Survival outcomes with warfarin compared with direct oral anticoagulants in cancer-associated venous thromboembolism in the United States: A population-based cohort study

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Abstract

Background

Direct oral anticoagulants (DOACs) have comparable efficacy with low-molecular-weight heparin (LMWH) for the treatment of cancer-associated venous thromboembolism (VTE). Whether there is a mortality benefit of DOACs compared with warfarin in the management of VTE in cancer is not established.

Methods and findings

Utilizing the United States’ Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases from 2012 through 2016, we analyzed overall survival in individuals diagnosed with a primary gastric, colorectal, pancreas, lung, ovarian, or brain cancer and VTE who received a prescription of DOAC or warfarin within 30 days of VTE diagnosis. Patients were matched 1:2 (DOAC to warfarin) through exact matching for cancer stage and propensity score matching for age, cancer site, cancer stage, and time interval from cancer to VTE diagnosis. The analysis identified 4,274 patients who received a DOAC or warfarin for the treatment of VTE within 30 days of cancer diagnosis (1,348 in DOAC group and 2,926 in warfarin group). Patients were of median age 75 years and 56% female. Within the DOAC group, 1,188 (88%) received rivaroxaban, and 160 (12%) received apixaban. With a median follow-up of 41 months, warfarin was associated with a statistically significantly higher overall survival compared to DOACs (median overall survival 12.0 months [95% confidence interval (CI): 10.9 to 13.5] versus 9.9 months [95% CI: 8.4 to 11.2]; hazard ratio (HR) 0.85; 95% CI: 0.78 to 0.91; p < 0.001). Observed differences in survival were consistent across subgroups of cancer sites, cancer stages, and type of VTE. The study limitations include retrospective design with potential for unaccounted confounders along with issues of generalizability beyond the cancer diagnoses studied.

Conclusions

In this analysis of a population-based registry, warfarin was associated with prolonged overall survival compared to DOACs for treatment of cancer-associated VTE.

Abstract

Adeel Khan and co-workers study anticoagulant prescriptions and survival outcomes in patients with cancer-associated venous thromboembolism.

Author summary

Why was this study done?

In population-based studies, warfarin has been associated with improved overall survival compared with low-molecular-weight heparin (LMWH) for the treatment of cancer-associated thrombosis.
Based on demonstration of antithrombotic efficacy, direct oral anticoagulants (DOACs) are commonly prescribed for management of venous thromboembolism (VTE) in cancer.
Whether there is an overall survival difference in the treatment of VTE in cancer with DOACs compared with warfarin is not known.

What did the researchers do and find?

This was a retrospective cohort study of the Surveillance, Epidemiology, and End Results (SEER)-Medicare database comparing the overall survival of exact-stage and propensity score–matched elderly patients with cancer and VTE ( N = 4,274) who received DOACs or warfarin.
Warfarin was associated with a significantly prolonged overall survival compared with DOACS in the treatment of VTE in cancer.

What do these findings mean?

Emerging population-based evidence suggests an overall survival benefit with warfarin compared with other anticoagulants for treatment of VTE in cancer.
Warfarin has been shown to have antineoplastic activity in preclinical models.
Prospective randomized trials evaluating potential survival differences with warfarin are warranted.

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Most cited references 37

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Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.

Agnes Lee, Mark N Levine, Ross Baker … (2003)

Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer. Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months). During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group. In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding. Copyright 2003 Massachusetts Medical Society

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Epidemiology of venous thromboembolism.

John Heit (2015)

Thrombosis can affect any venous circulation. Venous thromboembolism (VTE) includes deep-vein thrombosis of the leg or pelvis, and its complication, pulmonary embolism. VTE is a fairly common disease, particularly in older age, and is associated with reduced survival, substantial health-care costs, and a high rate of recurrence. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and various risk factors. Major risk factors for incident VTE include hospitalization for surgery or acute illness, active cancer, neurological disease with leg paresis, nursing-home confinement, trauma or fracture, superficial vein thrombosis, and-in women-pregnancy and puerperium, oral contraception, and hormone therapy. Although independent risk factors for incident VTE and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be fairly constant, or even increasing.

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Oral rivaroxaban for symptomatic venous thromboembolism.

Giancarlo Agnelli, Hervé Decousus, F Piovella … (2010)

Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

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Author and article information

Contributors

Adeel M. Khan:

ORCID: https://orcid.org/0000-0002-9462-6316

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing

Thita Chiasakul:

ORCID: https://orcid.org/0000-0002-0443-1751

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Robert Redd:

ORCID: https://orcid.org/0000-0002-1329-5288

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Investigation

Rushad Patell: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing

Ellen P. McCarthy:

ORCID: https://orcid.org/0000-0003-1705-6249

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing

Donna Neuberg:

ORCID: https://orcid.org/0000-0003-2566-3145

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing

Jeffrey I. Zwicker: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Suzanne C. Cannegieter: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS Med

Journal ID (iso-abbrev): PLoS Med

Journal ID (publisher-id): plos

Title: PLoS Medicine

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1549-1277

ISSN (Electronic): 1549-1676

Publication date (Electronic): 25 May 2022

Publication date Collection: May 2022

Volume: 19

Issue: 5

Electronic Location Identifier: e1004012

Affiliations

[1 ] Division of Hematology and Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America

[2 ] Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand

[3 ] Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America

[4 ] Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts, United States of America

[5 ] Divisions of Gerontology and General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America

Leiden University Medical Center, NETHERLANDS

Author notes

I have read the journal’s policy and the authors of this manuscript have the following competing interests. J.I.Z. has received research funding from Incyte and Quercegen; consultancy services to Sanofi, CSL, and Parexel; and honoraria from/advisory board participation with Pfizer/Bristol Myers Squibb (BMS), Portola, and Daiichi. The remaining authors declare no competing financial interests.

* E-mail: jzwicker@ 123456bidmc.harvard.edu

Author information

Adeel M. Khan https://orcid.org/0000-0002-9462-6316

Thita Chiasakul https://orcid.org/0000-0002-0443-1751

Robert Redd https://orcid.org/0000-0002-1329-5288

Ellen P. McCarthy https://orcid.org/0000-0003-1705-6249

Donna Neuberg https://orcid.org/0000-0003-2566-3145

Article

Publisher ID: PMEDICINE-D-22-00351

DOI: 10.1371/journal.pmed.1004012

PMC ID: 9182592

PubMed ID: 35613184

SO-VID: 2b6951c3-3df4-4f40-99bc-401d1682d76d

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 31 January 2022

Date accepted : 4 May 2022

Page count

Figures: 3, Tables: 1, Pages: 15

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: U01HL143365

The study was funded by the National Heart, Lung, and Blood Institute CLOT Consortium (U01HL143365).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Custom metadata

PLOS Publication Stage vor-update-to-uncorrected-proof

Publication Update 2022-06-09

Data Availability Data cannot be shared publicly because the SEER MEDICARE database requires individual institution data use agreements for access. Instructions for access to SEER-Medicare database are provided at https://healthcaredelivery.cancer.gov/seermedicare/obtain.

Survival outcomes with warfarin compared with direct oral anticoagulants in cancer-associated venous thromboembolism in the United States: A population-based cohort study

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Abstract

Background

Methods and findings

Conclusions

Abstract

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Related collections

Karger: Oncology

Most cited references 37

Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.

Epidemiology of venous thromboembolism.

Oral rivaroxaban for symptomatic venous thromboembolism.

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