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

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

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Safety and Efficacy of Apixaban Thromboprophylaxis in Ambulatory Cancer Patients By Renal Function: A Subgroup Analysis of the Avert Trial

Blood ◽

10.1182/blood-2021-149681 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3229-3229

Author(s):

Tzu-Fei Wang ◽

Ranjeeta Mallick ◽

Marc Carrier ◽

Philip S. Wells

Keyword(s):

Renal Function ◽

Cancer Patients ◽

Major Bleeding ◽

Research Funding ◽

Performance Status ◽

Primary Efficacy ◽

Efficacy And Safety ◽

Bleeding Events ◽

Major Bleeding Events ◽

Overall Mortality

Abstract Background Patients with cancer have an increased risk of venous thromboembolism (VTE) and associated morbidity and mortality. Renal dysfunction is more common in patients with cancer, leading to heightened risks of bleeding and thrombotic complications. In the AVERT trial, thromboprophylaxis with apixaban resulted in a significantly lower rate of VTE and higher rate of major bleeding compared to placebo among intermediate-to-high-risk ambulatory cancer patients starting chemotherapy. As apixaban depends on some degree of renal clearance, there may be concerns regarding the safety and efficacy of apixaban thromboprophylaxis in patients with renal insufficiency. In this post-hoc analysis of AVERT, we evaluated the efficacy and safety of apixaban thromboprophylaxis according to renal function at randomization. Methods Eligible patients were randomized to apixaban (2.5mg twice daily) or placebo. First dose of study drug was given within 24 hours of the first chemotherapy administration with the intended treatment period of 180 days. For this subgroup analysis, the efficacy and safety of apixaban thromboprophylaxis was evaluated accordingly to renal function (calculated creatinine clearance [CrCl] by Cockcroft-Gault Equation) at randomization. Patients with CrCl < 30 mL/min were excluded from the trial. The primary efficacy outcome was objectively confirmed major VTE (proximal deep vein thrombosis or pulmonary embolism) within 180 days (±3 days) following randomization. The primary efficacy outcome was evaluated by modified intention-to-treat analysis, which included all patients who had undergone randomization and received at least one dose of study medication on or before day 180 (±3 days). The primary safety outcome was major bleeding defined by the International Society on Thrombosis and Haemostasis criteria. The primary safety outcome was evaluated by on-treatment analysis, when events were counted only if they occurred on study drugs or up to two days after discontinuation of the study drugs. Secondary outcomes included clinically relevant non-major bleeding and overall mortality. Results A total of 574 patients underwent randomization, with 563 patients included in the original primary efficacy and safety analysis (288 apixaban and 275 placebo). Upon randomization, 66 (11.5%) patients had CrCl < 60 mL/min and 508 (88.5%) patients had CrCl ≥ 60 mL/min. Patients with CrCl < 60 mL/min were significantly older, more female, had lower weight and fewer with body mass index (BMI) > 35 kg/m 2 and poorer ECOG performance status (Table 1). In patients with CrCl < 60 mL/min, VTE occurred in no patient on apixaban compared to 1 on placebo, and major bleeding episode occurred in 1 on apixaban and 0 on placebo. In patients with CrCl ≥ 60 mL/min, VTE occurred in 13 out of 257 (5.1%) in the apixaban group and 28 out of 242 (11.6%) in the placebo group [HR 0.41 (95% CI 0.26-0.64), p=0.0001] (Table 2). There were no significant differences between apixaban and placebo groups in major bleeding and clinically relevant non-major bleeding events. Overall mortality was significantly lower in the apixaban group (HR 0.25 [95% CI 0.13-0.45], p<0.0001) in patients with CrCl ≥ 60 mL/min. Conclusions In the AVERT trial, patients with CrCl < 60 mL/min were significantly older, more likely to be female, with lower weight or BMI and poorer ECOG performance status. There were very few VTE or major bleeding events in patients with CrCl < 60 mL/min. In patients with CrCl ≥ 60 mL/min, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE and overall mortality compared to placebo, with no significant differences in the rates of major bleeding or clinically relevant non-major bleeding events. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Carrier: Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Servier: Honoraria; Pfizer: Honoraria, Research Funding; Bayer: Honoraria. Wells: Daiichi Sankyo: Honoraria; BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria. OffLabel Disclosure: apixaban for primary thromboporphylaxis in ambulatory cancer patients receiving chemotherapy

