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.

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Intracranial Hemorrhage in Patients with Primary Brain Tumors Treated with Therapeutic Enoxaparin: A Matched Cohort Study

Blood ◽

10.1182/blood.v128.22.142.142 ◽

2016 ◽

Vol 128 (22) ◽

pp. 142-142 ◽

Cited By ~ 1

Author(s):

Charlene Mantia ◽

Erik Uhlmann ◽

Maneka Puligandla ◽

Donna S. Neuberg ◽

Griffin M. Weber ◽

...

Keyword(s):

Cohort Study ◽

Venous Thromboembolism ◽

Brain Tumors ◽

Intracranial Hemorrhage ◽

Cumulative Incidence ◽

Competing Risk ◽

Matched Cohort ◽

Intracranial Hemorrhages ◽

Primary Brain Tumors ◽

Therapeutic Anticoagulation

Abstract BACKGROUND Venous thromboembolism occurs in approximately 15-30% of individuals with primary brain tumors (e.g. glioblastoma, astrocytoma, and oligodendroglioma). Spontaneous intracranial hemorrhage (ICH) is also a frequent complication of primary brain tumors thus complicating the decision to administer therapeutic anticoagulation. Therapeutic anticoagulation does not appear to increase the risk of intracranial hemorrhage among patients with solid tumor brain metastases but whether anticoagulation is safe to administer to patients with primary brain tumors is less clear. The aim of this study was to determine the rate of intracranial hemorrhage associated with therapeutic enoxaparin for treatment of venous thromboembolism in patients with primary brain tumors compared to those patients with brain tumors not exposed to therapeutic anticoagulation. METHODS A 1:1 matched, cohort study was performed using a large hospital-based online medical record database (CQ2) linking ICD-9 codes with prescription medication records, cases were initially identified based on coding for primary brain tumors, venous thromboembolism, and prescription of enoxaparin. Matched controls were identified using a "round-robin" algorithm that ranked controls according to a scoring formula based on successful match for year of diagnosis, age, and gender. A blinded review of radiographic imaging was performed and intracranial hemorrhages were categorized as trace, measurable, and significant. Measurable intracranial hemorrhages were those defined as greater than 1 mL in volume and "significant" intracranial hemorrhages were defined as greater than 10 mL in volume, symptomatic (defined as focal neurologic deficit, headache, nausea, or change in cognitive function), or required surgical intervention. Time-to-event statistical analysis was performed using a competing risk analysis to account for death from any cause as an absorbing competing risk. Statistical comparison of event rates between cases and controls was performed using Fine and Gray competing risk regression. RESULTS A total of 100 patients with primary brain tumors were included in the study. The most common diagnosis was glioblastoma (85%), followed by anaplastic oligodendroglioma (8%), and anaplastic astrocytoma (7%). The two cohorts were well matched for age (60 years old), gender (65% male), and types of treatment received (99% radiation, 34% stereotactic radiosurgery, and 71% surgical resection). There was no statistical difference in the rate of measurable intracranial hemorrhage for the group of patients who received therapeutic enoxaparin at any point following the diagnosis of glioma compared to those who did not receive anticoagulation (subdistribution ratio hazard ratio 1.09, 95% CI 0.53-2.22). The 1-year cumulative incidence of measurable hemorrhage among those who were treated with enoxaparin was 23.6% compared with 20.0% in the control group (Gray's test P=0.48). The 1-year cumulative incidence of significant hemorrhage was 13.1% in those receiving enoxaparin compared with 6.0% in controls (sHR 1.45, 95% CI .47-4.65, P=0.68). The median survival was similar for the enoxaparin (1.56 years) and controls (1.63 years, Log rank P=0.81). CONCLUSION Intracranial hemorrhage is common in patients with primary brain tumors. In this matched cohort analysis utilizing a blinded radiologic review, the administration of therapeutic low molecular weight heparin did not significantly increase the risk of intracranial hemorrhage in the setting of glioma and venous thromboembolism. In patients with primary brain tumors, the diagnosis of venous thromboembolism treated with therapeutic enoxaparin did not impact overall survival. Disclosures Zwicker: Quercegen Pharma: Research Funding.

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Safety of Direct-Acting Oral Anticoagulants Versus Enoxaparin in Patients with Primary and Metastatic Brain Tumors

Blood ◽

10.1182/blood-2018-99-115666 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2521-2521

Author(s):

Brian J. Carney ◽

Erik J. Uhlmann ◽

Maneka Puligandla ◽

Charlene Mantia ◽

Griffin M. Weber ◽

...

