Treatment Of Cancer-related Venous Thromboembolism Research Articles

Cancer-associated thromboembolism: could direct-acting oral anticoagulants be a promising therapeutic option? Literature review

Abstract Background Cancer-associated thromboembolism (CAT) is usually managed with low-molecular-weight heparins (LMWHs) or vitamin K antagonists (VKAs). The recent data suggest that direct-acting oral anticoagulants (DOACs) might have a role in the management of CAT both in terms of prevention and treatment. The aim of this article is to review the current literature regarding the use of DOACs in patients with cancer. Methods PUBMED and ClinicalTrials.gov were searched to identify prospective trials on patients with cancer managed with DOACs as either primary prophylaxis or treatment of venous thromboembolic events. Results In terms of primary prophylaxis, five studies (CASSINI, ADVOCATE, MYELAXAT, NCT02958969, and AVERT) have been identified. When considered together, CASSINI and AVERT showed a significant benefit of rivaroxaban and apixaban, respectively, versus placebo for the prevention of venous thromboembolism (VTE), with a low incidence of major bleeding and no significant difference in mortality. ADVOCATE, MYELAXAT, and NCT02958969 showed that apixaban was well tolerated in patients with metastases receiving chemotherapy or those with multiple myeloma receiving immunomodulatory imide drugs. With respect to VTE treatment, 3 studies (HOKUSAI-VTE, SELECT-D, and ADAM-VTE) were identified. These studies demonstrated significantly lower rates of VTE recurrences in patients treated with edoxaban, rivaroxaban, or apixaban, without compromise on safety. Conclusions DOACs seem a promising therapeutic option in CAT. As cancer is a heterogeneous disease, future research will clarify the role of these newer anticoagulant agents in both prevention and treatment of cancer-related VTE.

Direct Oral Anticoagulant Drugs: On the Treatment of Cancer-Related Venous Thromboembolism and their Potential Anti-Neoplastic Effect.

Cancer patients develop a hypercoagulable state with a four- to seven-fold higher thromboembolic risk compared to non-cancer patients. Thromboembolic events can precede the diagnosis of cancer, but they more often occur at diagnosis or during treatment. After malignancy itself, they represent the second cause of death. Low molecular weight heparins are the backbone of the treatment of cancer-associated thromboembolism. This treatment paradigm is possibly changing, as direct oral anticoagulants (DOACs) may prove to be an alternative therapeutic option. The currently available DOACs were approved during the first and second decades of the 21st century for various clinical indications. Three molecules (apixaban, edoxaban and rivaroxaban) are targeting the activated factor X and one (dabigatran) is directed against the activated factor II, thrombin. The major trials analyzed the effect of these agents in the general population, with only a small proportion of cancer patients. Two published and several ongoing studies are specifically investigating the use of DOACs in cancer-associated thromboembolism. This article will review the current available literature on the use of DOACs in cancer patients. Furthermore, we will discuss published data suggesting potential anti-cancer actions exerted by non-anticoagulant effects of DOACs. As soon as more prospective data becomes available, DOACs are likely to be considered as a potential new therapeutic option in the armamentarium for patients suffering of cancer-associated thromboembolism.

The role of direct oral anticoagulants in cancer-related venous thromboembolism: a perspective beyond the guidelines.