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Efficacy and Safety of Primary Thromboprophylaxis for the Prevention of Venous Thromboembolism in Patients with Cancer and Central Venous Catheter: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2021-146904 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2139-2139

Author(s):

Allen Li ◽

Willem Brandt ◽

Cameron Brown ◽

Tzu-Fei Wang ◽

Rick Ikesaka ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Venous Catheter ◽

Bleeding Complications ◽

Efficacy And Safety ◽

Central Venous ◽

Advisory Committees ◽

Patients With Cancer

Abstract Background Venous thromboembolism (VTE) is a leading cause of mortality in patients with cancer and is associated with significant morbidity and healthcare expenditure. The risk of VTE is also increased following the insertion of a central venous catheter (CVC) for chemotherapy deliverance and supportive care. The risks and benefits of primary thromboprophylaxis in patients with cancer and newly inserted CVC are unclear. Objective We sought to assess the rates of VTE and major bleeding complications to determine the safety and efficacy of primary thromboprophylaxis in adult patients with cancer and a CVC. Methods A systematic search of MEDLINE, EMBASE, and all EBM was conducted. Randomized controlled trials (RCTs) of adult patients with cancer and a CVC receiving primary thromboprophylaxis or observation/placebo were included. The primary efficacy and safety outcomes were total VTE and major bleeding episodes, respectively. Results A total of 9 RCTs (3155 patients) were included in the analysis. The total rates of VTE were significantly lower in patients receiving primary thromboprophylaxis compared to those not receiving primary prevention (7.6% vs. 13%; Odds Ratio (OR) 0.51, 95% CI 0.32 to 0.82, p < 0.01, I² = 52%) (Figure 1). The rate of major bleeding complication was not increased in patients receiving thromboprophylaxis (0.9% vs. 0.7%; OR 1.12, 95% CI 0.29 to 4.40, p = 0.87, I² = 32%) (Figure 2). Conclusions Primary thromboprophylaxis significantly reduced the risk of VTE without increasing the risk of major bleeding complications in patients with cancer and CVC. Future studies are needed to confirm these findings. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Ikesaka: LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wells: Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; BMS/Pfizer: Research Funding; Servier: Honoraria. Carrier: Servier: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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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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Dalteparin Thromboprophylaxis in Cancer Patients at High Risk for Venous Thromboembolism: A Randomized Trial

Blood ◽

10.1182/blood.v126.23.427.427 ◽

2015 ◽

Vol 126 (23) ◽

pp. 427-427 ◽

Cited By ~ 7

Author(s):

Alok A. Khorana ◽

Charles W. Francis ◽

Nicole Kuderer ◽

Marc Carrier ◽

Thomas L. Ortel ◽

...

