Cancer-Associated Thrombosis: Anatomic Distribution of the Index Event Is Not a Reliable Predictor of Recurrence Risk

Abstract Introduction: Cancer associated thrombosis (CAT) is a common complication of cancer, associated with significant morbidity and mortality. While incidence varies with cancer type, stage, chemotherapy, and other factors, estimates are that up to 20% of cancer patients will experience at least one venous thromboembolic (VTE) episode. VTE consist of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and there is a spectrum of vascular involvement. DVTs are classified as proximal (popliteal vein or above) and PE may be subsegmental, segmental, lobar, main, or saddle embolism. Our standard approach has been to treat all DVTs and all PEs in cancer patients, regardless of the size of the involved vessel. However, it is not clear if the risk of recurrent VTE in a patient with a "small" subsegmental PE, or a calf vein DVT, is comparable to that of an individual with a larger vascular involvement. In this study, we characterized the largest vessel involved in the initial VTE episode, and the relationship with recurrent VTE. Methods: All patients at MSKCC with CAT are monitored within an existing Quality Assessment initiative. From 1/1/2014 through 10/31/2016, 1072 patients with CAT were treated with rivaroxaban (Riva). (The overall outcomes of this cohort are the subject of a separate abstract.) In this study we compared the rate of recurrent VTE in patients with a distal (calf) DVT with proximal DVT, and PE. We designated the most proximal, or largest thrombosed vessel. As patients with a PE do not routinely undergo Doppler leg ultrasound, we are unable to differentiate PE with a DVT from those without. We also analyzed if the PE was unilateral or bilateral. We used competing risk endpoints for the purpose of this analysis, including recurrent VTE, major bleeding, clinically relevant non-major bleeding leading to discontinuation of Riva, and death. Results: In the Table, we present the data on the relationship of the initial VTE and the risk of recurrence. The majority of CAT events (55%) were PE. There were no significant differences in the rates of recurrent VTE between patients with a PE, a distal DVT or proximal DVT. Within patients with a PE as the index VTE event, there was no significant association between the risk of recurrent VTE and the size of the PE. A subsegmental PE as an index event was associated with a comparable rate of recurrent VTE when compared with segmental and more proximal vessel involvement. The only meaningful trend towards a higher rate of recurrent VTE was in patients whose index event was a bilateral PE, compared with unilateral, although this association did not reach statistical significance. Conclusions: The goal of this Quality Assessment initiative was to evaluate the risk of recurrent VTE in cancer patients to determine if distal DVT's or subsegmental PEs had a significantly lower rate of recurrence than other VTE episodes. Our analysis indicated that the risk of recurrent VTE is not related to the size of the index thrombosed vessel. Within PE, from large, proximal index events through to subsegmental PE, the risk of recurrent VTE is comparable. Similarly, there was only a trend towards lower risk of recurrent VTE in patients with an index distal DVT, versus proximal DVT. But this association was not statistically significant, with overlapping 95% confidence intervals. The one parameter that appeared to have the strongest prediction of recurrent VTE was patients with bilateral PE, versus unilateral. However, this too was only a trend, not statistically significant, and was not one of the parameters within our initial hypotheses. We were unable to identify any subgroup of index VTE, based on vessels involved, that had a significantly lower rate of recurrent VTE while on anticoagulation. Within cancer patients, a subsegmental PE or a distal, calf vein DVT are associated with a risk of recurrent VTE comparable to thrombosis of larger vessels. Table Table. Disclosures Soff: Janssen: Research Funding; Amgen: Research Funding. Mantha:Janssen: Research Funding; GLG: Consultancy; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy.

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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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Evaluation of Rivaroxaban and Dalteparin in Cancer Associated Thrombosis

Blood ◽

10.1182/blood.v126.23.432.432 ◽

2015 ◽

Vol 126 (23) ◽

pp. 432-432

Author(s):

Ateefa Chaudhury ◽

Asha Balakrishnan ◽

Christy Thai ◽

Bjorn Holmstrom ◽

Michael V. Jaglal

Keyword(s):

