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

Cancer Clinical Trial

— CANVAS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02744092
• Other study ID #: AFT-28
• Secondary ID: CER-1503-29805
• Status: Completed
• Phase: N/A
• Start date: December 13, 2016
• Est. completion date: February 22, 2021

Study information

• Verified date: February 2023
• Source: Alliance Foundation Trials, LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 811
• Est. completion date: February 22, 2021
• Est. primary completion date: October 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

• 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

• Treating physician intends to put participant on anticoagulation therapy for at least three months.

• Age >= 18 years

• Platelet count is >= 50,000/mm^3 (<= 7 days prior to enrollment)

• CrCl (Creatinine Clearance) is >= 15 ml/min (<= 7 days prior to enrollment)

Exclusion Criteria:

• Diagnosis of acute leukemia

• 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

• Ongoing, clinically significant bleeding (CTCAE grade 3 or 4)

• 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

• Therapy with any azole antifungals (e.g., itraconazole, ketaconazole, voriconazole) at the time of enrollment

Related Conditions & MeSH terms

• Blood Clot
• Cancer
• Deep Vein Thrombosis (DVT)
• Embolism
• Pulmonary Embolism
• Pulmonary Embolism (PE)
• Thromboembolism
• Thrombosis
• Venous Thromboembolism
• Venous Thrombosis

Intervention

Drug:
• Rivaroxaban
Anticoagulation therapy.
• Apixaban
Anticoagulation therapy.
• Edoxaban
Anticoagulation therapy.
• Dabigatran
Anticoagulation therapy.
• Warfarin
Anticoagulation therapy.
• Dalteparin
Anticoagulation therapy.
• Enoxaparin
Anticoagulation therapy.
• Fondaparinux
Anticoagulation therapy.