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Board Of Directors ◽

Cancer Patients ◽

Research Funding ◽

Primary Efficacy ◽

Advisory Committees ◽

Intention To Treat ◽

Efficacy Outcome ◽

Risk Patients

Abstract Background: Ambulatory cancer patients at high-risk for venous thromboembolism (VTE) can be identified using a validated risk score. We evaluated the benefit of outpatient thromboprophylaxis with dalteparin in such high-risk patients in a multicenter randomized controlled trial. Methods: Cancer patients at high risk for VTE (Khorana score ≥3) and initiating a new systemic chemotherapy regimen were screened for VTE and, if negative, randomized to either dalteparin 5000 units daily subcutaneously or no prophylactic anticoagulation for 12 weeks. Subjects in both arms were screened with lower extremity ultrasounds every 4 weeks on study. Primary efficacy endpoint was any VTE over 12 weeks and primary safety endpoint was clinically relevant bleeding events over 13 weeks. The study was terminated due to poor accrual. Results: Of 117 enrolled patients, 19 were not randomized due to the presence of VTE on initial screening (N=10, 8.5%) or for other reasons (N=9). The mean age was 59 years with 46% female and 54% male, similar in both arms. The most common primary sites of cancer were pancreas, gastro-esophageal junction, lung and lymphoma. Over three-fourths of patients in each arm had an ECOG performance status of 0 or 1.Of 98 patients randomized, VTE occurred in 12% (N=6/50) of patients on the dalteparin arm and 21% (N=10/48) on the control arm (hazard ratio, HR 0.69, 95% CI 0.23-1.89) (absolute risk reduction 9%, relative risk reduction 42%, number needed to treat = 12). Major bleeding was similar (N=1) in each arm but clinically relevant bleeding was higher in the dalteparin arm (N=7 versus 1 in the control arm) (HR = 7.0, 95% CI 1.2-131.6). There was no difference in overall survival. Conclusions: Thromboprophylaxis is associated with a non-significant reduced risk of VTE with no effect on major bleeding or survival but increased risk of clinically relevant bleeding in this underpowered study population. The Khorana score successfully identifies patients with high incidence of VTE both at baseline and during study. The high incidence of baseline VTE suggests that consideration should be given to screening high-risk patients in clinical practice prior to starting systemic therapy. Future studies should continue to focus on risk-adapted approaches to reduce the burden of VTE in cancer. (Funded by NIH/NHLBI R01HL095109; clinicaltrials.gov identifier: NCT00876915). Table 1. Baseline Characteristics of Patients Enrolled in the PHACS trial Dalteparin Observation Total Enrolled (n) Baseline VTE, n (%) DVT PE Other reasons for not randomizing Randomized (n) Age, mean (SD), y --- --- --- --- --- 50 60 (10) --- --- --- --- --- 48 58 (12) 117 10 (9%) 6* (5%) 4 (3%) 9 98 59 (11) Gender, n (%) Female 21 (42%) 24 (50%) 45 (46%) Male 29 (58%) 24 (50%) 53 (54%) Primary Tumor Site, No. (%) Gynecologic 4 (8%) 4 (8%) 8 (8%) Colorectal 1 (2%) 3 (6%) 4 (4%) GE junction 8 (16%) 4 (8%) 12 (25%) Lung 6 (12%) 7(15%) 13 (27%) Genitourinary 2 (4%) 0 (0%) 2 (2%) Lymphoma 5 (10%) 2 (4%) 7 (15%) Breast 1 (2%) 1 (2%) 2 (2%) Pancreatic 19 (38%) 17 (35%) 36 (37%) Gastric 4 (8%) 6 (13%) 10 (10%) Other 0 (0%) 4 (8%) 4 (4%) Previous history of VTE, n (%) 4 (8%) 2 (4%) 6 (6%) *NOTE: 1 subject had both DVT and PE at baseline screening Abbreviations: DVT, deep vein thrombosis; PE pulmonary embolism; VTE, venous thromboembolism; ECOG: Eastern Cooperative Oncology Group Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Disclosures Khorana: Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; sanofi: Consultancy, Honoraria. Off Label Use: Randomized trial of dalteparin as prophylaxis. The drug is approved for treatment of cancer-associated thrombosis but not for prophylaxis.. Francis:Eisai: Consultancy, Research Funding; Portola: Consultancy, Honoraria; NHLBI: Consultancy; Lilly: Consultancy. Kuderer:Hospira: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy. Carrier:Leo Pharma: Consultancy, Research Funding; BMS: Research Funding; Bayer: Consultancy, Honoraria; Pfizer: Consultancy. Ortel:Instrumentation Laboratory: Consultancy; Instrumentation Laboratory: Research Funding; Eisai: Research Funding; Daiichi Sankyo: Consultancy. Wun:Janssen: Consultancy. Iyer:Ipsen Pharmaceuticals: Consultancy; Genentec: Research Funding; Bristol Myers Squibb: Honoraria. Lyman:Amgen: Research Funding.

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Safety of Weight-Adjusted Dosing of LMWH in Clinically Obese Cancer Patients with Venous Thromboembolism

Blood ◽

10.1182/blood.v128.22.882.882 ◽

2016 ◽

Vol 128 (22) ◽

pp. 882-882

Author(s):