Cancer-related venous thromboembolism (Wickham et al., Intern Med J 42(6):698-708, 2012) is an important source of morbidity and mortality in that population. The standard of care for the treatment of cancer-related venous thromboembolism (VTE) is a low molecular weight heparin (LMWH) for long periods of time. The favorable clinical trial results for efficacy and safety and availability of direct oral anticoagulants (DOAC) have remodeled the care and options for treatment of venous thromboembolism in the adult population. The data of cancer population-subgroup analysis of those studies have shown that DOAC are as effective and safe as conventional long-term oral anticoagulation with vitamin K antagonists (VKA). Additionally, non-controlled retrospective and prospective cohort data have been published describing efficacy and safety outcomes for the use of DOAC in cancer-related VTE. Altogether, the results from clinical studies have shown that direct oral anticoagulants may represent a treatment option for cancer-related VTE and an alternative to anticoagulation with VKA. Little is known about the patient-centered and system-based variables that determine the use of DOAC outside consensus guidelines, neither is known the impact of different anticoagulant modalities in adherence and quality of life in cancer patients. The objectives of this manuscript are to summarize the clinical trial-based and cohort data of cancer patients treated with DOAC for VTE and to highlight the aspects that may influence adherent to therapy, effectiveness, and safety outcomes in the treatment of cancer-related VTE.

VTE-Related Healthcare Resource Utilization and Costs Associated with Venous Thromboembolism in Cancer Patients Treated with Anticoagulants

Introduction: The standard of care for treatment of cancer-related venous thromboembolism (VTE) is a low molecular heparin (LMWH). In our previous claimsbased analysis, we showed that besides LMWH oral anticoagulants, warafrin and rivaroxaban are widely prescribed in clinical practice (Khorana, 2015). The objective of this study is to compare VTE-related healthcare resource utilization and costs of cancer patients treated with anticoagulant therapies.Methods: Medical and pharmacy claims from the Humana Database between 1/1/2013 and 05/31/2015 were analyzed. Newly diagnosed cancer patients with a first VTE diagnosis occurring after their first cancer diagnosis and with ≥1 dispensing of an anticoagulant agent within 7 days after their VTE diagnosis, were selected. Based on the first anticoagulant agent received, patients were classified into one of the following cohorts: LMWH, warfarin, and rivaroxaban. Inverse probability of treatment weights based on propensity score was used to adjust for differences between treatment cohorts. Baseline characteristics were evaluated during the 6 month period prior to the index VTE. VTE-related resource utilization and costs were identified with a primary or secondary diagnosis of deep vein thrombosis or pulmonary embolism and were evaluated for the entire follow up period, starting from the initiation of the anticoagulant therapy until the earliest either end of enrollment or end of data availability (05/31/2015). Resource utilization components included: number of hospitalizations, hospitalization days, emergency room (ER) visits, and outpatient visits. Comparisons between the different treatment cohorts were performed using rate ratios (RR) and statistical differences between groups as well as 95% confidence intervals [95% CI] were calculated using Poisson regression models. Healthcare costs were evaluated in per-patient-per-year (PPPY) and compared using mean cost difference.Results: A total of 2,428 patients (LMWH: n=660; warfarin; n=1,061; rivaroxaban: n=707) were included. Baseline demographic and clinical characteristics were well balanced across the treatment cohorts including hospitalizations, emergency room (ER) visits, and outpatient visits. Compared to patients treated with LMWH, patients treated with rivaroxaban had significantly fewer VTE-related hospitalizations, hospitalization days, ER visits, and outpatient visits (Figure 1). This resulted in significantly higher VTE-related health care cost difference of $12,000 for LMWH relative to rivaroxaban treatment cohort (Table 1).Patients treated with rivaroxaban had significantly lower VTE-related resource utilization compared to patients treated with warfarin (Figure 1). The total VTE-related costs were however similar between two cohorts (Table 1). The higher drug costs ($1,519) were offset by significantly lower outpatient (-$1,039) and hospitalization costs (-$522) in rivaroxaban relative to warfarin cohort.Conclusion: Healthcare resource use and costs associated with VTE treatment in cancer patients are the highest with LMWH relative to warfarin and rivaroxaban treatments. Healthcare resources use and costs are significantly higher in warfarin relative to rivaroxaban cohort but these resource costs were offset by higher drug costs of rivaroxaban. These results are in line with previous study in cancer patients that found fewer re-hospitalizations related to VTE recurrences in patients treated with rivaroxaban compared to patient treated with LMWH or warfarin (Streiff, 2016). [Display omitted] [Display omitted] DisclosuresStreiff:Roche: Research Funding; Portola: Research Funding; Janssen: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Milentijevic:Janssen Scientific Affairs: Employment, Equity Ownership. McCrae:Janssen: Membership on an entity’s Board of Directors or advisory committees. Fortier:Janssen Pharmaceuticals: Research Funding. Laliberté:Janssen Scientific Affairs: Research Funding. Lefebvre:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Khorana:Sanofi: Consultancy, Honoraria; Leo: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