Cancer Patients ◽

Anticoagulant Therapy ◽

Major Bleeding ◽

Cancer Center ◽

Minor Bleeding ◽

Efficacy And Safety ◽

Recurrent Vte ◽

Chi Square Analysis ◽

Cancer Associated Thrombosis ◽

Active Cancer

Abstract Introduction: Venous thromboembolism (VTE) in the form of deep venous thrombosis (DVT) or pulmonary embolism (PE) is a complication of malignancy. Several studies have demonstrated the superiority of dalteparin (Fragmin®), a low molecular weight heparin (LMWH), in comparison to oral vitamin K antagonists in preventing VTE recurrence in the setting of active cancer. LMWH is the preferred treatment of cancer associated thrombosis. However, the cost of LMWH can be prohibitive and the need for daily subcutaneous injections can decrease patients' quality of life. While rivaroxaban (Xarelto®), a Factor Xa inhibitor, has been approved for the treatment and secondary prevention of DVT and PE, there is limited data regarding its use in cancer patients. The objective of our study is to determine the efficacy and safety of rivaroxaban compared to dalteparin in cancer associated thrombosis. Methods: This is a retrospective chart review of cancer patients greater than age 18 treated at H. Lee Moffitt Cancer Center between May 3, 2010 and June 30, 2015 on anticoagulation with rivaroxaban or dalteparin. Patients were excluded if the length of anticoagulant therapy was < 30 days, anticoagulant therapy was initiated > 6 months after VTE diagnosis, the indication for treatment was not DVT/PE, if patients had contraindications to either LMWH or rivaroxaban, or patients were not on treatment doses of therapy. Out of 459 patients identified, 226 patients (107 in the rivaroxaban group, and 119 in the dalteparin group) were eligible for analysis based on our exclusion criteria. Efficacy was determined by the incidence of recurrent VTE, such as recurrent DVT, new fatal or non-fatal PE within 30 days. The secondary endpoint of the study was to determine the safety of rivaroxaban compared to dalteparin in cancer patients for the treatment of VTE. Safety was determined by the incidence and severity of bleeding. Major bleeding was defined as clinically overt if it was associated with a fall in hemoglobin of 2 g/dL or more, required transfusions of ≥ 2 units of packed red blood cells, involved retroperitoneal, intracranial, or critical site bleeding, or if it contributed to death. Minor bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of anticoagulation treatment, or associated with any other discomfort such as pain or impairment of activities of daily life. Descriptive statistical analyses were utilized. Chi square analysis and t- test were performed to compare categorical and continuous variables. All data was analyzed using SPSS version 21.0 statistical software. Results: Rivaroxaban had a similar rate of DVT and PE failure with 1 event versus 2 with dalteparin (p = 0.625). The rivaroxaban group had 0 major and 8 minor bleeds compared to 3 major and 8 minor bleeds in the dalteparin group with p values of 0.09 and 0.86 respectively. Comorbidities and risk factors for thrombosis were similar in both groups as summarized in Table 1. Table. Rivaroxaban vs. Dalteparin: No Significant Differences in the Efficacy and Safety Profile in Cancer Associated Thrombosis RivaroxabanN = 107 DalteparinN =119 P value DVT Failure within 30 days 1 (0.93%) 2 (1.68%) 0.625 PE Failure within 30 days 1 (0.93%) 1 (0.84%) 0.94 Major Bleeding 0 (0 %) 3 (2.5%) 0.09 Minor Bleeding 8 (7.5%) 8 (6.7%) 0.864 Median Age (Yrs) 61 65 0.93 MaleFemale 58 (54.2%) 49 (45.8%) 60 (50.4%) 59 (49.6%) 0.596 Active Cancer 96 (86.5%) 111 (93.2%) 0.350 Surgery within 30 Days 14 (13.1%) 13 (10.9%) 0.684 Hypertension 58 (54.2%) 61 (51.3%) 0.69 Diabetes 14 (13.1%) 14 (11.8%) 0.84 Coronary Artery Disease 6 (5.61%) 11 (9.2%) 0.326 History of Previous DVT 12 (11.2%) 5 (4.2%) 0.074 BMI >30 39 (36.4%) 48 (40.3%) 0.585 Creatinine Clearance (Cr Cl) 30 - 50 Cr Cl 50 - 70 7 (6.5%) 100 (93.3%) 7 (5.9%) 112 (94.1%) 0.837 Conclusions: Our study evaluated the safety and efficacy of rivaroxaban compared to dalteparin in patients with predominantly active cancer treated at a large comprehensive cancer center and found rivaroxaban to be comparable to dalteparin in this cohort. There were no significant differences in regards to recurrent VTE or major/minor bleeding with patients on rivaroxaban or dalteparin in our cohort of patients. Large randomized trials evaluating the efficacy and safety of rivaroxaban in the oncology population are needed to further validate our findings. Disclosures No relevant conflicts of interest to declare.

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Patients with Cancer Who Develop a First Venous Thromboembolic Event After Surgery Are at High Risk of Venous Thromboembolism Recurrence During the Anticoagulation Period

Blood ◽

10.1182/blood.v116.21.4202.4202 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4202-4202

Author(s):

Martha L Louzada ◽

Alejandro Lazo-Langner ◽

Marc Carrier ◽

Vi Dao ◽

Jerry Zhang ◽

...

