Direct oral anticoagulant use in gynecologic oncology: A Society of Gynecologic Oncology Clinical Practice Statement

doi:10.1016/j.ygyno.2020.11.020

Gynecologic Oncology

Volume 160, Issue 1, January 2021, Pages 312-321

https://doi.org/10.1016/j.ygyno.2020.11.020 Get rights and content

Highlights

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DOACs effective as LMWH for treatment of cancer-associated thrombosis.
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DOACs linked with higher bleeding risk, specifically with gastro and genitourinary cancers.
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Apixaban has similar safety profile to LMWH after major abdominopelvic surgery.
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Future studies to examine safety and efficacy in patients with gynecologic malignancy.

Abstract

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in women with gynecologic malignancies. This practice statement provides clinical data and overall quality of evidence regarding the use of direct oral anticoagulants (DOACs) in this patient population. Specifically, it reviews patient selection, safety measures, and nuances of perioperative use of these medications. The scope of this document is limited to DOAC use in gynecologic oncology rather than a broad discussion of VTE prophylaxis and management in general. The following recommendations and examination of extant data are based on DOAC trials conducted primarily in mixed populations with different cancer subtypes. Many of these trials include few, or no, women with gynecologic cancer. However, because there is very limited data in gynecologic cancer-specific populations, the results of these studies represent the best available evidence to support treatment recommendations in our patients. The members of the Society of Gynecologic Oncology (SGO) Clinical Practice Committee believe that the results of these studies may be extrapolated, with caution, to VTE treatment and prophylaxis for patients with gynecologic cancer.

Introduction

Venous thromboembolism (VTE) occurs in up to 25–38% of patients with gynecologic cancer and is associated with great morbidity and mortality [1,2]. The increased risk of VTE in patients with gynecologic cancer has been attributed to a combination of reduced mobility, central lines, vascular compression by disease, chemotherapy, obesity, and the increased thrombogenic potential of certain malignancies. Furthermore, patients with cancer-associated VTE are at increased risk of recurrent VTE and major bleeding events compared to their counterparts without cancer [3].

Traditionally, unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) have been the standard of care for the treatment and prophylaxis of VTE due to proven efficacy in this patient population and more predictable pharmacokinetics compared to vitamin K antagonists (VKAs) [4,5] such as coumadin. Direct oral anticoagulants (DOACs) have emerged as an alternative to injectable medications for both VTE treatment and prevention. When these compounds were first released, they were referred to in the literature as either non-VKA oral anticoagulants or novel oral anticoagulants (NOACs). However, given that these drugs are no longer novel and have been used in large randomized studies for over 10 years, they are now commonly referred to as DOACs [6]. DOACs include both direct factor Xa inhibitors (apixaban, betrixaban, edoxaban and rivaroxaban) and the oral direct thrombin inhibitor dabigatran [6]. Compared with LMWH which acts by binding to antithrombin III and indirectly inhibiting factor Xa, DOACs act by directly and irreversibly inhibiting factor Xa or thrombin (factor IIa). These drugs are an attractive option when compared to LMWH or VKAs given their oral administration, fixed dose regimen, and lack of need to perform routine blood monitoring tests. However, due to limited data in a gynecologic cancer-specific patient population, there are no formal recommendations regarding DOACs in gynecologic malignancy.

This clinical practice statement aims to inform providers about the safety and efficacy of DOACs in patients with gynecologic cancer. It further seeks to guide management of VTE treatment and prophylaxis in order to optimize effectiveness, patient safety, and patient satisfaction. Clinical questions regarding use of DOACs for individuals with gynecologic cancer are accompanied with overall strength of recommendation and grading of quality of evidence as recommended by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [7] (Supplementary Fig. S1).

Section snippets

Clinical questions

Clinical Question 1: What role should DOACs play in the treatment of gynecologic cancer-associated VTE?

Recommendation 1: (Strength of Recommendation- Strong, QoE Grade- Moderate)

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Patients with a gynecologic cancer-associated VTE should receive long-term treatment (at least 3–6 months) with LMWH, apixaban, edoxaban or rivaroxaban.
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The choice of anticoagulant used should be individualized and based on anticipated drug-drug interactions, renal clearance, and ability to tolerate oral medications.
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Special considerations for DOAC use in patients with cancer

1.
Cancer with high bleeding risk: DOACs are not recommended as first line treatment in patients with high risk of bleeding such as patients with luminal gastrointestinal cancers or renal cancers. DOAC therapy should also be avoided in patients with gastric or duodenal ulcers, gastritis, colitis, or esophagitis. While data specific to gynecologic malignancies does not exist, DOAC use should be avoided in patients with high bleeding risk and those with active bleeding.
2.
Altered gastrointestinal

Conclusions

DOACs are likely as effective as LMWH for VTE prophylaxis and treatment of cancer-associated thrombosis, but are associated with increased bleeding risk, specifically in patients with gastrointestinal cancers. Shared decision making should be employed when selecting an appropriate anticoagulant as both LMWH and DOACs can result in prohibitive out of pocket expenses to patients. Available evidence supports the use of apixaban and rivaroxaban for VTE prophylaxis in ambulatory women receiving

Author contributions

GMG- As the lead author of this study, Dr. Gressel wrote key portions of the manuscript and was principally involved in draft revision and organization of the document.