695P - Oral rivaroxaban versus subcutaneous low molecular weight heparin treatment for venous thromboembolism in patients with upper gastrointestinal, hepatobiliary and pancreatic cancer

Although low molecular weight heparin (LMWH) is preferred treatment of cancer-related venous thromboembolism (VTE), rivaroxaban is increasingly used owing to its convenience. We aimed to compare the LMWH and rivaroxaban maintenance therapy for VTE in patients with upper gastrointestinal (GI), hepatobiliary and pancreatic (HBP) cancer. From JAN 2004 to DEC 2014, a totla of 777 and 217 patients with upper GI or HBP cancer were prescribed LMWH and rivaroxaban, respectively. With exclusion of patients who had resectable disease, received treatment less than 14 days unless discontinued due to bleeding and took anticoagulation not for therapeutic purpose, 111 and 78 patients were analyzed, respectively. Most baseline characteristics were similar between the two groups (rivaroxaban vs. LMWH), except age ≥65 (57.1% vs. 29.7%, p = 0.001) and ECOG ≥2 (6.4% vs. 19.8%, p = 0.009). The recurrent or aggravated VTEs during anticoagulation were observed at 4 (5.1%) in the rivaroxaban group and 1 (0.9%) in the LMWH group (HR 4.41, 95% CI 0.48-40.13, p = 0.188). Regarding the safety, the rivaroxaban group had significantly higher incidences of total events of bleeding (37.2% vs. 18.0%; HR 2.06, 95% CI 1.17-3.65, p = 0.013) and clinical relevant bleeding (29.5% vs. 13.5%; HR 2.16, 95% CI 1.13-4.14, p = 0.021). Major bleeding events also tended to occur more frequently in the rivaroxaban group (16.7% vs. 7.2%; HR 2.29, 95% CI 0.95-5.53, p = 0.066). In multivariate analysis, treatment with rivaroxaban was significantly associated with total bleeding (HR 2.34, 95% CI 1.30-4.23, p = 0.005) and clinical relevant bleeding (HR 2.16, 95% CI 1.13-4.14, p = 0.021) after adjusting for possible confounding factors, such as age ≥65, sex, presence of a GI mucosa lesion, poor performance status, lower BMI (<18.5) and azotemia. Rivaroxaban had similar efficacy to LMWH for the treatment of cancer-associated VTE, but was associated with a higher rate of total bleeding and clinical relevant bleeding in patients with upper GI and HBP cancer. Further studies are needed to validate our findings.

OC-13 - Safe and effective use of direct oral anticoagulants (DOAC) versus conventional anticoagulation for the treatment of cancer-related venous thromboembolism