Keyword(s):

Brain Tumors ◽

Brain Metastases ◽

Cumulative Incidence ◽

Research Funding ◽

Oral Anticoagulants ◽

Intracranial Hemorrhages ◽

Primary Brain Tumors ◽

Increased Risk ◽

Direct Acting ◽

Direct Acting Oral Anticoagulants

Abstract Introduction Venous thromboembolism (VTE) is a common complication of cancer. Patients with primary brain tumors and brain metastases are at particularly high risk, with about 20-30% suffering a VTE event. The administration of enoxaparin appears to be safe in patients with brain metastases but confers an increased risk of intracranial hemorrhage (ICH) in patients with primary brain tumors. Direct-acting oral anticoagulants (DOACs) have demonstrated efficacy in the treatment of cancer-associated thrombosis with an increased risk of hemorrhage compared to low molecular weight heparin (LMWH). There are limited data on the safety of DOACs in patients with brain tumors. As the risk of ICH associated with parenteral anticoagulants differs for primary versus secondary brain tumors, we analyzed ICH outcomes for patients with VTE receiving enoxaparin or a DOAC. Methods A retrospective cohort study was performed using a hospital-based online medical record database (CQ2) linking ICD-9 and ICD-10 codes with prescription medication records. Cases were identified based on coding for primary brain tumors or brain metastases and prescription of either a DOAC or enoxaparin. A blinded review of radiographic imaging was performed, and intracranial hemorrhages were categorized as either trace, measurable, and 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 (defined as focal deficit, headache, nausea, or a change in cognitive function), or required surgical intervention. Gray's test was used to compare the cumulative incidence of ICH between the groups, with death as a competing risk. Results A total of 170 patients with primary brain tumors and brain metastases were included in the study. In the primary brain tumor cohort (N=65), 18 patients received a DOAC while 47 received enoxaparin. The cumulative incidence of any ICH at 12 months was 0% in patients receiving a DOAC compared to 36.8% (95% confidence interval 22.3-51.3%) in those receiving enoxaparin (P=0.012). There were no major ICH events in the DOAC group and 8 and in the LMWH group (12-month cumulative incidence of 0% versus 18.2%, 95% CI 8.4-31.0, P=0.062). In the brain metastases cohort (N=105), 21 patients received a DOAC while 84 received enoxaparin. The DOAC and enoxaparin groups were well-matched for tumor diagnosis (non-small lung cancer 52% and 51%, respectively) including those tumor types with a high incidence of ICH (i.e. melanoma 5% and 7% and renal cell carcinoma 14% and 11%, respectively). In patients with brain metastases, DOACs did not increase the risk of any ICH relative to enoxaparin (12-month cumulative incidence 27.8% versus 52.9%, P=0.15) nor major ICH (12-month cumulative incidence 11.1% vs 17.8%, P=0.38). Conclusions DOACs can be safely administered to patients with brain tumors. In patients with primary brain tumors (i.e. glioma), DOACs appear to be safer than LMWH and should be considered for this indication. Figure. Figure. Disclosures Zwicker: Incyte: Research Funding; Parexel: Consultancy; Quercegen: Research Funding; Daiichi: Honoraria.

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The Kids-DOTT Trial: Novel Aspects of the ‘Parallel Cohort RCT‘ Design and Its Application to the Investigation of Duration of Anticoagulant Therapy for Pediatric Venous Thromboembolism.

Blood ◽

10.1182/blood.v114.22.4169.4169 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4169-4169

Author(s):

Neil A. Goldenberg ◽

Mark Tripputi ◽

Mark A. Crowther ◽

Thomas C. Abshire ◽

Donna M. DiMichele ◽

...

Keyword(s):

