The incidence of major bleeding in adult patients with urogenital and gynecological cancer being treated with direct oral anticoagulants (DOACs): a systematic review.

BACKGROUND: Direct oral anticoagulants (DOACs) are the mainstay of treatment for venous thromboembolism (VTE) and non-valvular atrial fibrillation (AF), with or without an underlying cancer. Patients with cancer have a 2-3-fold increase in risk for bleeding complications compared to non-cancer patients taking anticoagulant therapy, however the incidence of bleeding for urogenital and gynecological cancers on DOACs are uncertain. AIMS: To assess the bleeding risk associated with the use of DOACs in patients with urogenital and/or gynecological cancers. METHOD: We conducted a systematic review of randomized controlled trials (RCTs) and prospective cohort studies to address the safety of DOACs for VTE and AF when used in patients with urogenital and/or gynecological malignancy. The primary outcomes assessed were major and clinically relevant non-major (CRNMB) bleeding, with minor bleeding considered as a secondary outcome. MEDLINE, EMBASE and COCHRANE Central Registry of Controlled Trials were searched up to and including Oct 28, 2022. The study protocol was registered in PROSPERO (CRD42022370981). Studies were independently assessed for inclusion and data extracted in duplicate. RESULT: Seven studies met our inclusion criteria (Fig. 1): 2 RCTs and 5 prospective cohort studies. A total of 676 patients treated with DOACs were included, 628 (92.8%) had VTE and 48 (7.1%) had AF. In patients with VTE treated with DOACs, the pooled major bleeding rate was 2.1%, 95% confidence intervals (CI) 0.9-3.3% (Fig. 2). Pooled estimates could not be determined for AF patients given small event and patient numbers. CONCLUSION: Major bleeding rates in urogenital and/or gynecological cancer patients treated with DOACs are similar to that of the general cancer population.

Safety and Effectiveness of Direct Oral Anticoagulants for the Treatment of Gastrointestinal Cancer-Associated Venous Thromboembolism.

BACKGROUND: Patients with gastrointestinal cancer (GICA) are at high risk for venous thromboembolism (VTE). Data from randomized clinical trials in cancer-associated VTE suggest that direct oral anticoagulants (DOACs) conferred similar or superior efficacy but a heterogeneous safety profile in patients with GICA. We compared the safety and effectiveness of DOACs in patients with GICA and VTE at MD Anderson Cancer Center. MATERIALS AND METHODS: This was a retrospective chart review of patients with GICA and VTE receiving treatment with DOACs for a minimum of 6 months. Primary outcomes were the proportion of patients experiencing major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and recurrent VTE. Secondary outcomes were time to bleeding and recurrent VTE. RESULTS: A cohort of 433 patients with GICA who were prescribed apixaban (n = 300), or rivaroxaban (n = 133) were included. MB occurred in 3.7% (95% confidence interval [CI] 2.1-5.9), CRNMB in 5.3% (95% CI 3.4-7.9), and recurrent VTE in 7.4% (95% CI 5.1-10.3). The cumulative incidence rates of CRNMB and recurrent VTE were not significantly different when comparing apixaban to rivaroxaban. CONCLUSION: Apixaban and rivaroxaban had a similar risk of recurrent VTE and bleeding and could be considered as anticoagulant options in selected patients with GICA and VTE.

Survey of medical oncologists and trainee practice on venous thromboembolism prophylaxis and treatment in solid cancers.

Venous thromboembolism (VTE) has a significant adverse impact on the outcomes of patients with active solid malignancies. Prophylaxis is indicated for cancer-associated VTE (CA-VTE) using the Khorana score for risk stratification. We surveyed medical oncology fellows and trainees regarding their practice in CA-VTE. Regarding treatment of CA-VTE, practice was consistent with guidelines. However, regarding prophylaxis for CA-VTE, there was a high degree of uncertainty, which highlights the need for ongoing education.

Unanswered questions in cancer-associated thrombosis.

Cancer-associated venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. Treatment of cancer-associated VTE comes with a heightened risk of anticoagulant-related bleeding that differs by choice of anticoagulant as well as by patient- and disease-specific risk factors. Available data from randomized controlled trials and observational studies in cancer-associated VTE suggest that direct oral anticoagulants are effective, continuing anticoagulation beyond six months is indicated in those with active cancer and that patients who develop 'breakthrough' thrombotic events can be effectively treated. We review the evidence that addresses these key clinical questions and offer pragmatic approaches in individualizing care. While significant investigative efforts over the past decade have made impactful advances, future research is needed to better define the factors that contribute to anticoagulant-related bleeding and VTE recurrence, in order to aid clinical decision-making that improves the care of patients with cancer-associated VTE.