Cancer is a risk factor for the development of venous thromboembolism (VTE). The standard of care for the treatment of cancer-related VTE is a low molecular weight heparin (LMWH) formulation. The treatment for these events can be painful, lengthy, and expensive. The development of DOAC has created new options for the treatment of VTE. Data from a recent systematic review suggested that the safety and effectiveness of DOAC in patients with cancer is equivalent to that of traditional therapies. If equivalent to LMWH, the use of DOAC in the treatment of cancer-related VTE would reduce the risk of VTE recurrence while giving patients freedom from subcutaneous injections. Our primary aim was to determine the rate of VTE recurrence in patients on anticoagulation. Secondary aims were determination of the rate of anticoagulant-associated clinically relevant bleeding and VTE recurrence-free survival. We performed retrospective analysis (2014-2015) of the electronic medical records (EMR) of adult patients with cancer-related VTE treated with anticoagulation. We selected 122 patients for our final analysis according to the inclusion criteria. Demographic, laboratory, cancer diagnosis, and VTE diagnosis data were collected. We documented VTE recurrence as well as clinically relevant bleeding. Non-parametric statistical procedures were used to determine differences in variables associated with this study among the anticoagulant class groups, with a test significance level of 0.05. Among 122 patients, 89 (73%) were treated with LMWH, 26 (21%) were treated with DOAC, and 7 (6%) were treated with warfarin. The majority of VTE occurred in patients with advanced disease. The most common index event was pulmonary embolism (49%) followed by catheter-associated deep venous thrombosis (DVT) (24%). Recurrence of VTE occurred in 7.7% of patients receiving DOAC and 7.9% of patients receiving LMWH (P=NS). Major bleeding occurred more often with the use of DOAC (11.5%) than with LMWH (10.1%), but non-major bleeding was more common in patients receiving LMWH (9.0% versus 7.7%). These differences were not statistically significant. There was no mortality attributed to bleeding complications. The VTE recurrence-free survival rates were not statistically different among LMWH versus DOAC (Figure1). Recurrence of cancer-associated VTE is not uncommon, and the treatment of VTE has significant hemorrhagic risks. Our analysis suggests that there is no significant difference in the rate of VTE recurrence and anticoagulant-related bleeding when using oral DOACs versus LMWH. Further studies are needed to compare the safety and effectiveness of these methods of anticoagulation.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants (DOAC) Versus Conventional Anticoagulation for the Treatment of Cancer-Related Venous Thromboembolism: A Retrospective Analysis

IntroductionCancer is a risk factor for the development of venous thromboembolism (VTE). There is significant morbidity and mortality associated with VTE, and the treatment for these events can be painful, lengthy, and expensive. The development of DOACs has offered several new options for the treatment of VTE. Recent data suggested that the safety and effectiveness of DOACs in patients with cancer is equivalent to that of traditional oral therapies. The standard of care for the treatment of cancer-related VTE is a low molecular weight heparin (LMWH) formulation. If equivalent to LMWH, the use of DOACs in the treatment of cancer-related VTE would reduce the risk of VTE recurrence while potentially giving patients freedom from subcutaneous injections.MethodsWe performed a retrospective analysis of the electronic medical records (EMR) of adult patients with newly diagnosed or recurrent cancer-related VTE, who were treated with therapeutic dose of an anticoagulant for the index VTE and did not have other underlying thrombophilia or indication for long-term anticoagulation. Patients were treated at the benign hematology clinic during 2014. We screened a sample of 197 patients; 89 were selected in our final analysis according to the inclusion criteria. We used EMR to collect demographic data, laboratory values, details of cancer diagnosis, and details of VTE diagnosis. We documented patients who experienced recurrent VTE as well as those who experienced anticoagulant-associated clinically relevant bleeding. We used a multivariate analysis of this data to account for demographic, clinical, and tumor-related variables associated with this study. The primary outcome was the rate of recurrence of VTE after the initiation of anticoagulation. Secondary outcomes were the rate of anticoagulant-associated clinically relevant bleeding, as well as event-free survival for VTE recurrence.ResultsAmong the 89 patients that were included in our final analysis, 63 (71%) were treated with subcutaneous formulations of low molecular weight heparin (LMWH), 20 (22%) were treated with DOACs, and 6 (7%) were treated with warfarin. The Eastern Cooperative Oncology Group (ECOG) score for these patients ranged from 0 to 3. The majority (69%) of VTE occurred in patients with stage III or IV disease. Almost all of the patients (91%) were diagnosed with VTE in the setting of active cancer; a small percentage of cases occurred in patients with a recent or remote history of malignancy. Patients had 36 different histological types of cancer, but the most common were invasive ductal carcinoma of the breast (21%), lymphoma (9%), and adenocarcinoma of the colon or rectum (6%). Most of the patients (91%) were free of primary or metastatic disease of the central nervous system, but nearly 1 in 5 (17%) had evidence of hepatic metastases at the time of the index event. The most common index event was pulmonary embolism (53%) followed by catheter-associated deep venous thrombosis (DVT) (28%) and proximal lower limb DVT (12%). Recurrence of VTE occurred in 10.0% of patients receiving DOACs and 11.1% of patients receiving LMWH (P=NS). When VTE recurrence occurred, it was most likely in the form of pulmonary embolism (44%), splanchnic vein thrombosis (22%), or proximal lower limb DVT (11%). Clinically relevant bleeding was slightly higher with the use of DOACs (20%) versus LMWH (17%). Interestingly, major bleeding occurred more often with the use of DOACs (15%) than with LMWH (6.3%), although clinically relevant non-major bleeding was more common in patients receiving LMWH (11%) than in those receiving DOACs (5%). There was no mortality attributed to bleeding complications. The VTE recurrence-free survival rates were not statistically different (P=0.222) among patients treated with LMWH versus DOACs (Figure 1)ConclusionCancer-associated VTE is associated with significant morbidity and mortality. Recurrence of VTE is not uncommon, and caution must be exercised throughout the treatment of VTE due to the significant anticoagulant-associated hemorrhagic risks. LMWHs are effective for the treatment of cancer-related VTE, but injections are cumbersome and painful for many patients. Our analysis suggests that there is no significant difference in the rate of VTE recurrence when using oral DOACs versus subcutaneous LMWH. DOACs appeared to be at greater risk of major bleeding. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Compliance of recommendations with French clinical practice in the management of thromboembolism in patients with cancer: The CARMEN study.