JZM - As study co-authors, Drs. Marcus and Mullen wrote and organized several key portions of the manuscript.

MMM- As study co-authors, Drs. Marcus and Mullen wrote and organized several key portions of the manuscript.

AKS- As the senior author of this study, Dr. Sinno wrote key portions of the manuscript as was principally

Declaration of Competing Interest

Dr. Marcus reports grants from Merck as well as service on an advisory board for Tesaro. All compensation for these activities was accepted by her institution.

References (73)

A. Li et al.
Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): a systematic review and meta-analysis
Thromb. Res.
(2019)
E.L. Barber et al.
Prevention of venous thromboembolism in gynecologic oncology surgery
Gynecol. Oncol.
(2017)
C. Kearon et al.
Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report
Chest
(2016)
R.D. Hull et al.
Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer
Am. J. Med.
(2006)
M. Carrier et al.
Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis
Thromb. Res.
(2014)
F. Posch et al.
Treatment of venous thromboembolism in patients with cancer: a network meta-analysis comparing efficacy and safety of anticoagulants
Thromb. Res.
(2015)
A.A. Khorana et al.
Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH
J. Thromb. Haemost.
(2018)
N.D. Brunetti et al.
Direct oral anti-coagulants compared with vitamin-K inhibitors and low-molecular-weight-heparin for the prevention of venous thromboembolism in patients with cancer: a meta-analysis study
Int. J. Cardiol.
(2017)
K. Kroger et al.
Risk factors for venous thromboembolic events in cancer patients
Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.
(2006)
M. Di Nisio et al.
Venous thromboembolism in cancer patients receiving neoadjuvant chemotherapy: a systematic review and meta-analysis
J. Thromb. Haemost.
(2018)

A.A. Khorana et al.

Development and validation of a predictive model for chemotherapy-associated thrombosis

Blood

(2008)

N. van Es et al.

The Khorana score for the prediction of venous thromboembolism in patients with pancreatic cancer

Thromb. Res.

(2017)

A.S. Mansfield et al.

Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer

J. Thromb. Haemost.

(2016)

S. Noble et al.

Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: comment

J. Thromb. Haemost.

(2017)

C. Ay et al.

Prediction of venous thromboembolism in cancer patients

Blood

(2010)

I. Pabinger et al.

A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts

Lancet Haematol.

(2018)

M.R. Lassen et al.

Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial

Lancet

(2010)

J.D. Douketis et al.

Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Chest

(2012)

R.D. McBane et al.

Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial

J. Thromb. Haemost.

(2020)

D. Farge et al.

2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer

Lancet Oncol.

(2019)

A. Cohen et al.

Venous thromboembolism in gynecological malignancy

Int. J. Gynecol. Cancer

(2017)

C.L. Kushnir et al.

Perioperative care in gynecologic oncology

Curr. Opin. Obstet. Gynecol.

(2013)

E.A. Akl et al.

Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer

Cochrane Database Syst. Rev.

(2011)

G.H. Guyatt et al.

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

BMJ

(2008)

A.Y.Y. Lee et al.

Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial

J. Am. Med. Assoc.

(2015)

A.Y.Y. Lee et al.

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

N. Engl. J. Med.

(2003)

G. Meyer et al.

Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study

Arch. Intern. Med.

(2002)

L.A. Kahale et al.

Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer

Cochrane Database Syst. Rev.

(2018)

M.J. Martinez-Zapata et al.

Tinzaparin for long-term treatment of venous thromboembolism in patients with cancer: a systematic review and meta-analysis

Clin. Appl. Thromb. Hemost.

(2018)

N.S. Key et al.

Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update summary

J. Oncol. Pract.

(2019)

M.B. Streiff et al.

NCCN Guidelines® insights cancer-associated venous thromboembolic disease, version 1.2020 featured updates to the NCCN guidelines

J. Natl. Compr. Cancer Netw.

(2018)

W. Ageno et al.

Characteristics and management of patients with venous thromboembolism: the GARFIELD-VTE registry

Thromb. Haemost.

(2019)

G.E. Raskob et al.

Edoxaban for the treatment of cancer-associated venous thromboembolism

N. Engl. J. Med.

(2018)

A.M. Young et al.

Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D)

J. Clin. Oncol.

(2018)

G. Agnelli et al.

Apixaban for the treatment of venous thromboembolism associated with cancer

N. Engl. J. Med.

(2020)

C.W. Francis

Prevention of venous thromboembolism in hospitalized patients with cancer

J. Clin. Oncol.

(2017)

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Citation Excerpt :
Evidence from recent large, randomized clinical trials resulted in publication of the 2020 American Society for Clinical Oncology (ASCO) guidelines recommending risk-stratified pharmacologic thromboprophylaxis for patients receiving outpatient cancer-directed therapy with a KS ≥ 2 [5–7]. These recommendations were endorsed by the Society of Gynecologic Oncology (SGO) for patients with gynecologic malignancies in January 2021, but have not yet been widely adopted [7,8]. Studies addressing strategies for guideline implementation and data regarding outcomes of risk-stratified pharmacologic thromboprophylaxis are therefore limited.
Risk-stratified thromboprophylaxis is recommended for oncology patients with a Khorana risk score (KS) ≥ 2 receiving cancer-directed therapy. We describe a quality improvement (QI) initiative designed to increase adherence to thromboprophylaxis guidelines for patients with gynecologic malignancies initiating outpatient treatment.
Provider awareness and documentation of venous thromboembolism (VTE) risk assessment and thromboprophylaxis eligibility were identified as key QI drivers. Starting May 2021, a KS calculator and thromboprophylaxis algorithm were incorporated into outpatient documentation templates. Patients with gynecologic malignancies initiating outpatient therapy from January – December 2021 were eligible. The primary process measure was the percentage of patients with KS eligibility documented each month during the baseline (Jan – Apr) versus implementation (May – Dec) periods. Rate of appropriate thromboprophylaxis initiation and incidence of VTE served as outcome measures. Incidence of adverse bleeding events served as the balancing measure.
337 patients accounted for the initiation of 383 treatment regimens, including 128 in the baseline period and 255 in the implementation period. KS documentation increased significantly between the baseline and implementation periods (7% vs 62.4%, p < 0.001). 73 of the 177 eligible patients (46.2%; 166 unique patients) had appropriate documentation; of these, 57 initiated thromboprophylaxis. There was no difference in VTE rates or adverse bleeding events between eligible patients who initiated thromboprophylaxis compared with those who did not (12.3% vs 15.6%; p = 0.65 and 7.0% vs 8.2%; p = 1.0, respectively).
This QI initiative resulted in greater adherence to risk-stratified thromboprophylaxis guidelines. No bleeding signals were identified. Studies addressing cost, medication adherence, and long-term outcomes are necessary.

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Clinical Practice StatementDirect oral anticoagulant use in gynecologic oncology: A Society of Gynecologic Oncology Clinical Practice Statement

Highlights

Abstract

Introduction

Section snippets

Clinical questions

Special considerations for DOAC use in patients with cancer

Conclusions

Author contributions

Declaration of Competing Interest

Thromb. Res.

Gynecol. Oncol.

Chest

Am. J. Med.

Thromb. Res.

Thromb. Res.

J. Thromb. Haemost.

Int. J. Cardiol.

Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.

J. Thromb. Haemost.

Blood

Thromb. Res.

J. Thromb. Haemost.

J. Thromb. Haemost.

Blood

Lancet Haematol.

Lancet

Chest

J. Thromb. Haemost.

Lancet Oncol.

Venous thromboembolism in gynecological malignancy

Int. J. Gynecol. Cancer

Perioperative care in gynecologic oncology

Curr. Opin. Obstet. Gynecol.

Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer

Cochrane Database Syst. Rev.

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

BMJ

Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial

J. Am. Med. Assoc.

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

N. Engl. J. Med.

Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study

Arch. Intern. Med.

Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer

Cochrane Database Syst. Rev.

Tinzaparin for long-term treatment of venous thromboembolism in patients with cancer: a systematic review and meta-analysis

Clin. Appl. Thromb. Hemost.

Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update summary

J. Oncol. Pract.

NCCN Guidelines® insights cancer-associated venous thromboembolic disease, version 1.2020 featured updates to the NCCN guidelines

J. Natl. Compr. Cancer Netw.

Characteristics and management of patients with venous thromboembolism: the GARFIELD-VTE registry

Thromb. Haemost.

Edoxaban for the treatment of cancer-associated venous thromboembolism

N. Engl. J. Med.

Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D)

J. Clin. Oncol.

Apixaban for the treatment of venous thromboembolism associated with cancer

N. Engl. J. Med.

Prevention of venous thromboembolism in hospitalized patients with cancer

J. Clin. Oncol.

Clinical Practice Statement
Direct oral anticoagulant use in gynecologic oncology: A Society of Gynecologic Oncology Clinical Practice Statement