Venous Thromboembolism ◽

Anticoagulant Therapy ◽

Cumulative Incidence ◽

Trial Design ◽

Clinical Risk Factor ◽

Trial Participation ◽

Major Hemorrhage ◽

Equal Distribution ◽

Off Label ◽

Recurrent Vte

Abstract Abstract 4169 The randomized controlled trial (RCT) is the gold-standard clinical trial design by which safety and efficacy of new medical therapies are evaluated in comparison to placebo or established treatments. Randomization serves as a primary means of ensuring equal distribution of confounding factors, minimizing selection bias, and upholding key assumptions of the statistical analysis. In some circumstances, when prognostic heterogeneity is hypothesized but evidence is not definitive, lack of equipoise among experts in the field may preclude randomization in a particular subgroup. In traditional RCT designs, patients in this subpopulation are then excluded from trial participation. However, these patients often constitute an important subgroup of the disease population. By taking advantage of existing RCT infrastructure, efforts to evaluate such patients in a parallel cohort arm – using a “parallel-cohort RCT” design – would provide an efficient means of generating multi-center prospective data on natural history, toward the development of future RCTs involving these subgroups. A current example of the parallel-cohort RCT design is the Kids-DOTT trial, an ongoing investigator-initiated multi-center randomized trial of the duration of anti-thrombotic therapy for venous thrombosis in children. The target population is children with first-episode acute VTE (excluding pulmonary embolism) in whom a reversible prothrombotic clinical risk factor has been identified and comprehensive laboratory assessment reveals no severe or multi-trait thrombophilia. Children meeting eligibility criteria and in whom no persistent occlusive thrombosis at the six-week follow-up time point are randomized to shortened-duration (six weeks) versus conventional-duration (three months) anticoagulant therapy (Figure 1). The primary endpoint is the cumulative incidence (i.e., risk) of recurrent VTE at two years, and will be compared between the two arms. Secondary outcomes include cumulative incidence of post-thrombotic syndrome (PTS) at two years and of major hemorrhage during anticoagulant therapy. The primary hypothesis of the study is that shortened-duration anticoagulation is non-inferior to conventional-duration therapy. The study also evaluates two groups of patients in parallel cohorts (Figure 1). The first group is comprised of patients with a persistent occlusive thrombosis following the first six weeks of anticoagulation; this cohort is allocated to a conventional course of anticoagulation. The second parallel cohort in the Kids-DOTT trial consists of patients with persistent antiphospholipid antibodies, who are allocated to a course of anticoagulation ranging from 3 months to lifelong. For each of these subpopulations, there was lack of equipoise toward inclusion in the randomization to shortened- versus conventional-duration therapy, due to perception of possible increased recurrence risk. The specific aims involving the parallel cohorts are to determine whether: (1) persistent thrombotic veno-occlusion is a prognostic indicator of recurrent VTE and/or PTS, among children treated with a three month conventional course of anticoagulation (comparison of randomization arm B vs. parallel cohort arm C in Figure 1); and (2) duration of therapy influences risk of recurrent VTE and/or PTS among children with persistent APA, when anticoagulated for a minimum duration of three months (within parallel cohort arm D in Figure 1). In this way, the parallel-cohort RCT model of the Kids-DOTT trial provides additional efficiency in trial design, maximizing the information gained from subpopulations of interest that are excluded from randomization. Broader application of the parallel-cohort RCT design should be considered, particularly in rare disease areas, where efforts to maximize inclusion of the diseased population are critical to trial feasibility and applicability. Disclosures: Off Label Use: The presentation refers to the use of anticoagulants as a drug class in general in the treatment of venous thromboembolism (VTE) in children. Despite their use in the standard care for pediatric VTE, all anticoagulants remain off-label for this indication in children.

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Subgroup Analysis of Patients with Cancer in Xalia - a Non-Interventional Study of Rivaroxaban in Routine Treatment of Deep Vein Thrombosis

Blood ◽

10.1182/blood.v128.22.1438.1438 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1438-1438 ◽

Cited By ~ 1

Author(s):

Alexander G G Turpie ◽

Lorenzo G Mantovani ◽

Sylvia Haas ◽

Reinhold Kreutz ◽

Danja Monje ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Venous Thromboembolism ◽