Gillian Mount ◽

Michael J. Kovacs ◽

Alejandro Lazo-Langner ◽

Lenicio Siqueira ◽

Martha L Louzada

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Major Bleeding ◽

Research Funding ◽

Control Group ◽

Obese Patients ◽

Bleeding Events ◽

Compression Ultrasound ◽

Bleeding Episodes

Abstract Background: Obesity, defined as a body mass index (BMI) greater than 30 kg/m2, is a well-known risk factor for venous thromboembolism (VTE). Despite this observation, obese patients are under-represented in anticoagulation safety trials. Current guidelines recommend patients with active malignancy and VTE to be treated with long-term low molecular weight heparin (LMWH), but it is unclear whether this practice is safe in obese cancer patients. Objectives: We hypothesized there would be an increased risk of major or clinically significant non-major bleeding in obese cancer patients receiving long-term, actual weight-adjusted LMWH compared to non-obese patients with cancer- associated VTE. Methods: We conducted a single centre retrospective cohort study of obese cancer patients referred to our thrombosis clinic from January 2010 to December 2015. We included all obese cancer patients assessed at the Thrombosis unit who received anticoagulation with LMWH. Obesity was defined as weight above 90 Kg or BMI of 30 kg/m2 or more. The obese patients' data was compared to a non-obese control group of patients with active malignancy treated with LMWH. Major bleeding was defined as a hemoglobin drop of > 20 g/L; clinically overt bleeding; bleeding requiring 2 units or more of packed red blood cells; a hemorrhage requiring permanent cessation of anti-coagulation; or any retroperitoneal or intracranial hemorrhage. Diagnosis of deep venous thrombosis was confirmed when compression ultrasound of the lower extremities showed evidence of thrombus in the calf trifurcation or more proximal veins; or calf thrombosis associated with pulmonary embolism (PE). PE was confirmed when the ventilation-perfusion lung showed at least a large mismatched defect or CT pulmonary angiography demonstrated at least one segmental intra-luminal filling defect. Results: In total, 102 obese cancer patients and 81 non-obese cancer patients met our eligibility criteria. In the obese cohort, 43 (42%) were male, median age 64 (24-89), median weight 96.5 kg (67.3-158), and median BMI 33.7 kg/m2 (27.2-57). 90 (88%) patients had a solid tumour. Median dose of LMWH was 18,000 units (10,000 - 30,000): 78 (76%) were prescribed dalteparin and 22 (22%) tinzaparin. Median follow-up was 191 days (3 - 2622). Baseline characteristics of the control group were similar (Table 1). Total bleeding episodes were significantly different in the 2 groups: total bleeding events were 10 (9.8%) in the obese group (4 were under-dosed based on their weight) and 1 in the control group [RR=7.9; 95% CI (1.04 -60.76) p=0.046)]. Major bleeding events occurred in 6 (5.9%) obese and in none of the non-obese patients [RR=10.4; 95% CI (0.59 -181.05) p=0.11)]. Platelet counts were appropriate in all cases but one, where a non-major bleed occurred in an obese patient with a platelet count of 27. Recurrent VTE occurred in 8 (7.8%) obese and 4 control patients. In the obese cohort, 5 of those patients were receiving under-dosed LMWH based on their weight. There was no statistically significant difference regarding VTE recurrence risk in the obese and control groups [RR=1.59; 95% CI (0.50 -5.09) p=0.44)]. Interestingly, 31 of 96 obese patients (31%) with BMI 30 or above weighed less than 90 kg. Conclusions: Our findings differ from the available literature. In the CLOT trial, total and major bleeding episodes in the LMWH group occurred in 14% and 7%, respectively, with VTE recurrence of 9%. In comparison, our results demonstrate total and major bleeding episodes in our obese cancer patients on LMWH of 9.8% and 5.9%, respectively, with VTE recurrence of 7.8%. Total bleeding was statistically significant compared to a non-obese cancer population, however, limitations in sample size and event rate need to be taken into consideration when interpreting these results. Disclosures Kovacs: Daiichi Sankyo Pharma: Research Funding; Bayer: Honoraria, Research Funding; LEO Pharma: Honoraria; Pfizer: Honoraria, Research Funding. Lazo-Langner:Bayer: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. Louzada:Celgene: Consultancy, Honoraria; Pfizer: Honoraria; Bayer: Honoraria; Janssen: Consultancy, Honoraria.

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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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Risk Stratification for the Development of Venous Thromboembolism in Hospitalized Patients with Cancer

Blood ◽

10.1182/blood.v128.22.4728.4728 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4728-4728 ◽

Cited By ~ 1

Author(s):

Arabesque Parker ◽

Erica A. Peterson ◽

Agnes Y. Y. Lee ◽

Carine de Wit ◽

Marc Carrier ◽

...

