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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 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.

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).

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.

Deborah Schrag, MD MPH

Jean Connors, MD

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.

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.

Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer

Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer: A Randomized Effectiveness Trial (CANVAS Trial)

Individual-level de-identified datasets will be made available to investigators working under an institution with a Federal Wide Assurance (FWA) who formally submit a request to the study chairs at the Dana-Farber Cancer Institute. Prior to the release of datasets, DFCI will ensure certain requirements, e.g., IRB approval and data use agreement, are in place. These datasets will be available within 6 months of publication of the manuscript and following a formal request by an investigator to and approval from DFCI.

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.

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).

Change in physical health at 3 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 3-month follow-up assessment.

To compare the burden of anticoagulation therapy with DOAC vs. with LMWH/warfarin for cancer patients with VTE at 3 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).

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)

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.

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).

To compare the benefit of anticoagulation therapy with DOAC vs. with LMWH/warfarin for cancer patients with VTE at 3 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).

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).

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.

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.

Patient-Centered Outcomes Research Institute

Alliance Foundation Trials, LLC.

AEs were reported by physicians. Grade 3+ AEs were severe. Other AEs are grade 1 or 2 . Other AE section reports on events that were experienced in \>1% of patients, so total # of patients may not match the # of patients experiencing events. We did not report AEs by individual drug arm because we did not randomize drugs; comparisons amongst drugs will be subject to selection bias. Also, the protocol allowed patients to switch drugs, so it would be unclear which AE is affiliated with which drug.

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.

Rivaroxaban: Anticoagulation therapy.

Apixaban: Anticoagulation therapy.

Edoxaban: Anticoagulation therapy.

Dabigatran: Anticoagulation therapy.

Randomized Arm 1 (DOACs)

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.

Warfarin: Anticoagulation therapy.

Dalteparin: Anticoagulation therapy.

Enoxaparin: Anticoagulation therapy.

Fondaparinux: Anticoagulation therapy.

Randomized Arm 2 (LMWH)

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).

Rivaroxaban: Anticoagulation therapy.

Apixaban: Anticoagulation therapy.

Edoxaban: Anticoagulation therapy.

Dabigatran: Anticoagulation therapy.

Preference Cohort 1 (DOACs)

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.

Warfarin: Anticoagulation therapy.

Dalteparin: Anticoagulation therapy.

Enoxaparin: Anticoagulation therapy.

Fondaparinux: Anticoagulation therapy.

Preference Cohort 2 (LMWH)

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.

Dalteparin: Anticoagulation therapy.

Enoxaparin: Anticoagulation therapy.

Fondaparinux: Anticoagulation therapy.

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.

Dalteparin: Anticoagulation therapy.

Enoxaparin: Anticoagulation therapy.

Fondaparinux: Anticoagulation therapy.

Total

Age, Categorical

Age, median (q1, q3)

Age, Customized

Female

Male

Sex/Gender, Customized

Ethnicity (NIH/OMB)

Race (NIH/OMB)

This study has several limitations. First, participants and physicians were not blinded to treatment assignment. Second, because participants were randomized within 30 days of a new VTE diagnosis, some were treated with different therapy before randomization. Third, in patients with advanced-stage cancer, it was not possible to distinguish VTE from cancer as the cause of death. Fourth, the included population limits generalizability. Fifth, detailed medication diaries were not obtained.

Dr. Jean Connors

Primary analyses were performed on the participants who began protocol-directed therapy, the "as treated" population.

Cumulative Non-Fatal VTE Recurrence at 6 Months (%)

Cumulative Rates of Major Bleeding

Participants completing the 3-month survey assessment

Health Related Quality of Life Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire

Burden of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire

Mortality Reported by Participants' Surrogates (Via Study-specific Questionnaire) or Clinicians (Via Study-specific Case Report Form)

Participants completing the 6-month survey assessment

Benefit of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire

Participants completing the 6-moth survey assessment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer	NCT02744092	Cancer Venous Thromboe... Deep Vein Throm... Pulmonary Embol... Blood Clot	Rivaroxaban Apixaban Edoxaban Dabigatran Warfarin Dalteparin Enoxaparin Fondaparinux	18 Years -	Alliance Foundation Trials, LLC.
Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer	NCT02744092	Cancer Venous Thromboe... Deep Vein Throm... Pulmonary Embol... Blood Clot	Rivaroxaban Apixaban Edoxaban Dabigatran Warfarin Dalteparin Enoxaparin Fondaparinux	18 Years -	Alliance Foundation Trials, LLC.

Spots Global Cancer Trial Database for apixaban (eliquis)