Major Bleeding ◽

Research Funding ◽

Incidence Rates ◽

Vein Thrombosis ◽

All Cause Mortality ◽

Recurrent Vte ◽

Deep Vein ◽

Active Cancer

Abstract Background: XALIA is a prospective, non-interventional study of rivaroxaban in the treatment of acute deep vein thrombosis. The overall XALIA results showed that rivaroxaban was associated with similarly low rates of major bleeding and symptomatic recurrent venous thromboembolism (VTE) as standard anticoagulation. A subset of patients in XALIA had active cancer at the time of enrolment into the study. Purpose: To describe the demographics, clinical characteristics, treatment strategies and outcomes of patients in XALIA with cancer and VTE. The primary outcomes were major bleeding, recurrent VTE and all-cause mortality. Methods: Patients with deep vein thrombosis with or without concomitant pulmonary embolism aged ≥18 years who had active cancer and were scheduled to receive ≥3 months of anticoagulation with rivaroxaban or standard therapy were eligible. Therapy type, dose and duration were at the physician's discretion. For the purpose of this substudy, we defined the following treatment cohorts: rivaroxaban cohort (patients treated with rivaroxaban alone or who received heparin/fondaparinux for ≤48 hours before switching to rivaroxaban); early switchers cohort (patients treated with rivaroxaban who received heparin/fondaparinux for >48 hours-14 days and/or a vitamin K antagonist [VKA] for 1-14 days before changing to rivaroxaban); standard anticoagulation cohort (patients treated with heparin/fondaparinux and a VKA or a VKA only); and heparin/fondaparinux cohort (patients treated with heparin/fondaparinux alone). Results: Of 5136 patients in XALIA who received study medication, 587 (11.4%) had active cancer at baseline. Of these, 146 (24.9%) received rivaroxaban, 30 (5.1%) were early switchers, 167 (28.4%) received standard anticoagulation (of which 26 [4.4%] received a VKA only) and 244 (41.6%) received heparin/fondaparinux only, of whom 223 (38.0%) received low molecular weight heparin and the remainder other heparins or fondaparinux. Demographics are shown in Table 1. The most common type of active cancer at baseline in all cohorts was genitourinary, with the exception of the heparin/fondaparinux cohort where gastrointestinal cancer was the most common type (Table 2). The incidence rates for the primary outcomes for each cohort are shown in Figure 1. The rates of major bleeding were highest in the standard anticoagulation cohort (n=8 [4.8%]) and lowest in the early switchers (no major bleeding events occurred). The rates of recurrent VTE were similar in the in the rivaroxaban, early switcher and standard anticoagulation cohorts (n=5 [3.4%], n=1 [3.3%] and n=6 [3.6%], respectively) and were highest in the heparin/fondaparinux cohort (n=12 [4.9%]). All-cause mortality was highest in the heparin/fondaparinux cohort (n=61 [25.0%]) and lowest in the early switchers (no deaths occurred). Conclusions: In the real-world XALIA study, 38.0% of patients with cancer received treatment with low molecular weight heparin, which was in line with guidelines. The remaining patients received rivaroxaban, standard anticoagulation or were early switchers. For the three primary outcomes, the lowest incidence rates were observed in the early switcher cohort. The highest rates were in the standard anticoagulation cohort for major bleeding and the heparin/fondaparinux cohort for recurrent VTE and all-cause mortality; rates for all three primary outcomes were low in the rivaroxaban cohort, suggesting that rivaroxaban may be a safe and effective treatment option for patients with VTE and active cancer. Figure 1 Primary outcomes in patients with active cancer at baseline by treatment group. VTE, venous thromboembolism. Figure 1. Primary outcomes in patients with active cancer at baseline by treatment group. / VTE, venous thromboembolism. Disclosures Turpie: Janssen Research & Development, LLC: Consultancy, Honoraria; Bayer Pharma AG: Consultancy, Honoraria. Mantovani:Janssen-Cilag Ltd: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Sankyo: Consultancy; Bayer Pharma AG: Consultancy; Pfizer Inc: Research Funding. Haas:Sanofi SA: Consultancy; Pfizer Inc: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy; Bayer Pharma AG: Consultancy; Aspen Pharmacare: Consultancy. Kreutz:Bayer Pharma AG: Honoraria; Servier Laboratories Ltd: Consultancy; Lundbeck Ltd: Consultancy; Daiichi Sankyo: Consultancy; Berlin-Chemie Menarini: Consultancy; Bayer Pharma AG: Consultancy; Bristol-Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria. Monje:Bayer Pharma AG: Employment. Schneider:Bayer Pharma AG: Employment. van Eickels:Bayer Pharma AG: Employment. Gebel:Bayer Pharma AG: Employment. Ageno:Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer Pharmaceuticals: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Bayer Pharma AG: Consultancy, Honoraria.

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Risk of Recurrent Venous Thromboembolism and Bleeding in Patients with Cancer Associated Thrombosis

Blood ◽

10.1182/blood-2020-142805 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-18

Author(s):

Doaa Attia ◽

Xuefei Jia ◽

Mailey L Wilks ◽

Barbara Tripp ◽

Christopher D'Andrea ◽

...

