INTERVENTION: Dalteparin (Fragmin®, Pfizer), A low molecular weight heparin, the only licensed anticoagulant in the UK for the extended treatment and prevention of recurrence of VTE in cancer patients. Rivaroxaban (Xarelto®, Bayer), An oral direct Factor Xa inhibitor, licensed for the treatment of DVT and the prevention of recurrence of DVT and PE in adult patients. CONDITION: Topic: National Cancer Research Network; Subtopic/Disease: All Cancers/Misc Sites ; Cancer ; Malignant neoplasm, unspecified PRIMARY OUTCOME: VTE recurrence rates (including symptomatic VTE and incidental PE) calculated from the date of randomisation to the date of first VTE recurrence event. SECONDARY OUTCOME: 1. Acceptability of the study assessed by the numbers randomised and screening logs for reasons for non‐randomisation; 2. Biomarker correlation; 3. Compliance to treatment assessed by the frequency of withdrawals of therapy and duration of therapy; 4. Feasibility of conducting an economic evaluation; 5. Major bleeding and clinically relevant non‐major bleeding. Time to major bleed or clinically relevant non‐major bleed calculated from date of randomisation; 6. Overall survival; calculated from the date of randomisation to the date of death from any cause; 7. Patient experience measured using Anti‐Clot Treatment Scale (ACTS); 8. Progression‐free survival (adjuvant patients) calculated from the date of randomisation to the date of first progression or death from any cause; 9. Quality of life measured using the EuroQol EQ‐5D‐5L questionnaire; 10. Symptomatic VTE and incidental PE recurrence rates calculated from the date of randomisation to the date of first recurrence event; 11. Tumour efficacy measured using the Response Evaluation Criteria In Solid Tumors (RECIST) assessment INCLUSION CRITERIA: 1. Patients with active cancer. 2. Patients with a primary presentation of an objectively confirmed venous thromboembolism (VTE) symptomatic deep venous thrombosis (DVT) or symptomatic or incidental pulmonary embolism (PE). 3. Eastern Cooperative Oncology Group (ECOG) Performance Status is 0, 1 or 2. 4. Age 18 years or over and written informed consent given. 5. Adequate haematological function (recommended levels ? haemoglobin (Hb) > 10g/dl, white cell count (WCC) > 2x10(9)/l, platelets > 100 x10(9)/l). 6. Adequate hepatic and renal function ? liver enzymes < x3 upper limit of normal (ULN) creatinine clearance > 30 ml per minute
INTRODUCTION: Venous thromboembolism (VTE) in cancer patients is an increasingly frequent clinical problem. The overall impact of VTE on cancer patients can be considerable. Targeted patient selection by identifying patients with clinically significant recurrent VTE may have wider health economic benefits whilst reducing patient risk through over-treatment. In the UK, dalteparin is one licensed anticoagulant for the extended treatment and prevention of recurrence of VTE in cancer patients. Rivaroxaban is a highly selective direct Factor Xa inhibitor with oral bioavailability.
AIM: To assess VTE recurrence in selected cancer patients at risk of recurrence of VTE treated with rivaroxaban or dalteparin. The secondary objectives include safety, acceptability, biomarker identification and health economics.
MATERIALS AND METHODS: Select-d is a prospective, randomised, open label, multicentre pilot trial comparing dalteparin (200 IU/kg daily subcutaneously for 1 month and 150 IU/kg months 2-6); and rivaroxaban (15mg orally twice daily for 3 weeks and 20mg once daily for 6 months in total) for cancer patients with VTE - symptomatic and incidental pulmonary embolism (P)E or symptomatic lower limb proximal deep vein thrombosis (DVT) - with a second placebo-controlled randomisation (rivaroxaban vs placebo) comparing the duration of therapy (6 vs 12 months) in all patients with PE and those with a DVT who are residual vein thrombosis (RVT) positive. 70% of DVT patients are estimated to be RVT positive after initial treatment. 530 patients are being recruited toprovide reliable estimates of the primary outcome (VTE recurrence rates) to within the 95% confidence interval of 8% assuming VTE rates are 10% at six months.
RESULTS: As of 1st December 2015, 264 patients have been recruited from 61 open sites across the UK. Preliminary data indicate that the majority of patients presented with solid tumours (98%), ranging from early or locally advanced (41%) to metastatic disease (57%), and primarily comprising colorectal, lung, and breast malignancies. Only a small number of select-d patients presented with haematological malignancies (2%), which included; leukaemia, myeloma and lymphoma. Over half of the select-d patients had an incidental PE (54%); the remainder had symptomatic PE or DVT (46%). The median number of hours on anticoagulation prior to starting select-d randomised treatment was 48 hours.