Renal function and clinical outcome of patients with cancer-associated venous thromboembolism randomized to receive apixaban or dalteparin. Results from the Caravaggio trial

The effect of renal impairment (RI) on risk of bleeding and recurrent thrombosis in cancer patients treated with direct oral anticoagulants for venous thromboembolism (VTE) is undefined. We ran a prespecified analysis of the randomized Caravaggio study to evaluate the role of RI as a risk factor for bleeding or recurrence in patients treated with dalteparin or apixaban for cancerassociated VTE. RI was graded as moderate (creatinine clearance between 30-59 mL/minute; 275 patients) and mild (between 60- 89 mL/minute; 444 patients). In the 1142 patients included in this analysis, the incidence of major bleeding was similar in patients with moderate vs. no or mild RI (HR 1.06-95% CI: 0.53-2.11), with no difference in the relative safety of apixaban and dalteparin. Recurrent VTE was not different in moderate vs. no or mild RI (HR=0.67, 95% CI: 0.38-1.20); in moderate RI, apixaban reduced recurrent VTE compared to dalteparin (HR=0.27, 95% CI: 0.08-0.96; P for interaction 0.1085). At multivariate analysis, no association was found between variation of renal function over time and major bleeding or recurrent VTE. Advanced or metastatic cancer was the only independent predictor of major bleeding (HR=2.84, 95% CI: 1.20-6.71), with no effect of treatment with apixaban or dalteparin. In our study, in cancer patients treated with apixaban or dalteparin, moderate RI was not associated with major bleeding or recurrent VTE. In patients with moderate renal failure, the safety profile of apixaban was confirmed with the potential for improved efficacy in comparison to dalteparin. ClinicalTrials.gov identifier: NCT03045406.

Risk stratification for clinical severity of pulmonary embolism in patients with cancer: a narrative review and MASCC clinical guidance for daily care.

Pulmonary embolism (PE) is a leading cause of morbidity and mortality in patients with cancer. The clinical presentation and outcomes of PE range from an acute life-threatening condition requiring intensive care to a mild symptomatic condition associated with favorable outcomes and potentially candidate for early hospital discharge. The wide clinical spectrum of PE has led to the development of risk stratification models aimed at the triage of patients in emergency care departments and optimizing the utilization of health care resources. Incidental or unsuspected PE (UPE), detected during routine staging computed tomography scans, make up a significant proportion of this cohort among the oncology population. The present narrative review is aimed at examining the currently available PE risk assessment models developed for the general population and for patients with cancer including UPE. We include general recommendations for the daily care of patients with cancer-related PE and hypothesize on the factors that would potentially favor hospitalization with early discharge or ambulatory management in this setting.

Current Management of Cancer-associated Venous Thromboembolism: Focus on Direct Oral Anticoagulants.

Cancer-associated venous thromboembolism (CAT) is a common complication associated with high morbidity and mortality. In accordance with major clinical trials comparing low-molecular-weight heparin (LMWH) with a vitamin K antagonist (VKA), LMWH is currently the standard treatment for CAT, owing to its efficacy for thrombosis recurrence and improved safety profile compared to VKA. Over the past few years, direct oral anticoagulants (DOACs) have emerged as potential alternative therapies to LMWH due to their convenient route of administration and predictable pharmacokinetics, but evidence for their use in CAT is inconclusive, as only a small fraction of the study populations in these trials had CAT. Recently, two large head-to-head trials comparing DOACs to LMWH in CAT patients reported comparable efficacies of DOACs with increased bleeding risk. Occasionally, CAT treatment can be challenging due to the heterogeneity of underlying malignancies and comorbidities. Renal insufficiency and gastrointestinal defects are the main obstacles in anticoagulant selection. Careful choice of treatment candidates and proper anticoagulant strategies are critical for the treatment of CAT; hence, more studies are required to address these challenges.

Venous thromboembolism treatment outcomes in cancer patients and effect of third-party payers on anticoagulant choice.