Keyword(s):

Cancer Patients ◽

Research Funding ◽

Recurrence Risk ◽

Major Surgery ◽

Group Index ◽

Patients With Cancer ◽

Significant Difference ◽

Recurrent Vte ◽

Cancer Associated Thrombosis ◽

Similar Risk

Abstract Abstract 4202 Background: It is unknown whether patients with cancer who develop VTE after a surgical procedure have the same risk of recurrent VTE as clinical patients cancer-associated thrombosis. VTE recurrence risk in non-cancer patients with VTE after surgery is approximately 1% in the 3 months following completion of anticoagulation. It is unknown whether surgical patients with cancer follow the low risk of recurrence as other provoked VTEs or whether they have the high recurrence risk typical of cancer patients. Methods: We performed a post-hoc analysis of a single centre retrospective cohort study conducted at the Thrombosis Unit of the Ottawa Hospital. The charts of patients with cancer and VTE followed from 2002 to 2004 and from 2007 to 2008 were reviewed. We sought to compare the risk of recurrent VTE between patients with cancer who developed a first VTE after major surgery with all other patients with cancer-associated thrombosis. We included patients > or = 18 years of age with active malignancy and objectively diagnosed index VTE [pulmonary embolism (PE), proximal deep venous thrombosis (DVT) of the legs or arms, PE + DVT; unusual site thrombosis]. After the first VTE, all patients received a minimum of 6 months of anticoagulation. In the surgery group, index VTE was considered associated with the intervention if it occurred within the first 3 months after the procedure. Results: 543 patients were included. 121 patients had VTE after surgery and 17 (13.1%) developed a recurrence during therapeutic anticoagulation. Of 422 clinical patients, 61 (14.7%) had a recurrent VTE (Table). The relative risk of recurrent VTE comparing patients who had and who did not have surgery was non-significant (RR= 0.97 (95%CI: 0.587 – 1.574; p= 1.000) suggesting that patients with cancer who undergo surgery have similar risk of developing a recurrent VTE during anticoagulation as patients with cancer-associated VTE who do not undergo surgery. VTE recurrence occurred predominantly within the first 6 months of anticoagulation [Surgery: 9 of 17 patients (52.9 %); no surgery: 45 of 61 (73.7%) patients (p=0.1377)] (Figure). There was no significant difference in VTE recurrence risk according to anticoagulant strategy, tumor site, histology, TNM stage, age or gender between surgery and no surgery groups. Conclusion: Patients with cancer who develop VTE after surgery have similar risk of developing a recurrent VTE during the anticoagulation period as clinical patients with cancer-associated VTE. Disclosures: Rodger: Pfizer: Research Funding; Leo Pharma: Research Funding; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Institutes of Health Research: Research Funding; Heart and Stroke Foundation: Research Funding.

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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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Safe and Effective Use of Rivaroxaban for Treatment of Cancer-Associated Venous Thromboembolic Disease: A Quality Improvement Initiative

Blood ◽

10.1182/blood.v126.23.431.431 ◽

2015 ◽

Vol 126 (23) ◽

pp. 431-431 ◽

Cited By ~ 2

Author(s):

Simon Mantha ◽

Yimei Miao ◽

Debra Sarasohn ◽

Jonathan Kessler ◽

Rekha Parameswaran ◽

...

Keyword(s):