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Major Bleeding ◽

Research Funding ◽

Cleveland Clinic ◽

Treatment Groups ◽

Recurrent Venous Thromboembolism ◽

Recurrent Vte ◽

Cancer Associated Thrombosis

Background: The treatment paradigm for cancer associated thrombosis (CAT) has evolved over recent years from using low molecular weight heparin (LMWH) to direct oral anticoagulants (DOACs). Some randomized trials suggest decreased rates of recurrent venous thromboembolism (VTE) in CAT patients treated with DOACs compared to LMWH but also reported increased rates of bleeding. The Cleveland Clinic Taussig Cancer Center has been treating cancer thrombosis in a centralized CAT clinic since 2014. Here we report our rates of bleeding and recurrent VTE in cancer patients treated with anticoagulation. Methods: We prospectively followed cancer patients referred to our clinic from 8/2014-10/2019. A total of 1548 patients were referred to the clinic, of whom 462 were diagnosed with an acute VTE. VTE events, including deep venous thrombosis, pulmonary embolism, and visceral thrombosis, were noted. The comparison of bleeding rates (defined using ISTH criteria for major and clinically relevant non major bleeding, CRNMB) among treatment groups (LMWH vs DOACs) was examined using chi-square test. Rate of recurrent VTE was analyzed using a competing model in which death was treated as a competing risk. Results: The study population comprised 462 patients with acute VTE with a mean age of 62.67±12.23 and 51.8 % males. Of these, 234 (52.9%) received LMWH, 161(36.4%) received DOACs, and 47 (10.6%) received other agents including warfarin for initial anticoagulation. Overall, the 6-month, 1 year, and 2-year VTE recurrence rate was 5.9%, 6.6%, 7.9%, respectively. Recurrent VTE rates were similar for LMWHs, DOACs and other agents (P>0.05). Of 368 patients for whom follow-up data was available, 74 (16.7%) had bleeding event , of which 25 (33.8%) had major bleeding and 49 (66.4%) had CRNMB at 6 month follow-up with no difference across three treatment groups (p=0.56). Conclusion: In this real-world practice setting, rates of recurrent VTE and bleeding were similar for DOACs and LMWH suggesting that with careful patient selection the concern for higher bleeding with DOACs in cancer patients can be safely overcome. Disclosures McCrae: Momenta Pharmaceuticals: Consultancy; Novartis: Honoraria; Rigel: Consultancy; Dova: Consultancy. Khorana:Merck: Research Funding; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria; Array: Other: Research funding (to institution); Janssen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; BMS: Honoraria, Research Funding; Leap: Research Funding.

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Patterns of Management and Adherence to Venous Thromboembolism (VTE) Treatment Guidelines In a National Prospective Cohort Study of VTE Management In the Canadian Outpatient Setting: Recovery Study

Blood ◽

10.1182/blood.v116.21.565.565 ◽

2010 ◽

Vol 116 (21) ◽

pp. 565-565

Author(s):

Susan R Kahn ◽

Sam Schulman ◽

Josée Martineau ◽

John A Stewart ◽

Anne McLeod ◽

...

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Median Duration ◽

Research Funding ◽

Treatment Guidelines ◽

Outpatient Setting ◽

Medical Admission ◽

Recurrent Vte ◽

Outpatient Settings

Abstract Abstract 565 Introduction: Little is known about patterns and quality of venous thromboembolism (VTE) management in Canadian outpatient settings, including how closely clinicians adhere to evidence based treatment guidelines. Such information could help identify gaps in patient care requiring attention. Objectives: To obtain prospective, clinical practice-based data from Canadian outpatient settings on 1) management of VTE; 2) determinants of patterns of VTE management; 3) degree of adherence with ACCP 2008 VTE treatment guidelines; and 4) frequency of bleeding and recurrent VTE during follow-up. Methods: We performed a multi-centre prospective observational study to evaluate physician practice patterns and degree of adherence to ACCP consensus guidelines for VTE treatment. From 2007–2010, we enrolled 915 consecutive patients with objectively confirmed acute symptomatic VTE who received treatment with the low molecular weight heparin (LMWH) enoxaparin alone or with warfarin in the outpatient setting (mainly thrombosis clinics) in 12 Canadian centers. Patients attended an enrolment visit, where data on demographics, site(s) of VTE, VTE risk factors, bleeding risk factors, creatinine clearance and initial treatment were recorded. A follow-up visit occurred when anticoagulant treatment was stopped or at 6 months, whichever occurred first. Indicators of adherence to VTE treatment guidelines included: (1) having received any thromboprophylaxis for VTE associated with transient risk factors (recent medical admission, major surgery or leg immobilization); (2) use of LMWH monotherapy to treat cancer-associated VTE; (3) at least 5 days median duration of LMWH in patients treated with initial LMWH overlapped with warfarin; (4) at least 1 day overlap of LMWH and warfarin once INR was therapeutic. Recurrent VTE, bleeding and adverse events were recorded throughout study follow-up. Results: At the time of abstract submission, end of study data were available for 747 of 915 enrolled patients. Average age was 56 years, 54% were male and mean body mass index was 28.3 kg/m2. Index VTE was lower or upper extremity deep venous thrombosis (DVT) in 511 (68.4%) patients, pulmonary embolism (PE) with or without DVT in 218 (29.2%) patients, and unusual site DVT in 18 (2.4%) patients. VTE was associated with cancer in 70 (9.4%) patients, transient risk factors in 289 (38.7%) patients, hormonal risk factors in 55 (7.4%) patients and was deemed unprovoked in 331 (44.3%) patients. Overall, enoxaparin was prescribed at a dose/frequency of 1.5 mg/kg QD in 85.4% of patients, 1.0 mg/kg BID in 14.6% of patients and 1.0 mg/kg QD for one patient who had creatinine clearance <30ml/min. Among patients with VTE risk factors such as recent medical admission, recent surgery or paralysis, only 37.3% had been prescribed thromboprophylaxis. Among patients with cancer-related VTE (n=70), 61.4% were prescribed LMWH monotherapy, a majority received 1.5 mg/kg once daily, and 42.9% received such treatment for >3 months. Among patients treated with initial LMWH overlapped with warfarin (n= 667; 89.3%), median duration of LMWH was 8 days (IQR 6–10 days), median duration of warfarin was 182 days (IQR 115–190) and median overlap with LMWH once INR was therapeutic was 1 day (IQR 1–2 days). However, 48 (7.2%) patients received <5 days LMWH and 99 (15%) patients had overlap <1 day. During follow-up, 16 (2.1%) patients had recurrent VTE, at a median of 71 days follow-up; rate of recurrent VTE was highest (8.6%) and occurred earliest (median, 49 days) in cancer patients. Major bleeding events (primarily GI or GU) occurred in 10 (1.3%) patients at a median of 23 days; at the time of bleed, 2 patients were receiving LMWH alone, 3 patients, LMWH and warfarin, and 5 patients, warfarin alone. Conclusions: Our study provides useful information on clinical features of patients, management of VTE and rates of recurrence and bleeding in Canadian outpatients. Our results suggest that there are important gaps in (1) use of thromboprophylaxis to prevent VTE and (2) use of LMWH monotherapy to treat VTE in cancer patients. Conversely, in patients treated with combination LMWH/warfarin therapy, adherence to recommendations regarding minimum duration of LMWH and minimum overlap of LMWH and warfarin once INR was therapeutic was quite good. Disclosures: Kahn: Sigvaris: Research Funding; sanofi-aventis: Advisory Board, Research Funding; Boehringer Ingelheim:. Schulman:Sanofi Aventis: Honoraria.