PURPOSE: The purpose of this study is to compare the rates of recurrent VTE among cancer patients treated with parenteral agents to the oral anticoagulants. METHODS: This single-center study was a retrospective chart review of cancer patients with recurrent VTE between January 1, 2009 and December 31, 2014. The primary outcome of the study is the rate of recurrent VTE in patients who received a parenteral anticoagulant (enoxaparin, dalteparin, fondaparinux) versus those who received oral anticoagulants (warfarin and rivaroxaban). Other outcomes investigated include risk factors associated with recurrent VTE events and influence of third-party payer on anticoagulant selection. RESULTS: Four hundred fifty-seven patients met inclusion criteria (178 in the oral anticoagulant group and 279 in the parenteral anticoagulant group). Patients with Medicare were more likely to have received an oral anticoagulant (P = 0.003) and patients with private insurance were more likely to have received a parenteral anticoagulant (P = 0.004). There were 23 recurrent VTE events, 12 events (6.7 %) in the oral anticoagulant group and 11 events (3.94 %) in the parenteral group (P = 0.182). The only significant risk factor noted to increase risk of recurrent VTE was the presence of an IVC filter (adjusted OR 4.38, 95 % CI 1.67-11.53, P = 0.003). CONCLUSIONS: While there is no statistical difference in VTE events between groups, the oral anticoagulant group numerically had a higher rate. Important associations were found to have an influence on anticoagulant selection and risk of recurrent VTE. These factors must be incorporated into decision making when treating cancer patients with VTE.

How to Treat Today? Oral and Facial Cancer-Associated Venous Thromboembolism.

The exact incidence of cancer-associated venous thromboembolism (CA-VTE) in patients with oral and facial cancer (OFC) is not exactly known, and this risk is empirically considered to be low. However, this suggestion may result in disease underdiagnosis, prolong the initiation of adequate therapy, and consecutively increase CA-VTE-related morbidity and mortality. In addition, there might be specific clinical problems in the treatment of CA-VTE in patients with oral and facial cancer, such as swallowing difficulties, that might limit the possibilities of oral anticoagulation. Finally, there are limited data regarding the optimal treatment of CA-VTE in patients with oral and facial cancer, and this includes data on novel therapeutic strategies, including the use of direct oral anticoagulants. This article reviews current data on the optimal treatment strategy for CA-VTE in patients with OFC.

Apixaban in Japanese patients with cancer-associated venous thromboembolism: a multi-center phase II trial.

BACKGROUND: Recent pivotal phase III trials involving direct oral anticoagulant (DOAC) versus low molecular weight heparin have demonstrated the utility of DOACs in Western patients with cancer-associated venous thromboembolism (VTE). However, these trials did not include Japanese patients. This phase II trial evaluated the safety and efficacy of apixaban in Japanese patients with cancer-associated VTE (UMIN000028447). METHOD AND RESULTS: Apixaban was initiated at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 23 weeks. The primary endpoint was the incidence of major or clinically relevant non-major (CRNM) bleeding events during the treatment period. The study was terminated due to safety concerns after enrolling 27 patients. Median age was 71 years; median body weight was 51.3 kg; and major primary tumor sites were the gastrointestinal tract (26%) and lung (19%). During the median follow-up period of 5.4 months, major or CRNM bleeding occurred in in 26% of patients (major, n = 5; CRNM, n = 2; 95% confidence interval, 11-46%). No recurrent VTE or VTE-related death occurred. Estimated overall survival at 6 months was 68%. CONCLUSION: This study demonstrated the excessive bleeding risk of apixaban at the standard dose in Japanese patients with cancer-associated VTE.

Practical Considerations for the Management of Cancer-Associated Venous Thromboembolism: A Guide for the General Oncology Practitioner.

Cancer-associated venous thromboembolism is a devastating complication of cancer and is associated with significant morbidity and mortality. The cornerstone of cancer-associated venous thromboembolism treatment is anticoagulation, and in recent years, there have been notable randomized clinical trials that have revealed insights into the efficacy and safety of direct oral anticoagulants and low-molecular-weight heparin in the treatment of cancer-associated thrombosis. Deciding on the ideal anticoagulation treatment plan for a patient with a cancer-associated thrombosis is a complex task that requires an understanding of clinical trial data, society guidelines, and, most importantly, consideration of many cancer-related, treatment-related, and patient-related factors. This article summarizes important factors to consider when deciding on anticoagulation therapy for a patient with cancer-associated thrombosis.

Arguments for Using Direct Oral Anticoagulants in Cancer-Related Venous Thromboembolism.

(1) Background: Patients with cancer with a hypercoagulable state present an increased incidence of venous thromboembolism (VTE). Neoplastic patients with concurrent VTE undergoing anticoagulant treatment face a series of issues. (2) The aim of the present paper is to systematically summarize current VTE management in patients with neoplasia and to review the current clinical evidence from meta-analyses of randomized controlled trials and guidelines regarding the administration of direct oral anticoagulants (DOACs) for cancer-associated VTE. (3) Search Strategy: We performed a review on meta-analyses of randomized controlled trials and guidelines in favor of the administration of DOACs in patients with cancer-associated VTE published in the last 6 years in the Medline (PubMed) and Embase databases. (4) Results: 21 meta-analyses, 14 randomized controlled studies comparing DOACs to VKAs and LMWH, and 7 national and international guidelines were identified. We identified five studies that show the antineoplastic effect of DOAC on experimental models. (5) Conclusions: DOACs can be seen as the first choice for VTE treatment in neoplastic patients who have a low risk of bleeding, who do not have severe renal impairment, and who are not undergoing treatments that could interact with DOAC's mechanism of action.