Lower Extremity ◽

Cancer Patients ◽

Major Bleeding ◽

Clinical Pathway ◽

Bleeding Risk ◽

Event Type ◽

Patients With Cancer ◽

Recurrent Vte ◽

Cancer Associated Thrombosis ◽

Low Rate

Abstract Background: Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. LMWH injections are painful and costly. Rivaroxaban, an oral direct factor Xa inhibitor, was FDA approved in 2012 for treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but there has been a knowledge gap for its use in patients with cancer-associated thrombosis (CAT). Under a Quality Assurance Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT, and began to offer rivaroxaban as an alternative to enoxaparin, in January 2014, for patients who met appropriate clinical criteria. We are tracking all cancer patients with PE or symptomatic proximal DVT, whose full course of anticoagulation is with rivaroxaban (allowing up to 3 days of initial parenteral anticoagulation). We now report the characteristics of the first 200 patients, and an outcome analysis of our first 100 patients, who have been treated for at least 6 months or otherwise reached an endpoint. Materials and Methods: The Clinical Pathway guidelines will be available on request, pending publication. Patients were not treated with rivaroxaban if they had active gastrointestinal or genitourinary lesions, or had undergone gastric resection due to anticipated excess bleeding risk or reduced absorption. This excluded under 5% of patients. The Pathway provided dosing guidelines in the setting of thrombocytopenia, advanced age, transient renal, or hepatic dysfunction. Primary endpoints include new or recurrent PE, symptomatic proximal lower extremity DVT, major bleeding (ISTH definition), clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. Considering those outcomes as competing risks, the cumulative incidence of each event type was calculated using R 3.2.0 for Windows and package "Survival". Results: The characteristics of our first 200 patients are in Table 1. 70% of the patients had PE. Of the solid tumor patients, 65.6% had metastatic disease. The first 100 patients have completed at least 6 months of rivaroxaban anticoagulation or otherwise reached a primary endpoint. At 6 months, the cumulative incidence of death was 14.4% (95% CI=6.8-21.4%), new or recurrent VTE was 4.3% (95% CI=0.1-8.4%), major bleeding was 1.1% (95% CI=0-3.1%), and clinically relevant non-major bleeding leading to rivaroxaban discontinuation was 7.9% (95% CI=2.1-13.3%). Conclusions: In the analysis of the first 100 patients entered into our QAI program, the rates of major bleeding, and new or recurrent VTE compare favorably to two published studies of LMWH for treatment of cancer associated thrombosis. In the CLOT study (Lee et al, NEJM, 2003) and the Daltecan study (Francis et al, JTH, 2015), the 6-month rates of new or recurrent VTE were approximately 9%, and the rates of major bleeding were 6% and 9.5% respectively. Our final analysis awaits the completion of 6 months follow-up on 200 patients, to be completed in December 2015. But the rates of major bleeding and recurrent VTE at this point suggest safety and efficacy to be at least non-inferior to LMWH, with the advantage of reduced patient burden, and support the ongoing use of our Clinical Pathway. Our low rate of major bleeding likely is influenced by the exclusion of patients with active GI or GU lesions, who would be expected to have a high bleeding risk with an oral direct anticoagulant. However, we estimate this excluded less than 5% of cancer patients with VTE. Further, we anticipated reduced drug clearance in the elderly, and used a reduced dose for patients greater than 75 years of age. This appeared to be associated with no loss in efficacy, and helped maintain a low rate of major bleeding. A randomized trial is the optimal approach to establish non-inferiority or superiority of rivaroxaban to LMWH for cancer associated thrombosis. However, our QAI Clinical Pathway provides guidance and reassurance for rivaroxaban use until a randomized trial is conducted. Table. Baseline Characteristics of Patients Characteristic Number of Individuals Gender Male 82 Female 118 Event Type PE, with or without DVT 140 Proximal, Symptomatic Lower extremity DVT 60 Cancer Type Solid Tumor 186 Hematologic Malignancy 14 Cancer Stage (Of Solid Tumors) No Evidence of Disease (Post-Cancer Surgery) 11 (5.9%) 1 1 (0.5%) 2 4 (2.2%) 3 16 (8.6%) 4 122 (65.6%) Unknown 32 (17.2%) Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Is Anaemia Another Bleeding Risk in Cancer-Associated-Thrombosis?

Blood ◽

10.1182/blood-2020-136069 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-15

Author(s):

Nicolas Janus

Keyword(s):

Red Blood Cells ◽

Cancer Patients ◽

Major Bleeding ◽

Blood Cells ◽

Research Funding ◽

Bleeding Risk ◽

Risk Of Bleeding ◽

Definition Of ◽

Cancer Associated Thrombosis ◽

The Impact

INTRODUCTION AND AIMS: Anaemia is very common in cancer patients. However, the impact of anaemia in venous thromboembolic (VTE) patients on the risk of bleeding is not well-known. Consequently, the question of the impact of anaemia in cancer-associated-thrombosis (CAT) patients is important. METHODS: All the literature (PubMed) was reviewed about the potential links between cancer, CAT and anaemia. However, there were no dedicated studies on this topic. Furthermore, the WHO definition of anaemia was the one used in most of the publications RESULTS: Several studies investigated about all the risks of bleeding/VTE in atrial fibrillation and VTE patients, including anaemia. Most of them reported that anaemia exposed VTE patients to a higher risk of bleeding. The COMMANDER study, evaluated the influence of anaemia in VTE patients and reported that VTE patients with mild and moderate/severe anaemia had higher risk for major bleeding and that the risk for major bleeding increased according to the severity of anaemia. The RIETE (Registro Informatizado Enfermedad Tromboembólica) reported that anaemia was found in 57% of the patients with cancer and in 28% without cancer (odds ratio 3.46; 95% CI 3.33-3.60), exposing to a higher risk of major bleeding. The same registry reported also that in CAT patients, anaemia had a two-fold higher rate of major bleeding and fatal bleeding than CAT patients without anaemia. This link between anaemia and bleeding in cancer patients are multifactorial. Indeed, there are both quantitative and qualitative changes in red blood cells that could affect bleeding and thrombosis, as well as interactions of red blood cells with cellular and molecular components of the haemostatic system. Indeed, for example, low haematocrits are associated with bleeding. Finally, it is interesting to notice that there is a gap between the definition of anemia in CAT patients when compared to not CAT cancer patients. Indeed, WHO definition is quite common in VTE and CAT patients but EORTC/NCCN are used in cancer patients for several reasons. As a consequence, it could be important to align on this point. CONCLUSIONS: Anaemia, cancer and thrombosis are closely linked. It is important to screen and manage both anaemia in CAT patients because of the increased risk of bleeding. Consequently, it is important to consider this bleeding risk in CAT patients before initiating an anticoagulants treatment or prophylaxis in cancer patients. Disclosures Janus: Bayer:Honoraria, Research Funding;Pierre Fabre Oncology:Research Funding;Novartis:Honoraria;Gilead:Honoraria, Research Funding;Vifor Pharma:Honoraria, Research Funding;Fresenius Medical Care:Honoraria;Amgen:Honoraria, Research Funding;B-Braun:Honoraria;Guerbet:Research Funding;TEVA:Research Funding;IPSEN:Honoraria;Pfizer:Consultancy, Honoraria;Roche:Honoraria, Research Funding;Daichii-Sankyo:Honoraria, Research Funding;LEO Pharma A/S:Current Employment, Honoraria.

