Major Venous Thromboembolism Research Articles

Retrospective review of D-dimer testing for venous thrombosis recurrence risk stratification: is this a useful test in the real world?

Predicting the risk of recurrence after venous thromboembolism (VTE) remains an important clinical challenge. Post-anticoagulation cessation D-dimer has previously been shown to be associated with increased VTE recurrence in unprovoked major VTE, however this is not routinely used clinically and has not been validated in provoked VTE and isolated distal DVT (IDDVT). We aimed to retrospectively evaluate this practice in the real-world setting including examining its use in provoked VTE and IDDVT. Consecutive patients diagnosed with DVT or PE between January 2013 and December 2016 were retrospectively evaluated. Clinical features, VTE risk factors, recurrence and bleeding rates were evaluated for patients with normal and abnormal post-anticoagulation D-dimer, as well as those patients who did not undergo D-dimer testing. Patients with active malignancy, superficial vein thrombosis and inadequate follow-up were excluded. Of the 1033 patients with a diagnosis of VTE in the study period, 173 were included in the "D-dimer tested" group, and 254 in the "D-dimer un-tested" comparison group. Abnormal post-anticoagulation D-dimer was significantly associated with VTE recurrence (HR 5.96, 95% CI 2.15-14.57, p < 0.001). Abnormal D-dimer was also associated with high risk of VTE recurrence in travel-provoked VTE (67.61 events per 100 patient-years), and unprovoked IDDVT (HR 14.37, 95% CI 1.75-117.83, p = 0.013). Males with abnormal post-anticoagulation D-dimer were associated with the highest risk of VTE recurrence (HR 12.95, 95% CI 2.78-60.20, p = 0.001). Patients with unprovoked proximal DVT and/or PE who underwent D-dimer testing had a lower VTE recurrence rate compared to those who did not have D-dimer testing (HR 0.28, 95% CI 0.10-0.80, p = 0.017). We confirm the utility of post-anticoagulation cessation D-dimer testing to stratify VTE recurrence risk in the real-world setting, including potentially a role of this assay for predicting subsequent VTE in travel-provoked VTE and unprovoked IDDVT.

Apixaban and dalteparin in active malignancy‐associated venous thromboembolism: The ADAM VTE trial

BackgroundLow‐molecular‐weight heparin is the guideline‐endorsed treatment for cancer‐associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, limited data support its use in cancer patients. ObjectivesThe primary outcome was major bleeding. Secondary outcomes included VTE recurrence and a composite of major plus clinically relevant non‐major bleeding (CRNMB). Patients/MethodsPatients with cancer‐associated VTE were randomly assigned to receive either apixaban 10 mg twice daily for seven days followed by 5 mg twice daily for six months or subcutaneous dalteparin (200 IU/kg for one month followed by 150 IU/kg once daily). ResultsOf 300 patients randomized, 287 were included in the primary analysis. Metastatic disease was present in 66% of subjects; 74% were receiving concurrent chemotherapy. Major bleeding occurred in 0% of 145 patients receiving apixaban, compared with 1.4% of 142 patients receiving dalteparin [P = .138; hazard ratio (HR) not estimable because of 0 bleeding event in apixaban group]. Recurrent VTE occurred in 0.7% of apixaban, compared to 6.3% of dalteparin patients [HR 0.099, 95% confidence interval [CI], 0.013‐0.780, P = .0281). Major bleeding or CRNMB rates were 6% for both groups. ConclusionsOral apixaban was associated with low major bleeding and VTE recurrence rates for the treatment of VTE in cancer patients.

Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis

Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

One year prognosis in venous thromboembolism patients treated with direct oral anticoagulants versus standard anticoagulation: Outcomes from the REMOTEV registry

In phase 3 clinical trials, direct oral anticoagulants (DOACs) as compared to standard anticoagulation (SACO) showed non-inferiority in terms of efficacy (venous thromboembolism (VTE) recurrence, all-cause death) and significantly reduced major bleeding risk. However, real-life studies remain of paramount importance when extending this observation to the general population. This study aimed to provide safety and efficacy data of DOACs use in routine patient care in a non-selected symptomatic VTE population, from the REMOTEV registry. REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with DOACs (rivaroxaban or apixaban) or SACO (vitamin K antagonists or low molecular weight heparin alone) for at least 3 months with a follow-up of 1 year for VTE recurrence, death and bleeding complications. Patients with active cancer were excluded. From October 23rd, 2013 to December 15th, 2017, among 1159 consecutive patients included in REMOTEV, 908 were cancer-free and had completed the follow-up of 12 months or until death occurred. Among them, 905 received an anticoagulant treatment with DOAC ( n = 724, 80%) or SACO ( n = 181, 20%). The median age was 68 (51–79, 25th–75th percentiles), 88% had PE with (62%) or without (26%) deep vein thrombosis. The major bleeding, VTE recurrence and all-cause death rates were of 3.2%, 3.8%, 4.4% in the DOAC group and, respectively, of 6.6%, 5.5% and 12.1% in the SACO group. Major bleeding (HR 0.47 [95% CI, 0.24–0.94], P < 0.05), all-cause death (HR 0.36 [95% CI, 0.21–0.61], P < 0.001) and the composite of recurrent VTE, major bleeding and all-cause mortality (HR 0.52 [95% CI, 0.36–0.75], P < 0.001), but not VTE recurrence (HR 0.70 [95% CI, 0.34–1.41], P = 0.32) were significantly lower in the DOAC group compared to the SACO group ( Fig. 1 ). In REMOTEV, DOAC treatment was associated with a lower risk of major bleeding and all-cause death after 1-year follow-up.