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Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study

Blood ◽

10.1182/blood-2015-02-626788 ◽

2015 ◽

Vol 126 (4) ◽

pp. 494-499 ◽

Cited By ~ 66

Author(s):

Jessica Donato ◽

Federico Campigotto ◽

Erik J. Uhlmann ◽

Erika Coletti ◽

Donna Neuberg ◽

...

Keyword(s):

Cohort Study ◽

Brain Metastasis ◽

Brain Tumors ◽

Brain Metastases ◽

Intracranial Hemorrhage ◽

Matched Cohort ◽

Metastatic Brain Tumors ◽

Matched Cohort Study ◽

Therapeutic Anticoagulation ◽

Key Points

Key Points Significant intracranial hemorrhage occurs in 20% to 50% of patients with metastatic brain tumors. Therapeutic anticoagulation in patients with brain metastasis did not increase the risk for intracranial hemorrhage.

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Validation of the Ottawa Score in Cancer Patients with Venous Thromboembolism. the Predicare Cohort Study

Blood ◽

10.1182/blood-2019-129087 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 167-167 ◽

Cited By ~ 1

Author(s):

Guy Meyer ◽

Celine Chapelle ◽

Philippe Girard ◽

Florian Scotté ◽

Anne Lamblin ◽

...

Keyword(s):

Cohort Study ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Cancer Patients ◽

