2010. Data analysis began in June 1999 and ended in April 2010. Surgery following a first VTE. Kaplan-Meier analyses were used to estimate cumulative incidences of recurrent VTE. Cox regression with a time-dependent covariate (surgery) was used to calculate the hazard ratio (HR) for developing recurrent VTE after surgery compared with no surgery. Overall, 3741 patients (mean [SD] age, 48.4 [12.8] years; 2020 [54.0%] women) with a history of VTE were included in the analysis, amounting to 18 899 person-years, with a median (interquartile range) follow-up of 5.7 (3.0-7.2) years. Of the 3741 patients, 580 (15.5%) underwent surgery and 601 (16.1%) developed a recurrent thrombotic event. The 1-month cumulative incidence of recurrent VTE for all surgery types was 2.1% (95% CI, 1.2%-3.6%), which increased to 3.3% (95% CI, 2.1%-5.1%) at 3 months and 4.6% (95% CI, 3.1%-6.6%) at 6 months. At 6 months, risk of recurrent VTE ranged from 2.3% to 9.3%, depending on surgery type. In addition to surgery type, factor V Leiden mutation (HR, 3.4; 95% CI, 1.6-7.4) and male sex (HR, 2.7; 95% CI, 1.3-5.8) were associated with increased risk of recurrent VTE. Surgery was associated with an increased risk of recurrent VTE in patients with a history of VTE; risk remained high for up to 6 months after the procedure. This study suggests that high-risk individuals may be identified based on surgery type, sex, and the presence of factor V Leiden mutation. These findings stress the need for revision of the current thromboprophylactic approach to prevent recurrence in these patients.

Anticoagulation quality and clinical outcomes in multimorbid elderly patients with acute venous thromboembolism

BackgroundMultimorbid patients with acute venous thromboembolism (VTE) are often excluded from clinical trials and little is known about their prognosis. ObjectivesTo examine whether multimorbidity is associated with adverse clinical outcomes and lower anticoagulation quality in older patients with VTE. Patients/MethodsWe studied 991 patients aged ≥65 years with acute VTE in a Swiss prospective multicenter cohort study. A modified Charlson Comorbidity Index was used to measure multimorbidity, which was defined as the presence ≥2 of 17 predefined comorbid conditions. We examined the association between multimorbidity and recurrent VTE and major bleeding, adjusting for confounders and periods of anticoagulation. We assessed whether the percentage of time spent in the therapeutic international normalized ratio (INR) range varied by the number of comorbidities present. ResultsOverall, 708 (71%) patients were multimorbid. Multimorbid patients had a higher 3-year cumulative incidence of recurrent VTE (16.8 vs. 10.8%; P = 0.056) and major bleeding (18.7 vs. 9.0%; P = 0.001) than non-multimorbid patients. After adjustment, multimorbid patients had a significantly higher risk of recurrent VTE (sub-hazard ratio [SHR] 1.66, 95% confidence interval [CI] 1.08–2.57) and a higher risk of major bleeding (SHR 1.55, 95% CI 0.96–2.50), although the latter failed to achieve statistical significance. With increasing numbers of comorbid conditions, patients spent less time in and more time above and below the therapeutic INR range. ConclusionsMultimorbid patients with acute VTE have not only a lower anticoagulation quality but also more complications. Clinical trials should explicitly enroll multimorbid patients to determine the optimal anticoagulation strategy in such patients.

Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin

BackgroundFull- or lower-dose anticoagulant therapy or aspirin can be used for extended therapy in patients with venous thromboembolism (VTE), but information on their relative benefit-risk profiles is limited. MethodsData from the EINSTEIN-CHOICE trial were used to compare the benefit-risk profiles of extended treatment with rivaroxaban (20 or 10 mg once daily) and aspirin (100 mg once daily) in VTE patients who had completed 6 to 12 months of anticoagulation therapy. One-year cumulative incidences of recurrent VTE and major bleeding were estimated and benefits and risks were calculated by determining the between group differences in a hypothetical population of 10,000 VTE patients treated for 1 year. FindingsA total of 1107 patients were treated with 20 mg of rivaroxaban, 1127 with 10 mg of rivaroxaban, and 1131 with aspirin. The cumulative incidences of recurrent VTE in the rivaroxaban 20-mg, rivaroxaban 10-mg and aspirin groups were 1.9%, 1.6%, and 5.0%, respectively, whereas the cumulative incidences of major bleeding were 0.7%, 0.4% and 0.5%, respectively. The incidences of the combined outcome of recurrent VTE and major bleeding were 2.8% and 3.4% lower in the rivaroxaban 20-mg and 10-mg groups than in the aspirin group. For 10,000 patients treated for 1 year, there would be 284 (95% confidence interval [CI] 106 to 462) and 339 (95% CI 165 to 512) fewer events with rivaroxaban 20 mg or 10 mg than with aspirin. InterpretationCompared with aspirin, extended anticoagulation with once daily rivaroxaban reduces recurrent VTE with a favourable benefit-risk profile. FundingBayer AG.