Safety and Efficacy of High-Dose Unfractionated Heparin Versus High-Dose Enoxaparin for Venous Thromboembolism Prevention in Morbidly Obese Hospitalized Patients

Venous thromboembolism is a cause of morbidity and mortality in hospitalized patients, and morbid obesity increases this risk. Various prophylaxis dosing strategies have been investigated. However, it is unclear if high-fixed dose enoxaparin or high-fixed dose unfractionated heparin thromboprophylaxis is optimal for minimizing the incidence of major bleeding and reducing hospital-acquired venous thromboembolism. A single-center retrospective observational study was conducted in hospitalized patients who were morbidly obese (body mass index ≥40 kg/m2) and who received either high-fixed dose enoxaparin (40 mg every 12 hours) or unfractionated heparin (7500 units every 8 hours) for venous thromboembolism prophylaxis. Co-primary outcomes included incidence of major bleeding and venous thromboembolism diagnosed during hospitalization. Predictors of major bleeding were evaluated by multivariable regression. In the 305 patients included (n=190 unfractionated heparin, n=115 enoxaparin), the incidence of major bleeding was significantly higher in the unfractionated heparin group (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.07-3.13; P=0.025), with no significant difference in the incidence of venous thromboembolism diagnosed during hospitalization. The only independent predictors of major bleeding were intensive care acuity (OR 3.32, 95% CI 1.91-5.78; P <0.001) and selection of unfractionated heparin rather than enoxaparin for venous thromboembolism prophylaxis (OR 2.16, 95% CI 1.22-3.82; P=0.008). High-fixed dose unfractionated heparin for venous thromboembolism prophylaxis may lead to a higher risk of major bleeding events compared with high-fixed dose enoxaparin in patients who are morbidly obese.

P.161 Factors affecting the efficacy of adjunctive aripiprazole in risperidone- or paliperidone-induced hyperprolactinemia

The optimal cutoff for systolic blood pressure (SBP) level to define high-risk pulmonary embolism (PE) remains to be defined.To evaluate the relationship between SBP levels on admission and mortality in patients with acute symptomatic PE, the current study included 39,257 consecutive patients with acute symptomatic PE from the RIETE registry between 2001 and 2018. Primary outcomes included all-cause and PE-specific 30-day mortality. Secondary outcomes included major bleeding and recurrent venous thromboembolism (VTE).There was a linear inverse relationship between admission SBP and 30-day all-cause and PE-related mortality that persisted after multivariable adjustment. Patients in the lower SBP strata had higher rates of all-cause death (reference: SBP 110–129 mmHg) (adjusted odds ratio [OR] 2.9; 95% confidence interval [CI], 2.0–4.2 for SBP <70 mmHg; and OR 1.7; 95% CI, 1.4–2.1 for SBP 70–89 mmHg). The findings for 30-day PE-related mortality were similar (adjusted OR 4.4; 95% CI, 2.7–7.2 for SBP <70 mmHg; and OR 2.6; 95% CI, 1.9–3.4 for SBP 70–89 mmHg). Patients in the higher strata of SBP had significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR 0.7; 95% CI, 0.5–0.9 for SBP 170–190 mmHg; and OR 0.6; 95% CI, 0.4–0.9 for SBP >190 mmHg). Consistent findings were also observed for 30-day PE-related death.In patients with acute symptomatic PE, a low SBP portends an increased risk of all-cause and PE-related mortality. The highest mortality was observed in patients with SBP <70 mmHg.

Clinical implications of incidental venous thromboembolism in cancer patients.

