Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer
- Conditions
- CancerVenous ThromboembolismDeep Vein Thrombosis (DVT)Pulmonary Embolism (PE)Blood Clot
- Interventions
- Registration Number
- NCT02744092
- Lead Sponsor
- Alliance Foundation Trials, LLC.
- Brief Summary
The overarching objective of the study is to determine the effectiveness of LMWH/ warfarin vs. DOAC anticoagulation for preventing recurrent VTE in cancer patients. The intervention strategy is Direct Oral AntiCoagulants (DOAC) therapy with edoxaban, apixaban, rivaroxaban, or dabigatran. The comparator is low molecular weight heparin (LMWH) alone or with warfarin. The information gained will empower cancer patients and physicians to make more informed choices about anticoagulation strategies to manage VTE.
- Detailed Description
Venous blood clots affect nearly a million Americans each year. Venous clots in the legs are called deep venous thrombosis (DVT) and are dangerous because they travel to the lungs where they cause blockages known as pulmonary emboli (PE). DVT and PE are called venous thromboemboli (VTE). Cancer is a risk factor with nearly 200,000 VTEs in cancer patients each year. The purpose of VTE treatment is to prevent the initial clot from spreading and to prevent new clots from forming. This is accomplished by thinning the blood, or anticoagulation. Without anticoagulation, VTEs recur and are often fatal.
Recently, the FDA has approved 4 new Direct Oral AntiCoagulants (DOACs) for preventing VTE recurrence. Few cancer patients were included in the efficacy trials, and practice guidelines fall silent on whether switching to DOAC therapy is advisable. To fill this knowledge gap, the Alliance Foundation Trials LLC, a research network of academic and community practices across the US, is conducting a pragmatic randomized effectiveness trial.
The overarching objective of the study is to determine the effectiveness of LMWH/ warfarin vs. DOAC anticoagulation for preventing recurrent VTE in cancer patients. The investigators will conduct a trial of 811 cancer patients followed for 6 months. The intervention strategy is DOAC therapy with edoxaban, apixaban, rivaroxaban, or dabigatran. The comparator is LMWH alone or with warfarin. Within each arm, patients can choose the agent they prefer based on side effects, drug interactions, and practical issues such as co-pays. The trial compares these two strategies in terms of treatment: 1) benefits based on VTE recurrence; 2) harms based on bleeding rates; 3) burdens based on patients' reports of their experiences; and 4) mortality rates.
The investigators hypothesize that the benefits, harms and burdens of DOAC treatment will be non-inferior to, or better than, usual care with LMWH/ warfarin among cancer patients. The information gained will empower cancer patients and physicians to make more informed choices about anticoagulation strategies to manage VTE.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 811
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Diagnosis of advanced solid tumor cancer, lymphoma, or myeloma (no time restrictions or limitations) -OR- diagnosis of early stage solid tumor cancer, lymphoma, or myeloma <= 12 months prior to study enrollment
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Diagnosis of VTE <= 30 days prior to study enrollment for which potential benefits of anticoagulation therapy to prevent recurrence of VTE are felt by the treating physician to exceed the potential harms
- Any anticoagulation drug/strategy may be used to treat the index VTE; protocol treatment will begin <= 30days after the index VTE diagnosis date
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Treating physician intends to put participant on anticoagulation therapy for at least three months.
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Age >= 18 years
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Platelet count is >= 50,000/mm^3 (<= 7 days prior to enrollment)
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CrCl (Creatinine Clearance) is >= 15 ml/min (<= 7 days prior to enrollment)
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Diagnosis of acute leukemia
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Has ever received or is scheduled to receive an Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)
- Patients who have ever received an Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) ARE eligible.
- Patients who are scheduled to receive an Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) are NOT eligible
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Ongoing, clinically significant bleeding (CTCAE grade 3 or 4)
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Ongoing therapy with a P-gp inhibitor (e.g., nelfinavir, indinavir, or saquinavir-protease inhibitors for HIV) as these drugs interact with the factor Xa inhibitors
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Therapy with any azole antifungals (e.g., itraconazole, ketaconazole, voriconazole) at the time of enrollment
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Randomized Arm 1 (DOACs) Rivaroxaban Randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). There are four FDA-approved DOAC drugs that may be used for this study: Rivaroxaban, Apixaban, Edoxaban, or Dabigatran. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Randomized Arm 1 (DOACs) Apixaban Randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). There are four FDA-approved DOAC drugs that may be used for this study: Rivaroxaban, Apixaban, Edoxaban, or Dabigatran. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Randomized Arm 1 (DOACs) Edoxaban Randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). There are four FDA-approved DOAC drugs that may be used for this study: Rivaroxaban, Apixaban, Edoxaban, or Dabigatran. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Randomized Arm 1 (DOACs) Dabigatran Randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). There are four FDA-approved DOAC drugs that may be used for this study: Rivaroxaban, Apixaban, Edoxaban, or Dabigatran. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Randomized Arm 2 (LMWH) Warfarin Randomized Arm 2 will get anticoagulation therapy with low molecular weight heparin (LMWH) with or without a transition to warfarin. There are three FDA-approved LMWH drugs that may be used for this study: Dalteparin, Enoxaparin, or Fondaparinux. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Preference Cohort 1 (DOACs) Rivaroxaban If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). Randomized Arm 2 (LMWH) Enoxaparin Randomized Arm 2 will get anticoagulation therapy with low molecular weight heparin (LMWH) with or without a transition to warfarin. There are three FDA-approved LMWH drugs that may be used for this study: Dalteparin, Enoxaparin, or Fondaparinux. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Randomized Arm 2 (LMWH) Dalteparin Randomized Arm 2 will get anticoagulation therapy with low molecular weight heparin (LMWH) with or without a transition to warfarin. There are three FDA-approved LMWH drugs that may be used for this study: Dalteparin, Enoxaparin, or Fondaparinux. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Randomized Arm 2 (LMWH) Fondaparinux Randomized Arm 2 will get anticoagulation therapy with low molecular weight heparin (LMWH) with or without a transition to warfarin. There are three FDA-approved LMWH drugs that may be used for this study: Dalteparin, Enoxaparin, or Fondaparinux. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. Preference Cohort 1 (DOACs) Apixaban If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). Preference Cohort 1 (DOACs) Edoxaban If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). Preference Cohort 1 (DOACs) Dabigatran If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). Preference Cohort 2 (LMWH) Dalteparin If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 2 will get anticoagulation therapy with Low Molecular Weight Heparin (LMWH) with or without a transition to warfarin. Preference Cohort 2 (LMWH) Warfarin If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 2 will get anticoagulation therapy with Low Molecular Weight Heparin (LMWH) with or without a transition to warfarin. Preference Cohort 2 (LMWH) Fondaparinux If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 2 will get anticoagulation therapy with Low Molecular Weight Heparin (LMWH) with or without a transition to warfarin. Preference Cohort 2 (LMWH) Enoxaparin If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized). Preference cohort: Non-randomized Arm 2 will get anticoagulation therapy with Low Molecular Weight Heparin (LMWH) with or without a transition to warfarin.
