Anticoagulants In Cancer-associated Venous Thromboembolism Research Articles

Direct Oral Anticoagulants for Cancer-Associated Venous Thromboembolism.

To present the randomized controlled trial (RCT) evidence and highlight the areas of uncertainty regarding direct oral anticoagulants (DOAC) for cancer-associated venous thromboembolism (CAT). In the last years, four RCTs have shown that rivaroxaban, edoxaban, and apixaban are at least as effective as low-molecular-weight heparin (LMWH) for the treatment of both incidental and symptomatic CAT. On the other hand, these drugs increase the risk of major gastrointestinal bleeding in patients with cancer at this site. Another two RCTs have demonstrated that apixaban and rivaroxaban also prevent CAT in subjects at intermediate-to-high risk commencing chemotherapy, albeit at the price of higher likelihood of bleeding. By contrast, data are limited about the use DOAC in individuals with intracranial tumors or concomitant thrombocytopenia. It is also possible that some anticancer agents heighten the effects of DOAC via pharmacokinetic interactions, up to making their effectiveness-safety profile unfavorable. Leveraging the results of the aforementioned RCTS, current guidelines recommend DOAC as the anticoagulants of choice for CAT treatment and, in selected cases, prevention. However, the benefit of DOAC is less defined in specific patient subgroups, in which the choice of DOAC over LMWH should be carefully pondered.

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

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

Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis

AbstractDirect oral anticoagulants (DOACs) are an emerging treatment option for patients with cancer and acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWHs) in these patients. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Summary relative risks (RRs) were calculated in a random effects meta-analysis. In the primary analysis comprising 2607 patients, the risk of recurrent VTE was nonsignificantly lower with DOACs than with LMWHs (RR, 0.68; 95% CI, 0.39-1.17). Conversely, the risks of major bleeding (RR, 1.36; 95% CI, 0.55-3.35) and CRNMB (RR, 1.63; 95% CI, 0.73-3.64) were nonsignificantly higher. The risk of the composite of recurrent VTE or major bleeding was nonsignificantly lower with DOACs than with LMWHs (RR, 0.86; 95% CI, 0.60-1.23). Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for patients with cancer and acute VTE, although caution is needed in patients at high risk of bleeding.

Direct oral anticoagulants in cancer-associated venous thromboembolism: It is high time for a change of therapeutic paradigm.

Direct oral anticoagulants in cancer-associated venous thromboembolism: It is high time for a change of therapeutic paradigm.

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 Versus Low-molecular-weight Heparin for Venous Thromboembolism in Advanced Upper Gastrointestinal Tract and Hepatopancreatobiliary Cancer.

The aim of this study was to examine the efficacy and safety of direct oral anticoagulants for cancer-associated venous thromboembolism (VTE) in patients with active cancer. This study included patients with advanced unresectable/metastatic upper gastrointestinal (GI) or hepatopancreatobiliary (HPB) cancers with high risks of VTE and bleeding. No significant differences were noted in potential bleeding factors between the rivaroxaban (n=105) and low-molecular-weight heparin (LMWH) (n=69) groups. Rivaroxaban exhibited similar risk of recurrent/aggravated VTE compared with LMWH (p=0.625) but increased risk of major bleeding (17.4% vs. 7.6%; p=0.072), clinically relevant bleeding (31.9% vs. 14.3%; p=0.019), and total bleeding (40.6% vs. 19%; p=0.010). The multivariate analysis regarded rivaroxaban as a significant factor for major bleeding (p=0.043) and clinically relevant bleeding (p=0.043). Rivaroxaban exhibits comparable efficacy but increases bleeding risks compared with LMWH in patients with active unresectable/metastatic upper GI tract or HPB cancers, requiring extra caution of higher major bleeding risks.

Direct oral anticoagulants in cancer-associated venous thromboembolism

This is a narrative review of the relevant literature on the epidemiology, pathogenesis, and treatment of venous thromboembolism (VTE) in cancer patients. In accordance with actual guidelines, the duration of anticoagulant therapy for cancer-associated venous thrombosis should be at least 6 months. The use of Vitamin K antagonists (VKA) is associated with an increased risk of VTE recurrence and bleeding, so low-molecular-weight heparin (LMWH), in particular dalteparin, has been the “gold standard” until recently. Compared to VKA, prolonged use of LMWH can reduce the incidence of VTE recurrence without affecting the risk of bleeding or death. The main disadvantage of LMWH is low compliance, leading to premature discontinuation of treatment or switching to alternative anticoagulants. Direct oral anticoagulants (DOACs) have changed the situation. Compared to VKA, they demonstrated increased efficacy with similar or improved safety in patients with cancer-related VTE. Recently, the results of specialized studies comparing the use of DOACs to the use of dalteparin in cancer patients have been published: SELECT-D (rivaroxaban), HOKUSAI-VTE Cancer (edoxaban), ADAM VTE (apixaban), and CARAVAGGIO (apixaban). Rivaroxaban showed higher efficacy than dalteparin with a similar risk of major bleeding, but with an increased risk of clinically relevant nonmajor (CRNM) bleeding. Edoxaban had the same efficacy as dalteparin, though it showed an increased risk of major but not CRNM bleeding. Apixaban showed similar efficacy and safety as dalteparin in the CARAVAGGIO study, but did not provide higher safety in the ADAM VTE study. It was noted that gastrointestinal and urogenital bleeding dominated the structure of hemorrhagic complications of DOACs. The results of published trials are reflected in the current guidelines of the specialized societies. DOACs are recommended for VTE treatment in cancer patients.