In cancer patients, current guidance suggests similar treatment for incidental and symptomatic venous thromboembolism (VTE), mainly based on retrospective data. We aimed to evaluate anticoagulant therapy in cancer patients with incidental and symptomatic VTE. The Hokusai VTE Cancer Study was a randomised controlled trial comparing edoxaban with dalteparin for cancer-associated VTE. The primary outcome was the composite of first recurrent VTE or major bleeding. Secondary outcomes included major bleeding, recurrent VTE and mortality. Outcomes in patients with incidental and symptomatic VTE were evaluated during the 12-month study period. 331 patients with incidental VTE and 679 patients with symptomatic VTE were enrolled, of whom the index event was confirmed by an independent radiologist. Median durations of anticoagulant treatment were 195 and 189 days, respectively. In patients with incidental VTE, the primary outcome occurred in 12.7% of patients, major bleeding in 6.6% of patients and recurrent VTE in 7.9% of patients. Out of the 26 VTE recurrences in patients with incidental VTE, five (31%) were incidental, seven (44%) were symptomatic and four (25%) were deaths for which pulmonary embolism could not be ruled out. In patients with symptomatic VTE, the primary outcome occurred in 13.8% of patients, major bleeding in 4.9% of patients and recurrent VTE in 10.9% of patients. All-cause mortality was similar in both groups. Clinical adverse outcomes are substantial in both cancer patients with incidental and symptomatic VTE, supporting current guideline recommendations that suggest treating incidental VTE in the same manner as symptomatic VTE.

Systolic blood pressure and mortality in acute symptomatic pulmonary embolism

BackgroundThe optimal cutoff for systolic blood pressure (SBP) level to define high-risk pulmonary embolism (PE) remains to be defined. MethodsTo evaluate the relationship between SBP levels on admission and mortality in patients with acute symptomatic PE, the current study included 39,257 consecutive patients with acute symptomatic PE from the RIETE registry between 2001 and 2018. Primary outcomes included all-cause and PE-specific 30-day mortality. Secondary outcomes included major bleeding and recurrent venous thromboembolism (VTE). ResultsThere was a linear inverse relationship between admission SBP and 30-day all-cause and PE-related mortality that persisted after multivariable adjustment. Patients in the lower SBP strata had higher rates of all-cause death (reference: SBP 110–129 mmHg) (adjusted odds ratio [OR] 2.9; 95% confidence interval [CI], 2.0–4.2 for SBP <70 mmHg; and OR 1.7; 95% CI, 1.4–2.1 for SBP 70–89 mmHg). The findings for 30-day PE-related mortality were similar (adjusted OR 4.4; 95% CI, 2.7–7.2 for SBP <70 mmHg; and OR 2.6; 95% CI, 1.9–3.4 for SBP 70–89 mmHg). Patients in the higher strata of SBP had significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR 0.7; 95% CI, 0.5–0.9 for SBP 170–190 mmHg; and OR 0.6; 95% CI, 0.4–0.9 for SBP >190 mmHg). Consistent findings were also observed for 30-day PE-related death. ConclusionsIn patients with acute symptomatic PE, a low SBP portends an increased risk of all-cause and PE-related mortality. The highest mortality was observed in patients with SBP <70 mmHg.

Safety and Effectiveness of Apixaban, LMWH, and Warfarin Among Venous Thromboembolism Patients with Active Cancer: A Retrospective Analysis Using Four US Claims Databases

Safety and Effectiveness of Apixaban, LMWH, and Warfarin Among Venous Thromboembolism Patients with Active Cancer: A Retrospective Analysis Using Four US Claims Databases