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Risk Stratification ◽

Board Of Directors ◽

Cancer Patients ◽

Major Bleeding ◽

Research Funding ◽

Low Risk ◽

Advisory Committees ◽

Risk Patients

Abstract Introduction: No method of venous thromboembolism (VTE) risk stratification exists for hospitalized cancer patients. The Khorana score is a validated tool in outpatients with cancer. The objective of this study was to assess the Khorana score for predicting development of VTE in cancer patients during admission to hospital. Methods: We conducted a retrospective analysis of data collected from healthcare records of consecutive, medically-ill cancer patients hospitalized between January and June 2010 in 3 academic medical centers in Canada. Objectively diagnosed symptomatic VTE during hospitalization, anticoagulant thromboprophylaxis (TP), and Khorana score variables were collected for every patient. Patients receiving therapeutic anticoagulation at admission, and those with incomplete data were excluded. The risk of VTE based on Khorana score category was evaluated using logistic regression. Continuous data were compared using a Student's t-test and expressed using the means and standard deviations. Categorical data were compared using the Pearson Chi-square test and were expressed as percentages. Statistical significance was defined as alpha less than 0.05. Results: 1398 patients were included. Mean age was 61.6 years, 51.2% were male, and mean BMI was 25.9 kg/m2. The most frequent tumor types were non-small cell lung carcinoma (12.7%) followed by lymphoma (10.9%). The median length of stay was 6 days (range 0-114 days). The most frequent reasons for hospitalization were chemotherapy (22.3%) followed by pain and palliation (21.4%). 34.5% received anticoagulant TP (n = 483/1398). The incidence of VTE was 2.9% (41/1398) overall, 5.4% (9/166) in high, 3.2% (26/817) in moderate, and 1.4% (6/415) in low Khorana score risk groups. High risk patients were significantly more likely than low risk patients to have VTE (p=0.016; OR 3.9, 95% CI 1.4-11.2). There was no difference in VTE incidence between patients who received anticoagulant TP and those who did not (3.5% vs 2.6%, p = 0.345). Patients with high risk Khorana score were more likely to receive anticoagulant TP than those with low risk Khorana score (46.4% vs. 23.9%, p <0.001, OR 2.8, 95% CI 1.9-4.0). Total incidence of major bleeding was 1.8% (25/1398). There was no difference in major bleeding between patients who received anticoagulant TP and those who did not (1.7% vs. 1.9%, p = 0.787). Conclusion: The Khorana score is predictive of VTE development in cancer patients who are hospitalized for medical illness and may be a useful tool for tailoring inpatient anticoagulant prophylaxis. Disclosures Lee: LEO: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Carrier:BMS: Research Funding; Leo Pharma: Research Funding. Wu:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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P569Efficacy and safety of direct Xa oral inhibitors versus warfarin in patients with atrial fibrillation and cancer: a meta-analysis of randomized controlled trials

EP Europace ◽

10.1093/europace/euaa162.244 ◽

2020 ◽

Vol 22 (Supplement_1) ◽

Author(s):

M Casula ◽

F Fortuni ◽

F Fabris ◽

S Leonardi ◽

M Gnecchi ◽

...

Keyword(s):