1580 Background: Long-term treatment with low-molecular-weight heparin (LMWH) is recommended for treatment of venous thromboembolism (VTE) in cancer patients. Few data are available on compliance in this population. Our study measured whether the management of VTE in patients with cancer was consistent with French recommendations. Methods: Compliance with recommendations (CR+) was analysed according to malignancy and VTE from a 500-patient cross-sectional observational study run between May and October 2010. CR+ was defined as the compliance to initial 10-day treatment followed by long-term LMWH for at least 3 months, avoiding LMWH in patients with renal insufficiency (SRI). All inpatients with a diagnosis of cancer and VTE of less than 6 months were included in the study. Results: Of 500 patients included in 47 centers, 242 (49%) were male, 81 (18%) had local (T+), 83 (18%) had loco-regional (N+) and 287 (64%) had metastatic malignancies. Malignancies were gastro-intestinal (25%), gynaecologic (23%), pulmonary (21%), haematological (14%), urologic (10%) or other (8%). Twelve patients had SRI. Overall, treatment was CR+ in 289/500 patients (58% [95% CI 53%-62%]). Out of 12 patients with SRI only 3 (25%) were treated long-term with vitamin K antagonists (VKA), as usually recommended. Tumour site influenced CR+ (p=0.02). Treatment for haematological malignancy was poorly compliant with recommendations (32%) while patients with lung malignancy had the best compliance (68%). TNM stage and VTE location had no influence on treatment compliance. Conclusions: In French practice, treatment of cancer-related VTE is CR+ in 58% of cases. TNM stage and VTE location do not influence compliance which remains insufficient, especially in patients with haematological malignancy. [Table: see text]

Management of venous thromboembolism in patients with cancer

The association between venous thromboembolism and cancer has been recognized for over 140 years. This article reviews current prevention, diagnosis and treatment of cancer-related venous thromboembolism, and highlights emerging anticoagulants and the possible anticancer effects of anticoagulants such as low molecular weight heparins.