Burden of Long-Term Morbidity Borne By Survivors of Acute Myeloid Leukemia (AML) Treated with Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: BMT is now an integral part of consolidation and/or salvage for patients with AML. With the growing population survivors, there is a need to understand the quality of survival. This would allow for appropriate resource allocation and implementation of risk-based screening for early detection of chronic health conditions over time. Yet, a comprehensive evaluation of the long-term burden of morbidity borne by AML patients treated with BMT remains unknown. We addressed this gap by evaluating long-term severe/life-threatening/fatal chronic health conditions (CHCs) in AML patients treated with BMT using the BMTSS. Methods: Patients were eligible if they had undergone an allogeneic or autologous BMT for AML between 1974 and 2014 at one of 3 BMT centers in the US, had survived for ≥2y after BMT, and were ≥21y of age at BMT. Of the 1,113 eligible subjects, 711 (64%) participated. BMT survivors identified a nearest-age sibling to constitute an unaffected comparison group (N=1,136). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHC diagnosis by their healthcare provider, including age at onset of CHC. Scoring was based on Common Terminology Criteria for Adverse Events ([CTCAE] v 5.0) to determine the severity of CHCs. Using multivariable logistic regression, we determined the risk of any severe (CTCAE grade 3) or life-threatening (CTCAE grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information regarding therapeutic exposures (pre-BMT and transplant-related) was abstracted from medical records. Cumulative incidence of CHCs (including fatal [CTCAE grade 5] CHCs) were calculated for BMT survivors, treating relapse-related death as a competing risk. Results: Mean age at BMT was 48.6±13.8y and at survey was 58.2±11.5y. Mean interval between BMT and study participation was 9.7±6.8y; 53% were females, and 78% were non-Hispanic white; 86% received allogeneic BMT (48% from an unrelated donor). Conditioning was Fludarabine/Melphalan-based in 53% and TBI-based in 35%; stem cell source was peripheral blood (70.3%), bone marrow (19.3%), and cord (10.4%). For the siblings, the mean age at survey was 56.9+13.4y; 61% were females, and 88% were non-Hispanic white. BMT survivors vs. sibs: 53.3% of the BMT survivors and 30.4% of the sibs reported grades 3-4 CHCs, placing the survivors at a 3.0-fold higher odds of grades 3-4 CHC (95%CI, 2.4-3.7, p&amp;lt;0.0001). The odds of developing the following CHCs were significantly higher in BMT survivors when compared with siblings: subsequent malignant neoplasms (SMNs: odds ratio [OR]=10.0, 95% CI, 5.5-17.9, p&amp;lt;0.0001), diabetes (OR=5.3, 95% CI, 3.0-9.3, p&amp;lt;0.0001), venous thromboembolism (OR=3.8, 95%CI, 2.5-5.8 p&amp;lt;0.0001), cataracts (OR=3.7; 95%CI, 2.7-5.0, p&amp;lt;0.0001), and major joint replacement (OR=1.5, 95% CI, 1.1-2.1, p=0.02). Among BMT survivors: The 10- and 20y cumulative incidence of a grade 3-5 CHC was 52.0%±1.4% and 66.2%±1.6%, respectively (Figure 1). 75 survivors had developed SMNs: skin (melanoma/ squamous cell [56%]), breast (13%), colon (7%), prostate (7%), and other cancers (24%). The 10- and 20y-cumulative incidence of the most common CHCs were as follows (Figure 2): SMN (10y: 17.9%±1.7%, 20y: 32.1%±2.9%), cataract (10y: 21.5%±1.9%, 20y: 31.5%±3.0%), major joint replacement (10y: 12.5%±0.9%, 20y: 17.5%±3.4%), venous thromboembolism (10y: 8.6%±1.1%, 20y: 13.2%±2.1%), and diabetes (10y: 6.0%±1.9%, 20y: 8.0%±1.5%). Conclusion: The burden of severe/life-threatening CHCs is substantially higher in BMT survivors when compared with an unaffected comparison group. The incidence of severe/ life-threatening/ fatal chronic health condition following BMT for AML exceeds 50% at 10y, and continues to increase with time, approaching 70% at 20y post-BMT. Subsequent malignant neoplasms, diabetes, thrombo-embolic events, cataracts, and major joint replacement constitute the largest burden of morbidity. These findings suggest the need for increased awareness of the long-term burden of morbidity, to ensure close monitoring of these survivors to anticipate and manage morbidity. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

Safety and Efficacy of Apixaban Thromboprophylaxis in Cancer Patients with Metastatic Disease: A Subgroup Analysis of the Avert Trial