Incidence of venous thromboembolism in patients with solid cancers in Japan: retrospective study of 2735 patients.

BACKGROUND: The incidence of cancer-associated venous thromboembolism (CA-VTE) in Japan has not been fully investigated. METHODS AND RESULTS: Clinicopathological information from patients with solid malignancies who first visited our department between November 2011 and March 2018 were retrospectively reviewed from medical records. The primary outcome was incidence of CA-VTE, defined as deep-vein thrombosis (DVT) and/or pulmonary embolism (PE). On median follow-up of 187 days, 91 of 2735 patients (3.3%) developed CA-VTE during their clinical course, giving an incidence rate of 40.7 per 1000 person-years. Of the 91 patients, 75 (82%) were diagnosed with DVT alone, 6 (7%) with PE alone, and 10 (11%) with both DVT and PE. CA-VTE was most frequent in non-small cell lung cancer (10.8%), followed by cancer of unknown origin (5.8%). Forty-four patients (48%) had one or more symptoms at the initial diagnosis of VTE. Five patients (6%) had a normal D-dimer level (≤ 1.0 µg/mL); of these, 2 were asymptomatic. CONCLUSIONS: In this retrospective study, the incidence of CA-VTE in Japanese patients with cancer was equivalent to that in Western populations. Approximately half of CA-VTE patients were asymptomatic and 6% had normal D-dimer levels, indicating the need for closer attention to occult CA-VTE.

Primary Thromboprophylaxis in Ambulatory Cancer Patients: Where Do We Stand?

Venous thromboembolism (VTE), comprising deep-vein thrombosis and pulmonary embolism, is a frequent complication in ambulatory cancer patients. Despite the high risk, routine thromboprophylaxis is not recommended because of the high number needed to treat and the risk of bleeding. Two recent trials demonstrated that the number needed to treat can be reduced by selecting cancer patients at high risk for VTE with prediction scores, leading the latest guidelines to suggest such an approach in clinical practice. Yet, the interpretation of these trial results and the translation of the guideline recommendations to clinical practice may be less straightforward. In this clinically-oriented review, some of the controversies are addressed by focusing on the burden of VTE in cancer patients, discussing the performance of available risk assessment scores, and summarizing the findings of recent trials. This overview can help oncologists, hematologists, and vascular medicine specialists decide about thromboprophylaxis in ambulatory cancer patients.

Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Anticoagulants for the treatment of venous thromboembolism in patients with cancer: A comprehensive systematic review, pairwise and network meta-analysis.

Cancer-associated venous thromboembolism (VTE) is associated with high VTE recurrence and bleeding. We included all randomized clinical trials that evaluated the efficacy and safety of various anticoagulants in cancer-associated VTE. Trial-level data were extracted from 13 trials. Aggregate odds ratios (ORs) were calculated using direct and network meta-analysis. The primary outcome was VTE (pulmonary embolism and/or deep vein thrombosis) recurrence. Secondary outcomes were major bleeding and all-cause mortality. We identified 13 trials with 4869 patient-years of follow-up (6595 total patients; mean age 62.4 ± 12.2; 50.4 % female; 17.7 % hematological malignancies). The most common cancer type was colorectal and 48 % had metastatic cancer at baseline. Compared to vitamin-K-antagonists (VKAs), non-vitamin-K-antagonist-oral-anticoagulants (NOACs) were associated with significantly reduced VTE recurrence (OR, 0.58; 95 % CI, 0.40-0.83) and reduced major bleeding risks (OR, 0.56; 95 % CI, 0.35-0.91). However, no differences were observed in the subgroup analysis of patients with active cancer. Although NOACs were associated with reduced VTE recurrence compared with low-molecular-weight-heparin (LMWHs) (OR, 0.46; 95 % CI, 0.25- 0.85), there was a significant increased major bleeding in high-quality trials. LMWHs were associated with significantly reduced VTE recurrence compared with VKAs (OR, 0.52; 95 % CI, 0.39-0.71) and similar bleeding risks. Conclusions: Among patients with cancer-associated VTE, NOACs were associated with significantly reduced VTE recurrence and bleeding compared with VKAs, however, with similar outcomes in the active cancer population. NOACs were associated with reduced VTE recurrence but higher bleeding risks compared with LMWHs. LMWHs were associated with significantly reduced VTE recurrence and similar bleeding compared with VKAs.