Atrial Fibrillation ◽

Randomized Controlled Trials ◽

Cancer Patients ◽

Major Bleeding ◽

Controlled Trials ◽

Primary Efficacy ◽

Efficacy And Safety ◽

Randomized Controlled ◽

The Mean ◽

Active Cancer

Abstract Background Patients with cancer are at higher risk of atrial fibrillation (AF) compared with the general population. Furthermore, cancer per se and anti-cancer treatments have been associated with thromboembolic complications and increased bleeding risk. Considering that only 12% of cancer patients can achieve a stable International Normalized Ratio target and the frequent need for invasive procedures, warfarin is not an ideal option. Direct oral anticoagulants may theoretically represent a valid alternative although their use in this population has been scarcely investigated. Purpose To compare efficacy and safety of direct oral Xa inhibitors (DOXaI) versus warfarin in patients with atrial fibrillation and cancer. Methods We searched electronic databases for randomized controlled trials (RCTs) that analyzed the use of DOXaI versus warfarin in patients with AF and cancer. The primary efficacy outcome was stroke or systemic embolism (SE). The secondary efficacy outcomes were ischemic stroke, myocardial infarction and all-cause death. The primary safety outcome was major bleeding; secondary safety outcomes were major or clinically relevant non-major bleeding, intracranial bleeding and any bleeding. The net clinical benefit was estimated as the composite of the two primary outcomes. A sensitivity analysis was performed to better define the incidence of these outcomes in patients with active cancer. The statistical software ProMeta 3 was used to estimate the risk ratio with a random-effect model. Results 3 RCTs counting a total of 3029 cancer patients (1682 on DOXaI and 1347 on warfarin), 1354 of whom with active cancer (856 on DOXaI and 502 on warfarin), were included in the analysis. Mean age was 75.6 ± 1.2 years, and 32% were female. Mean follow-up period was 2.2 ± 0.6 years. The most common cancer sites were prostate (23%), gastrointestinal tract (22.2%), breast (12.1%) and genitourinary tract (10.6%). The mean CHADS2 score was 2.9 ± 0.6 and the mean HAS-BLED score was 2.6 ± 0.4. There were no significant differences in the risk of stroke or SE (RR 0.76; 95% CI 0.52-1.10) as well as for all the other secondary efficacy outcomes. DOXaI significantly reduced the incidence of major bleeding in the overall cancer population (RR 0.79; 95% CI 0.63-0.99; p = 0.039); this finding was consistent also in patients with active cancer (RR 0.79; 95% CI 0.59-1.05) although the effect was not statistically significant. DOXaI also significantly reduced intracranial bleeding in overall cancer population (RR 0.12; 95% CI 0.02-0.63; p = 0.013) and any bleeding in active cancer patients (RR 0.87; 95% CI 0.77-0.98; p = 0.026). Furthermore, DOXaI significantly reduced the composite endpoints of major bleeding and stroke or SE in overall cancer population (RR 0.78; 95% CI 0.64-0.94; p = 0.008). Conclusions Our metanalysis shows that, in patients with atrial fibrillation and cancer, DOXaI are safer and have a similar efficacy compared with warfarin. Abstract Figure. Primary efficacy and safety outcomes

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Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies

Blood ◽

10.1182/blood.v120.21.20.20 ◽

2012 ◽

Vol 120 (21) ◽

pp. 20-20 ◽

Cited By ~ 6

Author(s):

Harry Roger Buller

Keyword(s):

Body Weight ◽

Venous Thromboembolism ◽

Major Bleeding ◽

Standard Therapy ◽

Pooled Analysis ◽

Fixed Dose ◽

Primary Efficacy ◽

Efficacy And Safety ◽

Efficacy Outcome ◽

Subgroup Analyses

Abstract Abstract 20 Harry R. Büller, MD, PhD on behalf of the EINSTEIN Investigators. Background The EINSTEIN DVT and EINSTEIN PE studies showed that a fixed-dose regimen of rivaroxaban was non-inferior to standard therapy of subcutaneous enoxaparin followed by vitamin K antagonist (VKA) for the treatment of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), with similar occurrence of clinically relevant bleeding (The EINSTEIN Investigators. N Engl J Med 2010;363:2499–510; The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–97). This prespecified pooled analysis compared rivaroxaban with the standard therapy for the primary efficacy and safety outcomes, including subgroup analyses for body weight, age, and renal function. Methods This data pool included all patients and events from EINSTEIN DVT (patients with acute symptomatic DVT without PE) and EINSTEIN PE (patients with acute symptomatic PE with or without DVT). Both studies shared an open-label, randomized, non-inferiority design and compared oral, fixed-dose rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous body weight-adjusted enoxaparin followed by warfarin or acenocoumarol (international normalized ratio 2–3) for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism (the composite of recurrent DVT or nonfatal or fatal PE); safety outcomes included the composite of major and clinically relevant non-major bleeding, and major bleeding alone. Adjudication was done by a single committee. Subgroup analyses for efficacy and safety were performed. Results The intention-to-treat population included 4150 rivaroxaban patients and 4131 enoxaparin/VKA patients. Rivaroxaban demonstrated non-inferior efficacy to enoxaparin/VKA for the primary efficacy outcome (rivaroxaban: 86 events [2.1%], enoxaparin/VKA: 95 events [2.3%]; hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.66–1.19; p<0.0001 for non-inferiority). Major and clinically relevant non-major bleeding occurred in 388 patients (9.4%) in the rivaroxaban group and 412 patients (10.0%) in the enoxaparin/VKA group (HR=0.93; 95% CI 0.81–1.06; p=0.272), and major bleeding occurred in 40 (1.0%, 3 fatal) and 72 (1.7%, 8 fatal) of the rivaroxaban and enoxaparin/VKA recipients, respectively (HR=0.54; 95% CI 0.37–0.79; p=0.002). Efficacy was consistent for rivaroxaban compared with enoxaparin/VKA among the various subgroups, whereas increasing age and declining renal function were associated with a strong reduction in major bleeding in favor of rivaroxaban (Table). Major bleeding was consistently lower in the rivaroxaban recipients for all body weight categories. Conclusion This analysis demonstrates that the simple, single-drug approach with oral rivaroxaban has an improved benefit–risk profile compared with standard therapy for the treatment of symptomatic venous thromboembolism. The reduction in major bleeding in favor of rivaroxaban was most pronounced in elderly patients and those with moderate renal impairment (creatinine clearance <50 mL/min), and was consistent among various body weight categories, thereby obviating the need for a rivaroxaban dose adjustment in these subgroups. Disclosures: No relevant conflicts of interest to declare.