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Use of Anticoagulants of Patients with Cancer-Associated Thrombosis Beyond 6 Months ; The Uscat Study, a 432-Patient Retrospective Non-Interventional Study

Blood ◽

10.1182/blood-2019-124745 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3664-3664

Author(s):

Isabelle Mahe ◽

Ludovic Plaisance ◽

Céline Chapelle ◽

Silvy Laporte ◽

Benjamin Planquette ◽

...

Keyword(s):

Board Of Directors ◽

Major Bleeding ◽

Cumulative Incidence ◽

Treatment Duration ◽

Research Funding ◽

Anticoagulant Treatment ◽

Advisory Committees ◽

Index Event ◽

Cancer Associated Thrombosis ◽

Support Research

Introduction Few data are available about the treatment and complications beyond 6 months and up to 12 months in Cancer-associated Thrombosis (CAT) patients initially treated with low-molecular-weight (LMWH). Study objectives were to document the prescription and use of the anticoagulant treatment beyond 6 months and up to 12 months in CAT patients initially treated with tinzaparin and to measure clinical outcomes. Methods Adult CAT patients with solid tumor, previously included in 2 prospective cohort studies (AXA - NCT02898051; PREDICARE - NCT03099031) and still alive at the end of the initial 6-month treatment period with tinzaparin were eligible to participate in this retrospective non-interventional French multicenter study. Main study outcome was the description of the anticoagulant treatment in the management of CAT patients in usual medical care from the 6th month to the 12th month. Secondary objectives included the incidence of VTE recurrence, bleeding and deaths. A sample size of 250 to 300 patients was considered appropriate to allow analyses of 6-to-12-month data post-index event based on descriptive statistics. Results A total of 432 patients aged 66.5±12.7 years of whom 52.1% female alive at the end of AXA and PREDICARE 6-month treatment period were included in this retrospective study; 332 patients were followed up to 12 months while 96 patients deceased before the end of the study and 4 patients were lost-to-follow-up. Most patients (91.9%) had a single-site cancer. Cancers were mostly solid tumors and primary sites were colorectal (21.6%), lung (20.1%) or breast (16.8%); a proportion of 82.1% of patients had stage III or IV malignancy while cancer was progressing in 51.2% of patients. Beyond 6 months, the anticoagulant treatment was maintained in 290 of 421 (68.9%) patients of whom 241 (83.1% [95% CI: 78.3%; 87.2%]) patients were treated with a LMWH and 233 (80.3%) with tinzaparin, 32 (11.0%) and 13 (4.5%) patients were treated with vitamin K antagonists (VKA) and direct oral anticoagulants (DOAC), respectively. The anticoagulant treatment was discontinued in 131 of 421 (31.1%) patients of whom 63 patients had already stopped the anticoagulant before 6 months while 68 patients stopped the anticoagulant treatment at 6 months. Mean treatment duration with LMWH beyond 6 months was 121.6 ± 65.6 days representing a mean total treatment duration of 288.4 ± 85.0 days since the index event. Between 6 and 12 months, 24 (5.7%) patients experienced a VTE recurrence corresponding to a cumulative incidence of 8% [95% CI: 4.2%; 15.1%], while 11 (2.7%) patients had a major bleeding corresponding to a cumulative incidence of 2.6% [95% CI: 1.3%; 5.1%]. VTE recurrence was more frequent in patients with colorectal and lung cancer while major bleeding was more frequent in patients with colorectal cancer (Table) A total of 96 (22.3%) deaths corresponding to a cumulative incidence of 30.7% [95% CI: 22.3%; 30.7%] were reported of which 55 (12.8%) related to cancer, 1 (0.2%) to bleeding and 8 (1.9%) to another cause while the cause of death was not documented for 32 (7.5%) patients. Clinical outcomes according the type of cancer are summarized in the Table. Conclusion These results reporting the clinical course up to 12 months of a large cohort of patients still alive at the end of the initial 6-month period following the VTE index event, provide data contributing to the clinician's therapeutic decision when facing a patient completing 6 months of anticoagulant for a CAT. Site of cancer has to be taken into account when assessing the risk of subsequent VTE recurrence and bleeding. Disclosures Mahe: BMS: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; LEO Pharma: Research Funding, Speakers Bureau; Bayer: Speakers Bureau. Laporte:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: 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; Leo-Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: 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; 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. Bertoletti:Sanofi: Research Funding, Speakers Bureau; BMS-Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Aspen: Consultancy, Speakers Bureau. Couturaud:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Falchiero:Astra-Zeneca: Consultancy; MSD: Consultancy; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Amgen: Consultancy; Roche: Speakers Bureau. Falvo:Medtronic: Consultancy; Toshiba: Consultancy; Leo-Pharma: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Bayer: Consultancy. Meyer:Bayer: Other: travel support; Boehringer Ingelheim: Research Funding; LEO pharma: Other: travel support, Research Funding; SANOFI: Other: travel support, Research Funding; BMS-Pfizer: Other: travel support, Research Funding.