Locations

Country	Name	City	State
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Mission Hospital - Memorial Campus	Asheville	North Carolina
United States	MultiCare Regional Cancer Center - Auburn	Auburn	Washington
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Billings Clinic	Billings	Montana
United States	Montana Cancer Consortium	Billings	Montana
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	DF/BWCC at Milford Regional Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Bozeman Health	Bozeman	Montana
United States	St. Elizabeth's Medical Center	Brighton	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Dayton Physicians LLC, Miami Valley South	Centerville	Ohio
United States	Advocate Illinois Masonic Medical Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Sharp Rees-Stealy	Chula Vista	California
United States	South County Hematology	Chula Vista	California
United States	Morton Plant Hospital	Clearwater	Florida
United States	Southeastern Medical Oncology Center	Clinton	North Carolina
United States	Ellis Fischel Cancer Center University of Missouri Healthcare	Columbia	Missouri
United States	Veterans Administration/Harry S Truman Memorial Hospital	Columbia	Missouri
United States	The James Cancer Hospital and Solove Research Institute	Columbus	Ohio
United States	New Hampshire Oncology - Hematology PA	Concord	New Hampshire
United States	Baylor Scott & White Research Institute	Dallas	Texas
United States	Baylor University Medical Center	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Carle on Vermillion	Danville	Illinois
United States	Dayton Clincial Oncology Program	Dayton	Ohio
United States	Dayton Physicians LLC, Samaritan North	Dayton	Ohio
United States	Veteran Affairs Medical Center	Dayton	Ohio
United States	Wright Patterson Medical Center	Dayton	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	The Center for Cancer Care-Duluth	Duluth	Georgia
United States	Duke University Health System	Durham	North Carolina
United States	Saint Elizabeth Medical Center South	Edgewood	Kentucky
United States	Carle - Effingham	Effingham	Illinois
United States	WellSpan Health Ephrata Cancer Center	Ephrata	Pennsylvania
United States	Green Bay Oncology, Ltd./St. Francis Hospital	Escanaba	Michigan
United States	NorthShore University HealthSystem Evanston Hospital	Evanston	Illinois
United States	Augusta Health Cancer Center	Fishersville	Virginia
United States	Fort Belvoir Community Hospital	Fort Belvoir	Virginia
United States	Saint Elizabeth Medical Center Fort Thomas	Fort Thomas	Kentucky
United States	Dayton Physicians LLC, Atrium	Franklin	Ohio
United States	Washington Hospital	Fremont	California
United States	Washington Hospital Healthcare System	Fremont	California
United States	VA Central California Fresno Medical Center	Fresno	California
United States	WellSpan Health Adams Cancer Center	Gettysburg	Pennsylvania
United States	MultiCare Regional Cancer Center - Gig Harbor Medical Park	Gig Harbor	Washington
United States	NorthShore University HealthSystem Glenbrook Hospital	Glenview	Illinois
United States	Southeastern Medical Oncology Center	Goldsboro	North Carolina
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Green Bay Oncology, Ltd./HSHS St. Mary's Hospital Medical Center	Green Bay	Wisconsin
United States	Green Bay Oncology, Ltd./HSHS St. Vincent Hospital	Green Bay	Wisconsin
United States	HSHS St. Mary's Hospital Medical Center	Green Bay	Wisconsin
United States	HSHS St. Vincent Hospital	Green Bay	Wisconsin
United States	Dayton Physicians, Wayne	Greenville	Ohio
United States	East Carolina University	Greenville	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	NorthShore University HealthSystem Highland Park Hospital	Highland Park	Illinois
United States	Breast Cancer Center at Memorial Regional Hospital	Hollywood	Florida
United States	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida
United States	Memorial Regional Hospital	Hollywood	Florida
United States	Hawaii Cancer Care Liliha	Honolulu	Hawaii
United States	Hawaii Cancer Care POB II	Honolulu	Hawaii
United States	Hawaii Oncology Inc Kuakini	Honolulu	Hawaii
United States	Hawaii Oncology Inc POB I	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	New Hampshire Oncology-Hematology PA	Hooksett	New Hampshire
United States	Franciscan St. Francis Health - Indianapolis	Indianapolis	Indiana
United States	Southeastern Medical Oncology Center	Jacksonville	North Carolina
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Kenansville Medical Center	Kenansville	North Carolina
United States	Greater Dayton Cancer Center	Kettering	Ohio
United States	Kettering Medical Center	Kettering	Ohio
United States	Kinston Medical Specialists, P.A.	Kinston	North Carolina
United States	Lenoir Memorial Hospital	Kinston	North Carolina
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Cancer Center Oncology Medical Group	La Mesa	California
United States	Hollis Cancer Center	Lakeland	Florida
United States	Ann M Wierman MD LTD	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Central Valley	Las Vegas	Nevada
United States	Nevada Cancer Specialists - Fort Apache	Las Vegas	Nevada
United States	Nevada Cancer Specialists - Oakey	Las Vegas	Nevada
United States	Nevada Cancer Specialists - Tenaya	Las Vegas	Nevada
United States	Gwinnett Medical Center	Lawrenceville	Georgia
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	WellSpan Health Sechler Family Cancer Center	Lebanon	Pennsylvania
United States	Chandler Medical Center - University of Kentucky	Lexington	Kentucky
United States	Dana-Farber/New Hampshire Oncology Hematology	Londonderry	New Hampshire
United States	James Graham Brown Cancer Center	Louisville	Kentucky
United States	Norton Hospital	Louisville	Kentucky
United States	University of Louisville Hospital	Louisville	Kentucky