Major Bleeding ◽

Research Funding ◽

Advisory Committees ◽

Patients With Cancer ◽

Recurrent Vte ◽

Support Research

Introduction Venous thromboembolism (VTE) is a difficult to treat condition in patients with cancer with a persisting risk of recurrent VTE during anticoagulant treatment with low-molecular weight heparin (LMWH). Recent data suggest that direct oral anticoagulants (DOACS) are associated with a lower risk of recurrence but a higher risk of bleeding in these patients. Predicting the risk of recurrent VTE with LMWH may help to select the best treatment option. We conducted a prospective multicenter observational cohort study in cancer patients with VTE treated with tinzaparin for 6 months in order to validate the Ottawa score (NCT03099031) and search for additional risk of recurrent VTE. The Ottawa score is composed of 5 variables, female sex (+1), lung cancer (+1), breast cancer (-1) cancer stage 1 (-2) and previous DVT (+1). A score ≤0 is associated with a low risk of recurrent VTE. Methods Adult cancer patients with recent diagnosis of documented symptomatic or incidental VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE) treated with tinzaparin for 6 months were included in the study. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment with tinzaparin. Other endpoints were symptomatic recurrent VTE, major bleeding, heparin induced thrombocytopenia (HIT), all-cause mortality within 3 and 6 months. All events were adjudicated by a Central Adjudication Committee. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. Cumulative incidences were presented with corresponding 95% confidence interval (95% CI). To validate the Ottawa score, the area under the curve (AUC) and its 95% CI were calculated on receiver operating characteristic (ROC) curve analysis; the most discriminant cut-off was then determined by calculating the Youden index. Univariate and multivariate analyses were performed to identify additional predictive factors of recurrent VTE to those included in the Ottawa score using the Fine and Gray method and adjusted on factors included in the Ottawa score. Hazard ratio and their 95% CI were calculated. Results A total of 409 patients were included and analyzed on an intention-to-treat basis; the median age was 68 years and 51% of patients were males. 60.4% of patients had a PE (with or without DVT) .64% received chemotherapy at inclusion or in the month before inclusion. Lung (31.3%) and digestive track (18.3%) cancers were the most common cancer types and 67.0% had stage IV cancers. According to Ottawa score, 58% of patients were classified at high clinical probability of recurrence (score ≥ 1). During the 6 months treatment period, 23 patients had a recurrent VTE, yielding a cumulative incidence of 6.1% (95% CI 4.0-9.3) with a median time for recurrent VTE of 33 days. The recurrence rate of VTE was estimated to 7.8% (95% CI 4.9-12.5) for patients classified at high risk of recurrence according to the Ottawa score (score ≥ 1) compared to 3.8% (95%CI 1.6-8.9) for other patients (Ottawa score < 1). AUC of the Ottawa score was 0.60 (95% CI 0.55-0.65). In multivariable analysis, none of the potential risk factors for recurrent VTE was significantly associated with recurrent VTE at 6 months. During the 6 months treatment period, 15 patients had a major bleeding and 2 patients experienced a HIT. At 3 and 6 months, 104 and 144 patients had died yielding a cumulative incidence of 26.1%, (95% CI 21.8-30.4) and 37.8% (95% CI 32.8-42.9), respectively. The main cause of death was underlying cancer. Conclusion In this prospective cohort of patients with cancer receiving LMWH for VTE, the Ottawa score did not accurately predict recurrent VTE. No other clinical predictor of recurrent VTE was identified in this study. Disclosures Meyer: Bayer: Other: travel support; LEO pharma: Other: travel support, Research Funding; SANOFI: Other: travel support, Research Funding; BMS-Pfizer: Other: travel support, Research Funding; Boehringer Ingelheim: Research Funding. Girard:Leo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Scotté:LEO Pharma A/S: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Tesaro: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; MSD: Honoraria, Research Funding, Speakers Bureau; Pierre Fabre Oncology: Honoraria, Research Funding, Speakers Bureau. Lamblin:Leo Pharma: Employment. Laporte:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boston scientific: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo-Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Frequency of Arterial Thromboemobolic Events in Patients with Cancer Associated Venous Thromboembolism

Blood ◽

10.1182/blood-2020-136101 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Doaa Attia ◽

Xuefei Jia ◽

Mailey L Wilks ◽

Barbara Tripp ◽

Christopher D'Andrea ◽

...

Keyword(s):

Myocardial Infarction ◽

Ischemic Stroke ◽

Venous Thromboembolism ◽

Cancer Patients ◽

Cumulative Incidence ◽

Arterial Thrombosis ◽

Research Funding ◽

Patients With Cancer ◽

Peripheral Arterial

Background:Patients with cancer are at high risk of both venous thromboembolism (VTE) and arterial events, however, little is known about the association between venous and arterial thromboembolic events in patients with cancer. In this study, we evaluated the incidence and relative risk of subsequent arterial thromboembolism in patients with a confirmed diagnosis of acute cancer-associated VTE. Methods:We conducted a retrospective cohort study at the Cleveland Clinic Taussig Cancer Institute of cancer patients with confirmed VTE who were referred to a centralized thrombosis clinic between January 2017-October 2019 with at least 6 months of follow-up. Arterial thrombotic events (ATE), including myocardial infarction, peripheral arterial thrombosis, and ischemic stroke, were identified by manual review of electronic medical records. The cumulative incidence rate of each ATE event was calculated. Results:The study population comprised 294 patients with a median age of (63.5) years (range 27-90), and 49.7 % were male. The cumulative incidence rate of overall ATE during the 6-month, 1-year, and 2-year follow-up period was 3.07%, 3.42%, and 3.42%, respectively. A total of 10 patients who experienced arterial events of whom 7 had ischemic stroke, 2 had myocardial infarction, 2 had peripheral arterial thrombosis where one patient had two arterial events of myocardial infarction and peripheral arterial thrombosis(Table 1 shows the incidence rates of arterial events). Amongst patients with ATE, 30 % were active smokers (n=3), 90% had hypertension (n=9), 20% had diabetes mellitus (n=2), 50% had a family history of coronary artery disease (n=5), 40% were on statin and daily aspirin use (n=4), 40% were obese with BMI >30 (n=4). 40% of ATE patients(n=4) were on a therapeutic anticoagulant therapy at the time of arterial thrombotic event (3 on enoxaparin, 1 on apixaban) Conclusion:Cancer patients with acute VTE have a substantial increased risk of subsequent arterial thromboembolism particularly in the first six months after VTE. Ischemic stroke was the most frequent arterial event and ATE events occured despite therapeutic anticoagulation in a large subset of our cohort. Further prospective studies are needed to better understand the risk of ATE in cancer patients, and further studies should be designed to mitigate the risk of arterial events in this patient population. Disclosures McCrae: Momenta Pharmaceuticals:Consultancy;Novartis:Honoraria;Rigel:Consultancy;Dova:Consultancy.Khorana:Pharmacyclics:Honoraria;Pharmacyte:Honoraria;Seattle Genetics:Honoraria;Leo Pharma:Honoraria;Medscape:Honoraria;Sanofi:Honoraria;Pfizer:Honoraria;Bayer:Honoraria;Janssen:Honoraria;Array:Other: Research funding (to institution);Merck:Research Funding;BMS:Honoraria, Research Funding;Leap:Research Funding.