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Tinzaparin Is Effective and Safe for the Treatment and Extended Secondary Prophylaxis In Cancer Patients with Venous Thromboembolism.

Blood ◽

10.1182/blood.v116.21.1104.1104 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1104-1104 ◽

Cited By ~ 1

Author(s):

Scott T Tagawa ◽

Ilene c Weitz ◽

Casey L. O'Connell ◽

Leanne Rochanda ◽

Mckenna Archer ◽

...

Keyword(s):

Cancer Patients ◽

Major Bleeding ◽

Initial Treatment ◽

Research Funding ◽

Patient Survival ◽

Pharmaceutical Research ◽

Secondary Prophylaxis ◽

Bleeding Events ◽

Recurrent Vte ◽

Major Bleeding Events

Abstract Abstract 1104 Background: Venous thromboembolism (VTE) is a major complication in cancer patients. The traditional treatment algorithm for VTE of UF or LMW heparin followed warfarin is associated with a higher risk of recurrent VTE and bleeding in cancer patients. A recent randomized trial has demonstrated that initial treatment and secondary prophylaxis with LMWH is associated with a lower VTE recurrence when compared to secondary prophylaxis with warfarin. We initiated a single arm Phase 2 IRB approved study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis (6 months) of VTE in cancer patients. Included in this study was a prospective analysis of plasma biomarkers to assess whether any biomarkers could predict treatment failure or be predictive of patient survival. Methods: Patients (pts)with objectively confirmed symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) or unexpected PE detected on staging CT scans by the criteria of OConnell et al. (JCO 24:4928, 2006) were eligible for this study, if they had an ECOG score <2 and an estimated 6 month survival. After informed consent, treatment was initiated with tinzaparin 175 U/Kg for 6 months. Planned enrollment was 100 pts. Pts who completed the 6 month study could continue on treatment for an additional 6 months if clinically appropriate. All pts who received at least one injection of tinzaparin were evaluable for efficacy and safety. Study endpoints were objectively confirmed DVT, PE or major bleeding events. Serial blood samples were obtained prior to treatment, at 1 wk, 1 month, 3 months and 6 months. Biomarkers to be studied included D-dimer (D-D), Thrombin-antithrombin complex (TAT), interleukin 6 and 8 (Il-6, Il-8) and plasma tissue factor. Only pts in whom the pretreatment, I week and 1 month blood samples were collected were included in the biomarker analysis. Results: At time of this submission 91 pts were treated on study. Of 91 pts enrolled 39 (42.9%) have completed the 6 months and 5 (5.5%) remain on active treatment. Eight (8.8%) pts withdrew from study for hospice care and one pt was withdrawn due to poor compliance. Forty-two (46%) pts died before 6 months. Ten (11%) pts continued on treatment after 6 months and one pt transitioned to warfarin treatment. Treatment endpoints included 8 (8.8%) pts with recurrent VTE (5 DVT, 3 PE); 2 occurred within the first 4 wks on treatment and the 6 events before month 3. No recurrent VTE occurred after 12wks. Three pts (3%) had major bleeding events. There were no fatal thrombotic or bleeding events. All deaths were considered due to progressive cancer, although the possible fatal VTE in pts who died at home or in hospice could not be excluded. There were 76 (83.5%) pts were evaluable for the biomarker study. Biomarker data failed to show a correlation between the level of D-D, TAT or Il-6 and patient survival from the time of their thrombotic event. However, in pts who developed recurrent VTE after 1 month, the D-D level at month 1 was higher than the pretreatment in 4/6 (66.7%) patients compared to 8/70 (11.4%) pts with no recurrence in whom month 1 samples were obtained. Conclusion: In this prospective study of tinzaparin for initial treatment and secondary prophylaxis of cancer-associated VTE, treatment appeared both safe and efficacious. Our recurrent VTE event rate of 8.8% compares favorably with the 8% recurrent VTE reported in the pts treated with dalteparin. The 3% of patients who had major bleeding events also compares favorably with the CLOT trial. Survival was difficult to predict at the time of enrollment since 46% failed to survive the 6 months. Biomarker data failed to predict survival, but patients who recurred after the first month were more likely to have month 1 D-D levels greater than pretreatment. The reason for the failure of tinzaparin treatment to effectively suppress thrombin generation in these patients remains unexplained. Disclosures: Tagawa: Leo Pharmaceutical: Research Funding; Celgene: Research Funding. Liebman:Leo Pharmaceutical: Research Funding; Celgene: Research Funding.