Background The risk of venous thromboembolism (VTE) is increased in patients with active cancer, contributing substantially to morbidity and mortality. Further, the VTE risk is even higher for patients with metastatic cancer than those with local disease. In the AVERT trial, apixaban thromboprophylaxis resulted in a significantly lower rate of venous thromboembolism and an increased rate of major bleeding than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. In this prespecified subgroup analysis of AVERT, we evaluated the efficacy and safety of apixaban thromboprophylaxis in patients with and without metastatic disease. Methods Eligible participants were randomized to receive either apixaban (2.5mg twice daily) or placebo (identical tablets twice daily) up to five days before the first administration of chemotherapy. The first dose of apixaban or placebo was given within 24 hours of the first chemotherapy administration, with the treatment period lasting 180 days. Patients were followed for up to 210 days or death, regardless of the duration of the treatment period. The primary efficacy outcome was objectively documented major VTE (proximal deep-vein thrombosis or pulmonary embolism) occurring within 180 days (±3 days ) following randomization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis criteria. For this subgroup analysis, the efficacy and safety of apixaban thromboprophylaxis was evaluated in patients with and without documented metastatic disease. The primary efficacy analysis was performed in the modified intention-to-treat population, which included all the patients who had undergone randomization and received at least one dose of apixaban or placebo on or before day 180 (±3 days). The primary safety analysis was performed in the on-treatment population, in which events were only counted if they occurred during the period the subject was taking the study drug (or up to two days post discontinuation). Results A total of 574 patients underwent randomization, with 563 patients included in the original primary efficacy and safety analysis. A total of 366 patients could be stratified according to the presence or absence of metastatic disease, with 138 having metastatic disease and 228 having non-metastatic disease. The baseline characteristics were balanced between the treatment and placebo arms in both the metastatic and non-metastatic groups (Table 1). In patients with metastatic disease, VTE occurred in 6 of out of 73 in the treatment group and 10 out of 65 in the placebo group [HR 0.55 95% CI 0.32-0.97, p=0.0381]. In patients with metastatic disease, major bleeding occurred in 3 out of 73 in the treatment group and 2 out of 65 in the placebo group [HR 1.47 95% CI 0.29-6.76, p= 0.69]. In patients with non-metastatic disease, VTE occurred in 4 out of 107 in the treatment group, and 14 out of 121 in the placebo group [HR 0.35 95% CI 0.20-0.61, p= 0.0002]. In patients with non-metastatic disease, major bleeding occurred in 1 out of 107 in the treatment group and 1 out of 121 in the placebo group [HR 1.20 95%CI 0.11-13.38, p=0.881]. Conclusions: In patients with and without metastatic disease, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE compared to placebo, with no significant difference in the rate of major bleeding. This subgroup analysis thus suggests that apixaban thromboprophylaxis is both safe and effective in cancer patients regardless of the presence of absence of metastatic disease. Table 1. Disclosures Wells: Daiichi Sankyo: Honoraria; BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria. Carrier:Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Servier: Honoraria. OffLabel Disclosure: Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. We looked at using apixaban 2.5mg BID for the primary thromboprophylaxis of ambulatory cancer patients initiating chemotherapy, at intermediate-high risk of venous thromboembolism.

1773P - Short-term outcomes of cancer patients with pulmonary embolism according to the setting (hospital-acquired vs. outpatient) at diagnosis

BackgroundPulmonary embolism (PE) is a common condition in patients with cancer, having a wide spectrum of clinical presentation (from acute life-threatening to truly asymptomatic incidental events). The aim of this study was to assess the prognostic relevance of the variable ‘setting’ (hospital-acquired vs. outpatient) at PE diagnosis. MethodsMulticenter observational ongoing registry of consecutive patients with cancer-associated PE (2005-2018) including incidental and acute symptomatic events. The main outcome measured was the rate of overall and PE-specific 30-day mortality. Secondary outcomes were: rates of 30-day major bleeding (MB) and venous thromboembolism (VTE) recurrence. ResultsWe included a total of 617 patients (61.6% male; median age 65+11.4 years; range 19-91 years) including N=522 (85%) outpatients and N=95 (15%) inpatients at PE diagnosis. The most frequent primary tumors were: lung 32%, colorectal 14%, urologic 13%, upper GI 12%, breast 9%, gynecologic 6% and other 9%). Most of the patients (79%) had metastatic cancer and nearly half (47%) were receiving chemotherapy.The PE was incidentally found in 54% of the cases. Overall 30-day mortality occurred in 95 patients (15% of the cohort), being greater in inpatients compared to outpatients (30% vs. 13%; p<0.0001). Only 13 patients presented PE-related mortality (3% of the cohort), with no significant differences according to the setting at PE diagnosis (3.2% in inpatients vs. 1.7% in outpatients; p=0.352). Similarly, there were no differences in 30-day MB (7.4% in inpatients vs. 4.4% in outpatients; p=0.217) or VTE recurrence (4.2% in inpatients vs. 3.3% in outpatients; p=0.637) according to the setting at PE diagnosis. ConclusionsHospital-acquired PE in cancer patients was associated with a greater overall 30-day mortality compared to outpatients at PE diagnosis. This finding may be relevant for the development of PE risk-assessment models in this setting. Legal entity responsible for the studyHospital Clínic de Barcelona. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

P9. Abstract Title: Systolic Blood Pressure and Mortality in Acute Symptomatic Pulmonary Embolism