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Direct Oral Anticoagulants (DOACs) Vs. Low Molecular Weight Heparins (LMWH) for Venous Thromboembolism (VTE) in Patients with Primary Brain Tumors or Secondary Brain Metastases

Blood ◽

10.1182/blood-2020-138635 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-6 ◽

Cited By ~ 1

Author(s):

Angela Lee ◽

Frank Oley ◽

Mimi Lo ◽

Richard Fong ◽

Mary McGann ◽

...

Keyword(s):

Cohort Study ◽

Brain Tumors ◽

Brain Metastases ◽

Major Bleeding ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Minor Bleeding ◽

Bleeding Events ◽

Primary Brain Tumors ◽

Recurrent Vte

Background: Management of venous thromboembolism (VTE) in patients with central nervous system (CNS) malignancies is challenging as there is an increased risk of recurrent VTE and intracranial hemorrhage (ICH). Low molecular weight heparins (LMWH) have historically been the standard of care for treatment of cancer-associated thrombosis (CAT). Current guidelines recommend direct oral anticoagulants (DOACs) for CAT treatment, but patients with CNS malignancies have limited representation in the supporting clinical trials. This multicenter, retrospective cohort study evaluated the safety and efficacy of DOACs compared to LMWH for CAT in patients with primary brain tumors or secondary brain metastases. Patients/Methods: In this multicenter, retrospective cohort study, adult patients with a diagnosis of primary brain tumor or secondary brain metastases who received either a DOAC or LMWH for CAT were evaluated. The primary outcome was the incidence of any bleeding event within a 6-month period following the initiation of anticoagulation. Secondary outcomes included incidence of recurrent VTE events, major bleeding, clinically relevant non-major bleeding (CRNMB), and minor bleeding, within a 6-month period following the initiation of anticoagulation. Patients were excluded if their indication for anticoagulation was stroke, non-cancer-associated VTE, or VTE prophylaxis, were on LMWH for one week or less while bridging to warfarin, or received a diagnosis of VTE at an outside hospital. All bleeding events were defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Primary and secondary outcomes were analyzed using Fisher's exact test for categorical variables and Wilcoxon rank-sum tests for non-parametric continuous variables. Results: Between January 1, 2012 to October 9, 2019, one-hundred eleven patients met inclusion criteria. Of the patients who met inclusion criteria, 26 (23.4%) patients had primary brain tumors and 85 (76.6%) patients had secondary brain metastases. Bleeding events occurred in 7 of 55 patients (12.7%) in the DOAC group compared to 13 of 56 (23.2%) patients in the LMWH group (RR 0.55, 95% CI 0.24-1.27). Recurrent VTE events occurred in 3 of 55 (5.5%) patients in the DOAC group compared to 3 of 56 (5.4%) patients in the LMWH group (RR 1.02, 95% CI 0.21-4.83). Major bleeding occurred in 3 of 55 (5.5%) patients in the DOAC group, compared to 4 of 56 (7.1%) patients in the LMWH group (RR 0.76, 95% CI 0.18-3.26). There were no differences in the rates of CRNMB and rates of minor bleeding between groups. Conclusion: In this multicenter retrospective cohort study, therapeutic anticoagulation with DOACs showed no significant difference in bleeding events or recurrent VTE events when compared to LMWH, in patients with primary brain tumors or secondary brain metastases. We conclude that DOACs may be potentially safe and efficacious for VTE treatment in patients with primary brain tumors or secondary brain metastases. As prescribing practices are expected to continue to shift towards DOACs, this study provides preliminary evidence of the safety of DOACs in this high-bleeding risk patient population. Disclosures No relevant conflicts of interest to declare.

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