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A Randomized Trial of Long-Term Tinzaparin, a Low Molecular Weight Heparin (LMWH), Versus Warfarin for Treatment of Acute Venous Thromboembolism (VTE) in Cancer Patients - the CATCH Study

Blood ◽

10.1182/blood.v124.21.lba-2.lba-2 ◽

2014 ◽

Vol 124 (21) ◽

pp. LBA-2-LBA-2 ◽

Cited By ~ 13

Author(s):

Agnes Y.Y. Lee ◽

Pieter W. Kamphuisen ◽

Guy Meyer ◽

Rupert Bauersachs ◽

Mette S. Janas ◽

...

Keyword(s):

Cancer Patients ◽

Major Bleeding ◽

Distant Metastasis ◽

Cumulative Incidence ◽

Research Funding ◽

Bleeding Events ◽

Open Label ◽

Once Daily ◽

Advisory Boards ◽

Recurrent Vte

Abstract Background Patients with cancer and VTE have a substantial risk of recurrent VTE. LMWH reduces the risk of symptomatic, recurrent VTE compared with warfarin and is recommended as the preferred anticoagulant by consensus guidelines. However, the evidence is based largely on a single, open-label randomized trial (CLOT; Lee et al NEJM 2003). Warfarin is still often used for the treatment of VTE in cancer patients worldwide. Methods The primary objective of this randomized, open-label, multicenter, Phase III trial (CATCH; NCT01130025) was to assess the efficacy of tinzaparin in preventing recurrent VTE in patients with active cancer and acute, symptomatic proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Patients were randomized (stratified by geographic region, tumor characteristic [distant metastasis, no distant metastasis, hematological malignancy] and history of VTE) to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 510 days overlapped and followed by dose-adjusted warfarin (target INR 2.03.0) for 6 months. The primary efficacy outcome was time to recurrent VTE verified by objective, standard imaging and blinded central adjudication; this was a composite primary endpoint that included symptomatic DVT and/or PE, incidental proximal DVT and/or PE and fatal PE. The primary safety endpoint was incidence of major bleeding. All patients were followed up to 6 months or death, whichever came sooner. Blinded central adjudication was also performed for all bleeding events and causes of death. A proportional hazards model for competing risks was applied to all randomized patients, treating all non-VTE-related deaths as competing events. An independent Data Safety Monitoring Board reviewed safety data at regular intervals. Results Nine hundred patients were included from 165 sites in 32 countries across 5 continents. Of these, 449 were randomized to tinzaparin and 451 to warfarin. Mean age was 59 years (range 1889); 59% female. A total of 77% of patients had a baseline ECOG performance status (PS) of 01 and 23% had a PS of 2. The most common primary tumor sites were gynecologic (23%), colorectal (13%), lung (12%), breast (9%); 10% had hematological malignancies. At the time of randomization, metastatic disease was present in 55% of patients and 44% had received prior cancer treatment (chemotherapy, surgery and/or radiation). Time-in-therapeutic range was 47% in the warfarin arm, with 27% above and 26% below the range. Over the 6-month trial period, 31 patients (6.9%) in the tinzaparin arm experienced recurrent VTE compared with 45 (10%) in the warfarin arm (hazard ratio [HR] 0.65 [95% CI 0.411.03; P=0.07]) (see figure). There were 2 patients with incidental VTE, both were in the warfarin arm. Symptomatic non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR 0.48 [95% CI 0.240.96]; P=0.04). Symptomatic non-fatal PE occurred in 3 patients in the tinzaparin arm and 2 in the warfarin arm; fatal PE occurred in 17 (3.8%) patients in each arm (HR 0.96 [95% CI 0.491.88]; P=0.90). There was no difference in the incidence of major bleeding events (n=13 [2.9%] in the tinzaparin arm and 12 [2.7%] in the warfarin arm), but significantly fewer patients experienced clinically relevant non-major bleeding with tinzaparin than warfarin (50 [11%] and 73 [16%] patients, respectively; P=0.03). No difference in mortality was seen with 6-month survival rates of 59% and 60%, respectively. Conclusions In cancer patients with symptomatic VTE, tinzaparin lowered the risk of recurrent VTE compared with warfarin, with a significant reduction in symptomatic DVT and clinically relevant non-major bleeding. No difference in major bleeding or overall mortality was observed. Figure. Cumulative incidence of recurrent VTE in the tinzaparin and warfarin groups. Figure. Cumulative incidence of recurrent VTE in the tinzaparin and warfarin groups. Disclosures Lee: Bayer: Advisory Boards Other, Honoraria; Bristol-Myers Squibb: Advisory Boards, Advisory Boards Other, Research Funding; Boehringer Ingelheim: Honoraria; Daiichi-Sankyo: Advisory Boards, Advisory Boards Other; Eisai: Research Funding; LEO Pharma: Advisory Boards Other; Pfizer: Advisory Boards Other, Honoraria, Research Funding; Sanofi-Aventis: Advisory Boards, Advisory Boards Other; Avivia: Advisory Boards, Advisory Boards Other. Kamphuisen:LEO Pharma: Honoraria, Research Funding. Meyer:Bayer: Research Funding; Boehringer Ingelheim: Research Funding; LEO Pharma: Research Funding; Sanofi-Aventis: Research Funding. Janas:LEO Pharma: Employment. Jarner:LEO Pharma: Employment. Khorana:LEO Pharma: Honoraria, Research Funding.