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Two Doses of Apixaban for the Extended Treatment of Venous Thromboembolism

Blood ◽

10.1182/blood.v120.21.lba-1.lba-1 ◽

2012 ◽

Vol 120 (21) ◽

pp. LBA-1-LBA-1 ◽

Cited By ~ 1

Author(s):

Giancarlo Agnelli ◽

Harry Roger Buller ◽

Alexander Cohen ◽

Madelyn Curto ◽

Alexander S. Gallus ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Primary Efficacy ◽

Advisory Committees ◽

Primary Efficacy Outcome ◽

Extended Treatment ◽

Safety Outcome ◽

Efficacy Outcome

Abstract Abstract LBA-1 Background: Apixaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for extended treatment of venous thromboembolism. Objectives: To compare the efficacy and safety of two doses of apixaban (2.5 or 5 mg twice daily) with placebo for the extended treatment of venous thromboembolism in patients who have completed 6 to 12 months of prior anticoagulant therapy. Methods: This randomized, double-blind study (ClinicalTrials.gov number, NCT00633893) compared two apixaban doses (2.5 or 5 mg twice daily) with placebo for 12 months in patients with venous thromboembolism who had completed 6–12 months of anticoagulation. The primary efficacy outcome was symptomatic recurrent venous thromboembolism or all-cause mortality. Secondary efficacy outcomes included (a) the composite of symptomatic venous thromboembolism or venous thromboembolism-related death, and (b) the composite of symptomatic venous thromboembolism, venous thromboembolism-related death, myocardial infarction, stroke, or cardiovascular-related death. The primary safety outcome was major bleeding; the secondary safety outcome was major and clinically relevant non-major bleeding. Results: The study included 2486 patients: 829, 840, and 815 randomized to placebo, apixaban 2.5 mg, and apixaban 5 mg, respectively. Rates of the primary efficacy outcome were 11.6% in the placebo group, compared with 3.8% and 4.2% in the apixaban 2.5 mg and 5 mg groups, respectively (absolute risk differences of 7.8% and 7.4%, respectively; 95% confidence intervals 5.3% to 10.3% and 4.8% to 10%, respectively; p<0.001 for both comparisons). Other outcomes are detailed in the Table. Conclusions: Both doses of apixaban reduced the risk of symptomatic recurrent fatal or non-fatal venous thromboembolism by approximately 80% without increasing the rate of major bleeding. In addition, both apixaban doses reduced arterial thrombotic events. The lower apixaban dose may be preferred for extended treatment, because of the trend for less clinically relevant non-major bleeding. Disclosures: Agnelli: Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy; Bayer Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Buller:Bayer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-aventis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Isis: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding. Cohen:Astellas: Consultancy, Research Funding; AstraZenica: Consultancy, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boheringer-Ingelheim: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mitsubishi Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Schering Plough: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Curto:Pfizer: Employment. Gallus:Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Bayer: Membership on an entity’s Board of Directors or advisory committees; boehringer-Ingelheim: Membership on an entity’s Board of Directors or advisory committees. Johnson:Pfizer: Employment. Porcari:Pfizer: Employment. Raskob:Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myer Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy; Quintiles: Consultancy; National Blood Clot Alliance: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Weitz:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

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