CONCLUSIONS: select-d is the first randomised trial for treatment of VTE, investigating the direct oral anticoagulants vs a low molecular weight heparin in patients with cancer. The results will support optimal treatment for this key patient group and are eagerly awaited.
Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.
BACKGROUND: The Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D) trial demonstrated reduction in recurrent venous thromboembolism (VTE) but increased bleeding with rivaroxaban compared with dalteparin for treatment of acute VTE in cancer patients, at 6 months. Uncertainty remains around optimal duration of anticoagulation.
OBJECTIVES: To assess VTE recurrence and bleeding, with anticoagulation or not, beyond 6 months.
PATIENTS/METHODS: In SELECT-D, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis (RDVT) or index pulmonary embolism (PE) were eligible for randomization to a further 6 months of rivaroxaban or placebo. Patients with no RDVT stopped anticoagulation. Primary outcome was VTE recurrence at 12 months. The second randomization closed prematurely because of low recruitment when 92 of the planned 300 patients were recruited.
RESULTS: Ninety-two of 136 eligible patients were randomized to rivaroxaban or placebo. The cumulative VTE recurrence after 6 months from the second randomization was 14% with placebo and 4% with rivaroxaban (hazard ratio, 0.32; 95% confidence interval [CI], 0.06-1.58). The major and clinically relevant non-major bleeding rates were 0% and 0% with placebo; and 5% (95% CI, 1-18) and 4% (95% CI, 1-17) with rivaroxaban. In an exploratory analysis, 7 (15%) of 46 placebo patients with RDVT or an index PE experienced recurrent VTE compared to none in the 35 patients in the RDVT-negative cohort (P = .03).
CONCLUSION: The SELECT-D trial was underpowered to detect a statistically significant reduction in recurrent VTE with extended anticoagulation. The absence of RDVT and/or index PE, defined a population at low risk of recurrence.
Dalteparin (Fragmin®, Pfizer), A low molecular weight heparin, the only licensed anticoagulant in the UK for the extended treatment and prevention of recurrence of VTE in cancer patients. Rivaroxaban (Xarelto®, Bayer), An oral direct Factor Xa inhibitor, licensed for the treatment of DVT and the prevention of recurrence of DVT and PE in adult patients.
CONDITION:
Topic: National Cancer Research Network; Subtopic/Disease: All Cancers/Misc Sites ; Cancer ; Malignant neoplasm, unspecified
PRIMARY OUTCOME:
VTE recurrence rates (including symptomatic VTE and incidental PE) calculated from the date of randomisation to the date of first VTE recurrence event.
SECONDARY OUTCOME:
1. Acceptability of the study assessed by the numbers randomised and screening logs for reasons for non‐randomisation; 2. Biomarker correlation; 3. Compliance to treatment assessed by the frequency of withdrawals of therapy and duration of therapy; 4. Feasibility of conducting an economic evaluation; 5. Major bleeding and clinically relevant non‐major bleeding. Time to major bleed or clinically relevant non‐major bleed calculated from date of randomisation; 6. Overall survival; calculated from the date of randomisation to the date of death from any cause; 7. Patient experience measured using Anti‐Clot Treatment Scale (ACTS); 8. Progression‐free survival (adjuvant patients) calculated from the date of randomisation to the date of first progression or death from any cause; 9. Quality of life measured using the EuroQol EQ‐5D‐5L questionnaire; 10. Symptomatic VTE and incidental PE recurrence rates calculated from the date of randomisation to the date of first recurrence event; 11. Tumour efficacy measured using the Response Evaluation Criteria In Solid Tumors (RECIST) assessment
INCLUSION CRITERIA:
1. Patients with active cancer. 2. Patients with a primary presentation of an objectively confirmed venous thromboembolism (VTE) symptomatic deep venous thrombosis (DVT) or symptomatic or incidental pulmonary embolism (PE). 3. Eastern Cooperative Oncology Group (ECOG) Performance Status is 0, 1 or 2. 4. Age 18 years or over and written informed consent given. 5. Adequate haematological function (recommended levels ? haemoglobin (Hb) > 10g/dl, white cell count (WCC) > 2x10(9)/l, platelets > 100 x10(9)/l). 6. Adequate hepatic and renal function ? liver enzymes < x3 upper limit of normal (ULN) creatinine clearance > 30 ml per minute