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Predictors of the Indefinite-Duration Anticoagulation Treatment Strategy In Patients with Cancer-Associated Thrombosis.

Blood ◽

10.1182/blood.v116.21.1097.1097 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1097-1097

Author(s):

David Spirk ◽

Wolfgang Korte ◽

Marc Husmann ◽

Beat Frauchiger ◽

Martin Banyai ◽

...

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Metastatic Disease ◽

Metastatic Cancer ◽

Anticoagulation Therapy ◽

Medical Attention ◽

Patients With Cancer ◽

Anticoagulation Treatment ◽

Recurrent Vte ◽

Cancer Associated Thrombosis

Abstract Abstract 1097 Background: In patients with cancer and acute venous thromboembolism (VTE), current consensus guidelines recommend anticoagulation therapy for an indefinite duration or until the cancer is resolved. Methods and results: Among 1’247 patients with acute VTE enrolled in the Swiss Venous Thromboembolism Registry (SWIVTER) from 18 hospitals, 315 (25%) had cancer of whom 179 (57%) had metastatic disease, 159 (50%) ongoing or recent chemotherapy, and 83 (26%) tumor surgery within 6 months. Patients with cancer were older (66±14 vs. 60±19 years, p<0.001), more often hospitalized at the time of VTE diagnosis (46% vs. 36%, p=0.001), immobile for >3 days (25% vs. 16%, p<0.001), and more often had thrombocytopenia (6% vs. 1%, p<0.001) than patients without cancer. The 30-day rate of VTE-related death or recurrent VTE was 9% in cancer patients vs. 4% in patients without cancer (p<0.001), and the rates of bleeding requiring medical attention were 5% in both groups (p=0.57). Cancer patients received indefinite-duration anticoagulation treatment more often than patients without cancer (47% vs. 19%, p<0.001), and LMWH mono-therapy during the initial 3 months was prescribed to 45% vs. 8%, p<0.001, respectively. Among patients with cancer, prior VTE (OR 4.0, 95%CI 2.0–8.0), metastatic disease (OR 3.0, 95%CI 1.7–5.2), outpatient status at the time of VTE diagnosis (OR 3.8, 95%CI 1.9–7.6), and inpatient treatment (OR 4.4, 95%CI 2.1–9.2) were independently associated with the prescription of indefinite-duration anticoagulation treatment. Conclusions: Less than half of the cancer patients with acute VTE received a prescription for indefinite-duration anticoagulation treatment. Recurrent VTE, metastatic cancer, outpatient VTE diagnosis, and VTE requiring hospitalization were associated with an increased use of this strategy. Disclosures: Spirk: sanofi-aventis (suisse) sa: Employment.

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