United States	University of Louisville Physicians, PSC	Louisville	Kentucky
United States	University of Louisville, Division of Surgical Oncology	Louisville	Kentucky
United States	Lowell General Hospital	Lowell	Massachusetts
United States	University of Wisconsin	Madison	Wisconsin
United States	Carle - Mattoon/Charleston	Mattoon	Illinois
United States	Toledo Clinic Cancer Center - Maumee	Maumee	Ohio
United States	Loyola University Medical Center	Maywood	Illinois
United States	Bon Secours Cancer Institute Medical Oncology at Memorial Regional	Mechanicsville	Virginia
United States	Woodland Cancer Care Center	Michigan City	Indiana
United States	Middlesex Hospital	Middletown	Connecticut
United States	Bon Secours Cancer Institute Medical Oncology at St. Francis	Midlothian	Virginia
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Masonic Cancer Center University of Minnesota Medical Center	Minneapolis	Minnesota
United States	University of Minnesota Health: Clinics and Surgery Center	Minneapolis	Minnesota
United States	University of Minnesota Medical Center, Fairview	Minneapolis	Minnesota
United States	Community Medical Center	Missoula	Montana
United States	Franciscan St. Francis Health - Mooresville	Mooresville	Indiana
United States	SUNY Upstate Medical University	New York	New York
United States	Green Bay Oncology, Ltd./HSHS St. Clare Memorial Hospital	Oconto Falls	Wisconsin
United States	Breast Cancer Center at Memorial Hospital West	Pembroke Pines	Florida
United States	Memorial Cancer Institute at Memorial Hospital West	Pembroke Pines	Florida
United States	Memorial Hospital West	Pembroke Pines	Florida
United States	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania
United States	Kootenai Health	Post Falls	Idaho
United States	MultiCare Regional Cancer Center - Puyallup	Puyallup	Washington
United States	Onslow Medical Center	Richlands	North Carolina
United States	Bon Secours Cancer Institute Medical Oncology at St. Mary's	Richmond	Virginia
United States	Reid Health	Richmond	Indiana
United States	Siteman Cancer Center - South County	Saint Louis	Missouri
United States	Siteman Cancer Center - West County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center - St. Peters	Saint Peters	Missouri
United States	Medical Oncology Associates- San Diego	San Diego	California
United States	Sharp Memorial Hospital	San Diego	California
United States	Sharp Rees-Stealy	San Diego	California
United States	UCSF Medical Center - Mission Bay	San Francisco	California
United States	NorthShore University HealthSystem Skokie ACC	Skokie	Illinois
United States	The Center for Cancer Care-Snellville	Snellville	Georgia
United States	Memorial Hospital at South Bend	South Bend	Indiana
United States	South Shore Hospital	South Weymouth	Massachusetts
United States	The Stamford Hospital	Stamford	Connecticut
United States	Saint Joseph's Medical Center	Stockton	California
United States	Green Bay Oncology, Ltd./Door County Memorial Hospital	Sturgeon Bay	Wisconsin
United States	Multicare Institute for Research & Innovation	Tacoma	Washington
United States	MultiCare Regional Cancer Center - Tacoma	Tacoma	Washington
United States	Union Hospital	Terre Haute	Indiana
United States	Toledo Clinic Cancer Center - Toledo	Toledo	Ohio
United States	Dayton Physicians LLC, Upper valley	Troy	Ohio
United States	The Carle Foundation Hospital/Carle Cancer Center	Urbana	Illinois
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina
United States	WellSpan Health York Cancer Center	York	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Alliance Foundation Trials, LLC.	Patient-Centered Outcomes Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cumulative Non-Fatal VTE Recurrence at 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.	6 months
Secondary	Cumulative Rates of Major Bleeding	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).	6 months
Secondary	Health Related Quality of Life Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire	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.	3 months
Secondary	Burden of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire	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).	3 months
Secondary	Mortality Reported by Participants' Surrogates (Via Study-specific Questionnaire) or Clinicians (Via Study-specific Case Report Form)	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)	6 months
Secondary	Health Related Quality of Life Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire	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.	6 months
Secondary	Burden of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire	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).	6 months
Secondary	Benefit of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire	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).	3-months
Secondary	Benefit of Anticoagulation Therapy Reported by Participants Via the Anti-Clot Treatment Scale (ACTS) Questionnaire	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).	6-months
Secondary	Health Related Quality of Life (Mental Health) Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire at 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.	3-months
Secondary	Health Related Quality of Life (Mental Health) Reported by Participants Via the Optum SF-12v2 Health Survey Questionnaire at 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.	6-months

External Links

•   FDA Package Insert for Apixaban (Eliquis)
•   FDA Package Insert for Dabigatran (Pradaxa)
•   FDA Package Insert for Dalteparin (Fragmin)
•   FDA Package Insert for Edoxaban (Savaysa)
•   FDA Package Insert for Enoxaparin (Lovenox)
•   FDA Package Insert for Fondaparinux (Arixtra)
•   FDA Package Insert for Rivaroxaban (Xarelto)
•   FDA Package Insert for Warfarin (Coumadin)