<h3>Importance</h3> The optimal cut-off for systolic blood pressure (SBP) to define high-risk pulmonary embolism (PE) remains to be defined. <h3>Objectives</h3> To evaluate the relationship between SBP on admission and short-term mortality and other cardiovascular events in patients with acute symptomatic PE. <h3>Design, Setting and Participants</h3> The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) Registry is an ongoing, multi-center, international, prospective registry of consecutive patients with symptomatic, objectively confirmed, acute venous thromboembolism (VTE). The current study included 39,257 patients from RIETE with acute symptomatic PE between 2001 and 2018. <h3>Main Outcomes and Measures</h3> Primary outcomes included all-cause and PE-specific 30-day mortality. Secondary outcomes included major bleeding and recurrent venous thromboembolism (VTE). <h3>Results</h3> There was a linear inverse relationship between admission SBP and 30-day all-cause and PE-related mortality that persisted after multivariable adjustment. Patients in the lower SBP strata had higher rates of all-cause death (reference: SBP 120-129 mmHg) (adjusted odds ratio [OR] 2.9, 95% confidence interval [CI] 2.0-4.2 for SBP <70 mmHg, and OR 1.7, 95% CI 1.4-2.1 for SBP 70-89 mmHg). The findings for 30-day PE-related mortality were similar (adjusted OR 4.4, 95% CI 2.7-7.2 for SBP <70 mmHg, and OR 2.6, 95% CI 1.9-3.4 for SBP 70-89 mmHg). After adjustment for all covariates, we did not find a significant relationship between admission SBP and recurrence or bleeding. <h3>Conclusions</h3> In patients with acute symptomatic PE, a low SBP portends an increased risk of all-cause and PE-related mortality. The highest mortality was observed in patients with SBP <70 mmHg.

Comparing Cardiovascular Safety of Febuxostat and Allopurinol in the Real World: A Population-Based Cohort Study

ObjectiveTo determine and compare the risk of cardiovascular events and mortality of febuxostat and allopurinol use. Patients and MethodsWe conducted a cohort study using the Taiwan National Health Insurance Research Database. New users of febuxostat and allopurinol between April 1, 2012 and December 31, 2015 were identified, and the two groups were 1:1 matched by propensity score, benzbromarone use history, renal impairment, and time of drug initiation. The risk of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), heart failure (HF) hospitalization, atrial fibrillation hospitalization, cardiovascular (CV) death, and all-cause mortality was assessed using Cox proportional hazards models. The dose-response relationship between xanthine oxidase inhibitor use and adverse CV outcomes were also determined. ResultsA total of 44,111 patients were included for each group, and all baseline covariates were well matched. Febuxostat users were at a significantly higher risk for HF hospitalization (hazard ratio [HR], 1.22; 95% CI, 1.13-1.33), atrial fibrillation hospitalization (HR, 1.19; 95% CI, 1.05-1.36), and CV death (HR, 1.19; 95% CI, 1.03-1.36) than allopurinol users, whereas no difference was found for the major adverse cardiac events composite endpoint, venous thromboembolism, myocardial infarction, ischemic stroke, and all-cause mortality. The elevated risk of HF hospitalization was consistent throughout the primary and sensitivity analyses. In addition, febuxostat increased the risk of adverse CV outcomes in a dose-dependent manner. ConclusionThe use of febuxostat, compared with allopurinol, was associated with a significantly increased risk of adverse CV events. Higher febuxostat doses had a greater impact. Further studies are needed to investigate the mechanisms linking febuxostat to adverse CV outcomes.

XALIA-LEA: An observational study of venous thromboembolism treatment with rivaroxaban and standard anticoagulation in the Asia-Pacific, Eastern Europe, the Middle East, Africa and Latin America

IntroductionThe prospective, non-interventional XALIA study investigated the safety and effectiveness of rivaroxaban and standard anticoagulation for the treatment of deep vein thrombosis (DVT). XALIA-LEA was conducted in regions not included in XALIA (Latin America, Eastern Europe, the Middle East, Africa, and the Asia-Pacific), and enrolled patients with isolated pulmonary embolism (PE). Materials and methodsAdult patients with acute venous thromboembolism (VTE) indicated for ≥3 months' anticoagulant treatment were eligible; treatment strategies were at the physician's discretion. Patients receiving rivaroxaban or standard anticoagulation (unfractionated or low-molecular weight heparin/fondaparinux alone or overlapping with and followed by a vitamin K antagonist [VKA]) were included in the safety analysis. “Early switchers” to rivaroxaban (i.e. after receiving heparin/fondaparinux for >2–14 days and/or a VKA for 1–14 days) were not included in the safety analysis set. ResultsOf the 1972 eligible patients, 1285 received rivaroxaban, 402 received standard anticoagulation, and 285 were early switchers. Most patients who received rivaroxaban were appropriately selected, received the correct dosing schedule, reported few adverse effects. Outcomes were similar to previously published results, with rivaroxaban associated with a low rate of major bleeding (1.6%), recurrent VTE (1.4%) and all-cause mortality (2.3%). Including early switchers, relatively fewer patients with index isolated PE received rivaroxaban (14.4%) versus standard anticoagulation therapy (20.9%). Some regional variations and differences in outcomes by VTE subtype were apparent with standard anticoagulation treatment. ConclusionXALIA-LEA reaffirms the safety and effectiveness of rivaroxaban for VTE treatment for countries not included in XALIA.