Rivaroxaban treatment for cancer-associated venous thromboembolism in a patient with heparin-induced thrombocytopenia: a case report.

Low molecular weight heparin (LMWH) is the first-line therapy in acute cancer-associated venous thromboembolism (CAT). However, heparin-induced thrombocytopenia (HIT) is a life-threatening adverse drug reaction that occurs in anticoagulation therapy with LMWH. This article reports the case of a 66-year-old Chinese male who received nadroparin 4100IU twice daily for treating CAT. Unfortunately, the epistaxis persisted and the blood count examination revealed serious thrombocytopenia on postoperative day 5. The patient was diagnosed with HIT and thereafter LMWH therapy was replaced with rivaroxaban. During three months follow-up, the patient had a good recovery without recurrent CAT or bleeding.

Trends of cancer-associated venous thromboembolism (VTE) in the United States (2005-2014).

INTRODUCTION: Cancer patients are prone to higher risk of venous thromboembolism (VTE) compared to the general population. However, the estimated incidence of cancer-associated VTE varied among the studies. The primary objective of this study was to determine the national annual incidence and examine the trend of cancer-associated VTE in the US over the years from 2005 to 2014. METHODS: A retrospective population based study was conducted using data from the Medical Expenditure Panel Survey. The study included all noninstitutionalized US adults aged ≥18 years who had a final person-weight > 0 to be representative of the national population. Simple linear regression (SLR) and Mann-Kendall (MK) tests were used to examine the trend of cancer-associated VTE over the years. RESULTS: On average, there were 15,570,000 adult persons living with a cancer condition every year. Female represented 53.8% of the study population, and the mean of age was 63.5 years. The overall annual incidence of cancer-associated VTE varied between 1.80 and 0.72% over the years, with an overall average of 1.18%. The study found a non-significant downward trend in the incidence of cancer-associated VTE over the years. Patients who had cancer-associated VTE were significantly older than patients without VTE (mean 68.64 vs. 62.68 years, p < .0001). CONCLUSION: The study found cancer patients continued to have the risk of VTE over the years. The non-significant downward trend in cancer-associated VTE suggests that health care practitioners are heading in the right direction, but enhanced preventative care is needed to avoid further incidents of cancer-associated VTE.

Apixaban for the treatment of cancer-associated venous thromboembolism and left atrial appendage thrombus refractory to optimal anticoagulation with warfarin: a case report.

BACKGROUND: Concomitant venous thromboembolism (VTE) and left atrial appendage (LAA) thrombus associated with cancer is exceedingly rare. The use of direct factor Xa inhibitors in patients with cancer is controversial. CASE SUMMARY: We report a rare case of concomitant VTE and LAA thrombus in an 85-year-old man with prostate cancer. He developed VTE and LAA thrombus, while on warfarin therapy for non-valvular atrial fibrillation. Despite optimal medical treatment with warfarin, systemic thrombosis developed. After thrombolysis, he was prescribed apixaban, an oral direct factor Xa inhibitor, as maintenance therapy. Deep venous thrombosis, pulmonary embolism, and LAA thrombus were effectively treated, and his symptoms resolved. DISCUSSION: Despite the fact that many patients with cancer are in a hypercoagulable state, to the best of our knowledge, this is a first case describing VTE and LAA thrombus presenting concomitantly during optimal warfarin therapy. This case demonstrates the importance of awareness of systemic thrombosis in patients with cancer regardless of vitamin K antagonist therapy. More cases and larger scale data are needed to investigate if factor Xa inhibitors are useful for treating systemic thrombosis in patients with cancer.

Cancer-Associated Venous Thromboembolism: A Practical Review Beyond Low-Molecular-Weight Heparins.

Patients with cancer are at significantly higher risk of developing, and dying from, venous thromboembolism (VTE). The CLOT trial demonstrated superiority of low-molecular-weight heparins (LMWH) over warfarin for recurrent VTE and established LMWH as the standard of care for cancer-associated VTE. However, with patients living longer with metastatic cancer, long-term injections are associated with significant cost and injection fatigue. Direct oral anticoagulants (DOACs) are an attractive alternative for treatment of cancer-associated VTE. Meta-analysis of subgroup data of patients with cancer from the large DOAC VTE trials and small non-randomized studies have found no difference in VTE recurrence or major bleeding. With this limited evidence, clinicians may decide to switch their patients who require long-term anticoagulation from LMWH to a DOAC. This requires careful consideration of the interplay between the patient's cancer and treatment course, with their underlying comorbidities.