- Primary Outcome Measures
Name Time Method Cumulative Non-Fatal VTE Recurrence at 6 Months (%) 6 months To compare the effectiveness of anticoagulation with a DOAC (intervention) with LMWH/warfarin (comparator) for preventing VTE recurrence in patients with cancer based on cumulative VTE recurrence reported by patients or clinicians at 6 months. Only VTEs that were nonfatal were considered because of the challenges of attributing cause of death in cancer patients to tumor progression vs. VTE.
- Secondary Outcome Measures
Name Time Method Cumulative Rates of Major Bleeding 6 months To compare the harms of DOAC vs. LMWH/warfarin therapy for cancer patients with VTE based on the cumulative rate of major bleeding at 6 months. d. Major bleeding was defined as Grade \>=3 on the Common Terminology Criteria for Adverse Events from the National Cancer Institute (NCI CTCAE) criteria version 5.0 (i.e., severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living).
Health Related Quality of Life Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire 6 months Change in physical health at 6 months. Health-related quality of life was measured using the 12-Item Short Form Health Survey (SF-12) sub-scales for physical and mental health (score range, 0-100; higher scores indicate better physical and mental health functioning). Survey content included minor verbiage changes for clarity. The presented scores in this results section indicate the change (difference) in mean scores between the baseline and 6-month follow-up assessment.
Burden of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire 6 months To compare the burden of anticoagulation therapy with DOAC vs. with LMWH/warfarin for cancer patients with VTE at 6 months. The burden scale has12 items and patients are asked to rate their experiences on a 5-point scale of intensity (1=not at all, 2=a little, 3=moderately, 4=quite a bit, 5=extremely). The ACTS burden tool is then scored using the totals from each question with a total score from 12 to 60 possible. Higher scores signify greater satisfaction (lower burden).
Mortality Reported by Participants' Surrogates (Via Study-specific Questionnaire) or Clinicians (Via Study-specific Case Report Form) 6 months To compare the impact of DOAC vs. LMWH/warfarin therapy on mortality in cancer patients with VTE based on survival at 6 months. Mortality was reported by participants' surrogates (via study-specific questionnaire) or clinicians (via study-specific case report form)
Benefit of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire 6-months To compare the benefit of anticoagulation therapy with DOAC vs. with LMWH/warfarin for cancer patients with VTE at 6 months. The benefits scale has 3 items and patients are asked to rate their experiences on a 5-point scale of intensity (1=not at all, 2=a little, 3=moderately, 4=quite a bit, 5=extremely). The ACTS benefits tool is then scored using the totals from each question with a total score from 3 to 15 possible. Higher scores signify greater satisfaction (greater benefits).
Health Related Quality of Life (Mental Health) Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire at 3-months 3-months Change in mental health at 3 months from baseline. Health-related quality of life was measured using the 12-Item Short Form Health Survey (SF-12) sub-scales for physical and mental health (score range, 0-100; higher scores indicate better physical and mental health functioning). Survey content included minor verbiage changes for clarity. The scores indicate change in score from baseline.
Health Related Quality of Life (Mental Health) Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire at 6-months 6-months Change in mental health at 6 months from baseline. Health-related quality of life was measured using the 12-Item Short Form Health Survey (SF-12) sub-scales for physical and mental health (score range, 0-100; higher scores indicate better physical and mental health functioning). Survey content included minor verbiage changes for clarity. The scores indicate change in score from baseline.
Trial Locations
- Locations (148)
South County Hematology
🇺🇸Chula Vista, California, United States
Sharp Rees-Stealy
🇺🇸San Diego, California, United States
Washington Hospital Healthcare System
🇺🇸Fremont, California, United States
Washington Hospital
🇺🇸Fremont, California, United States
VA Central California Fresno Medical Center
🇺🇸Fresno, California, United States
Cancer Center Oncology Medical Group
🇺🇸La Mesa, California, United States
Medical Oncology Associates- San Diego
🇺🇸San Diego, California, United States
Sharp Memorial Hospital
🇺🇸San Diego, California, United States
UCSF Medical Center - Mission Bay
🇺🇸San Francisco, California, United States
Saint Joseph's Medical Center
🇺🇸Stockton, California, United States
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