Influence of baseline anemia on long-term clinical outcomes in patients with venous thromboembolism: from the COMMAND VTE registry.

The influence of anemia on the long-term clinical outcomes has not been fully evaluated in patients with venous thromboembolism (VTE). We evaluated the influence of anemia among 3012 patients in the COMMAND VTE Registry with a median follow-up period of 1219days. The outcomes measures were ISTH major bleeding, recurrent VTE and all-cause death. There were 1012 patients (34%) with moderate/severe anemia (Hb ≤ 10.9g/dl), 615 patients (20%) with mild anemia (Hb 11.0-12.9g/dl for men, and 11.0-11.9g/dl for women), and 1385 patients (46%) without anemia. The cumulative 5-year incidence of major bleeding was significantly higher in patients with anemia (moderate/severe anemia: 17.6%, mild anemia: 12.1%, and no anemia: 8.7%, P < 0.001). After adjusting the confounders, the excess risk of mild and moderate/severe anemia, respectively, relative to no anemia for major bleeding remained significant (mild: adjusted HR 1.41: [95% CI 1.00-1.98], P = 0.048; moderate/severe: adjusted HR 1.91: [95% CI 1.42-2.58], P < 0.001, respectively). The excess risk of moderate/severe anemia relative to no anemia was also significant for mortality (adjusted HR 2.89: 95% CI 2.45-3.42, P < 0.001), but the risk was neutral for recurrent VTE (adjusted HR 1.05: 95% CI 0.76-1.45, P = 0.77). In conclusions, VTE patients with mild and moderate/severe anemia had higher risk for major bleeding events without significant excess risk for recurrent VTE events, and the risk for major bleeding events increased according to the severity of anemia. We should pay more attention to the optimal intensity and duration of anticoagulation in VTE patients with anemia.

Prospective Study of Apixaban for Primary Prevention of Venous Thromboembolism in Patients with Multiple Myeloma Receiving Immunomodulatory Therapy

IntroductionImmunomodulatory/cereblon-binding drugs (IMiDs), including lenalidomide and pomalidomide, have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic foundation at all phases of therapy. While these agents are generally well-tolerated, their increased risk of venous thromboembolism (VTE), in particular deep vein thrombosis and pulmonary embolism, presents a major clinical challenge for the treatment of MM. Apixaban, a direct oral anticoagulant which directly blocks Factor Xa, has been approved for treatment in patients with VTE. Apixaban has not been prospectively evaluated for thromboprophylaxis in MM in the US. In this phase IV single-arm study (NCT02958969), we prospectively evaluate the safety and efficacy of apixaban for primary prevention of VTE in patients with MM receiving IMiD therapy.MethodsFifty patients with MM on IMiD therapy received apixaban 2.5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for 6 months. Patients requiring therapeutic anticoagulation or with history of prior VTE were excluded. Patients stopped aspirin while on apixaban. Primary safety outcomes were rates of major hemorrhage and clinically relevant non-major hemorrhage over 6 months. Major bleeding was defined as overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, requiring transfusion of ≥ 2 units of blood, occurring in a critical site, or contributing to death. Clinically relevant non-major bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, surgical intervention, or interruption of the study drug. The primary efficacy outcome was the rate of symptomatic VTE over 6 months.ResultsBaseline characteristics are listed (Table). Median age was 63 years (range 51-74) with 50% of patients being male. Patients had received a median of 2 lines of therapy (range 0-8), and the majority (82%) had received prior autologous stem cell transplantation (AutoSCT). Patients received apixaban thromboprophylaxis in combination with lenalidomide (58%) or pomalidomide (42%). The majority (66%) received IMiDs for post-autoSCT consolidation or maintenance therapy. Most (80%) had traditional cardiovascular (CV) risk factors prior to initiation of apixaban, including hypertension (50%), obesity (46%), history of smoking (34%) and hyperlipidemia (32%).At planned interim analysis at 3 months (range 23-149 days) with data still being collected for planned 6 month study duration, no patients had experienced major hemorrhage or VTE. Two patients experienced clinically relevant, non-major hemorrhage, including one patient with unprovoked epistaxis lasting more than 5 minutes and another patient with mechanical trauma. These events were medically managed, and both patients were able to resume apixaban. One patient stopped therapy shortly after initiation due to allergic reaction to apixaban manifesting as generalized edema. No patients experienced stroke, myocardial infarction (MI), or death.ConclusionsIn this pilot study of 50 patients, low-dose apixaban was safe and well tolerated as thromboprophylaxis for patients with MM receiving IMiDs. No patients experienced VTE, major hemorrhage, stroke, or MI. Further randomized studies are needed to validate apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs. [Display omitted] DisclosuresMoslehi:Bristol-Myers Squibb: Consultancy, Research Funding. Jagasia:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.

Erratum: Effectiveness and Safety of Apixaban versus Warfarin as Outpatient Treatment of Venous Thromboembolism in U.S. Clinical Practice.

In the AMPLIFY clinical trial, apixaban was non-inferior to warfarin plus subcutaneous enoxaparin bridge therapy in the treatment of acute venous thromboembolism (VTE) and was associated with significantly less bleeding. This study evaluated their comparative effectiveness and safety in routine clinical practice. A matched-cohort design and data from four U.S. private health care claims databases were employed. Study population comprised patients who initiated outpatient treatment with apixaban versus warfarin (plus parenteral anticoagulant bridge therapy) within 30 days of their initial VTE episode; apixaban and warfarin patients were matched on age, characteristics of VTE episode, study database and propensity score. Major bleeding, clinically relevant non-major (CRNM) bleeding and recurrent VTE during the 180-day (maximum) follow-up period were compared using shared frailty models. During mean follow-up of 143 days among apixaban patients (n = 17,878) and 152 days among warfarin patients (n = 17,878), incidence proportions for apixaban versus warfarin, respectively, were 1.7% versus 2.3% for major bleeding, 7.0% versus 9.4% for CRNM bleeding and 2.3% versus 2.9% for recurrent VTE. In shared frailty models, risks of major bleeding (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.64–0.87), CRNM bleeding (HR = 0.77, 95% CI = 0.71–0.83) and recurrent VTE (HR = 0.80, 95% CI = 0.70–0.91) were lower for apixaban versus warfarin. In this large-scale evaluation of VTE patients receiving outpatient treatment with apixaban or warfarin in U.S. clinical practice, risks of major bleeding, CRNM bleeding and recurrent VTE were significantly lower among patients who received apixaban.

Low-Molecular-Weight Heparin for the Prevention of Venous Thromboembolism in Patients Undergoing Knee Arthroscopic Surgery and Anterior Cruciate Ligament Reconstruction: A Meta-analysis of Randomized Controlled Trials

Background: Low-molecular-weight heparin (LMWH) thromboprophylaxis is widely used for reducing the risk of thrombosis after major orthopaedic surgery. However, the effect and safety on knee arthroscopic surgery are still controversial. Purpose: To assess the efficacy and safety of LMWH for the prevention of symptomatic venous thromboembolism (VTE) after knee arthroscopic surgery and anterior cruciate ligament reconstruction (ACLR) by conducting a meta-analysis of randomized controlled trials (RCTs). Study Design: Meta-analysis. Methods: The authors searched the electronic databases of MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Web of Science for all studies from inception to June 30, 2017. All selected studies were categorized into 2 subgroups: simple knee arthroscopic surgery and ACLR. The primary effect and safety endpoint were the incidence of major VTE and major bleeding events (BEs), respectively. The secondary effect and safety endpoint were the incidence of all VTE and all BEs, respectively. Relative risks (RRs) with 95% CIs were calculated using Review Manager 5.3. Results: Eight RCTs with 4113 patients were included. For patients undergoing simple knee arthroscopic surgery, LMWH prophylaxis did not bring a significant reduction in the risk of major VTE (RR, 1.00 [95% CI, 0.37-2.67]; P > .99) and all VTE (RR, 0.63 [95% CI, 0.31-1.29]; P = .21) and did not increase the risk of major BEs (RR, 0.98 [95% CI, 0.06-15.72]; P = .99) but did have a higher risk of all BEs (RR, 1.64 [95% CI, 1.18-2.28]; P = .003) in comparison with non-LMWH prophylaxis. For patients undergoing ACLR, LMWH prophylaxis was associated with a significantly lower rate of major VTE (RR, 0.23 [95% CI, 0.12-0.43]; P < .001) and all VTE (RR, 0.22 [95% CI, 0.06-0.73]; P = .01) but no increase in major BEs (RR, 1.80 [95% CI, 0.19-17.25]; P = .61) and all BEs (RR, 1.12 [95% CI, 0.72-1.74]; P = .61) in comparison with non-LMWH prophylaxis. Conclusion: Compared with non-LMWH treatment, LMWH had no significant efficacy in preventing VTE in patients undergoing simple knee arthroscopic surgery but increased the risk of BEs. However, LMWH had significant efficacy in preventing VTE for patients mainly undergoing ACLR and did not increase the risk of BEs.

Effectiveness and safety of rivaroxaban versus warfarin in patients with unprovoked venous thromboembolism: A propensity-score weighted administrative claims cohort study

BackgroundIn 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. MethodsIn 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. FindingsWe 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. InterpretationConsistent 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.