Providers Increased the Use of Direct Oral Anticoagulants in Patients with Cancer-Associated Thromboembolism without Gaining Complete Confidence: A Health System-Wide Retrospective Registry Study and a Providers' Survey

BACKGROUND. In patients with cancer-associated venous thromboembolism (CAVT), recent randomized trials reported similar or improved efficacy of direct oral anticoagulants (DOACs) compared to standard-of-care low molecular weight heparin (LMWH) but noted increased bleeding in patients with gastrointestinal (GI) or genitourinary (GU) lesions. Both the National Comprehensive Cancer Network and the International Society on Thrombosis and Hemostasis have adapted guidelines on judicious use of DOACs in CAVT patients with GI or GU lesions. Differences in DOACs utilization may have significant impact on bleeding, recurrent thrombosis, and cost utilization. We sought to examine provider utilization and perception of different anticoagulants in CAVT. METHODS. We examined DOAC utilization in CAVT patients and surveyed hematology/oncology providers within the Yale New Haven Health System that includes 5 hospitals, an NCI-designated cancer hospital with a network of 14 regional cancer care centers. The utilization of DOACs was examined retrospectively from January 2014 through December 2018 with data query tools built into the Epic electronic medical record used throughout the Health System. The 17-question online survey was administered in June-July 2018 to 90 providers and a year later, to 101 providers. The Qualtrics survey platform was used to record anonymous responses. No incentive was provided for responses. For statistical comparisons, we used chi-square tests of proportions. RESULTS EMR: Use of rivaroxaban and apixaban rose from 22% to 30% and from 2% to 25%, respectively, while warfarin use dropped from 36% to 13%. Use of apixaban increased at a faster rate than that of rivaroxaban as indicated by statistically significant year-to-year changes for the former. Enoxaparin remained the most commonly used anticoagulant in CAVT, and although its use trended down, it remained similar throughout the study period (Fig 1). SURVEY: The response rates for the two surveys were 22% in 2018 (22 respondents) and 25% in 2019 (25 respondents). Far more providers felt completely comfortable with enoxaparin than apixaban (2018: 95% vs 50%, p=0.005; 2019: 92% vs 56%, p=0.008) or rivaroxaban (2018: 95% vs 45%, p=0.003; 2019: 92% vs 52%, p=0.004). Among DOACs, more providers felt completely comfortable with apixaban (50% in 2018, 56% in 2019) and rivaroxaban (45% in 2018, 52% in 2019) than with edoxaban (25% in 2018, 28% in 2019) or dabigatran (35% in 2018, 28% in 2019) (Fig 2). Provider comfort level with different anticoagulants in CAVT did not change between the two survey periods. Factors that added to the provider comfort level with DOACs included ease of patient use, favorable patient adherence and personal experience, favorable efficacy and safety data (Fig 3). Only a minority of providers (37% in 2018 and 38% in 2019) felt that the FDA approval of andexanet had an impact on their comfort level with DOACs in CAVT. At the same time, a majority of responders in 2019 (70%) identified lack of access to reversal agents as a factor that made them less comfortable (Fig 4). The majority of providers identified GI or GU lesions or instrumentation, active or major bleeding, brain lesions, and liver impairment as relative contraindications to DOAC use in CAVT. Only about half of providers felt that renal impairment (53% in 2018, 50% in 2019) or thrombocytopenia (53% in 2018, 42% in 2019) should be contraindications. The majority of providers (80% in 2018, 68% in 2019) felt that results of clinical trials of DOACs in CAVT made them more likely to use DOACs in CAVT. CONCLUSIONS: The use of DOACs in treatment of CAVT is increasing and in our Health System accounts almost entirely for a decrease in warfarin use in CAVT, while the use of enoxaparin has not substantially changed. In making decisions about anticoagulant choice in CAVT, providers are likely influenced by a number of factors including the results from clinical trials of DOACs in CAVT, although in our Health System a trend in increased DOAC utilization in CAVT began long before such clinical trial results were reported. Despite increased use of DOACs in CAVT, providers continue to feel most comfortable with enoxaparin, which remains the most commonly used anticoagulant in CAVT. Further prospective real-world data are needed to assess providers' prescribing factors, cost, and utilization patterns of DOACs in CAVT, and to assess how such practices impact bleeding and re-thrombosis rates. Disclosures No relevant conflicts of interest to declare.

P5239Cost-effectiveness of direct oral anticoagulants for cancer-associated venous thromboembolism

Abstract Background Direct oral anticoagulants (DOACs) are at least as effective as low-molecular weight heparins (LMWH) at preventing recurrence after cancer-associated venous thromboembolism (CA-VTE). DOACs are also oral and far less costly, but they may confer a higher bleeding risk than LMWH. Purpose To estimate the cost-effectiveness of DOACs and LMWHs for CA-VTE. Methods We developed a health state transition model to estimate recurrent VTE, bleeding events, quality-adjusted life years (QALY), and direct healthcare costs (2018 United States dollars) associated with DOACs vs. LMWH use. The model had four states: (1) long-term anticoagulation (first 3 months after VTE), (2) extended anticoagulation (more than 3 months after VTE), (3) off anticoagulants, and (4) death. We used a United States healthcare sector perspective, 3-month cycle length, and 1-year time horizon. Event probabilities were derived from the Hokusai Cancer VTE trial and other literature. Event and medication costs were obtained from national sources. We used a threshold of less than $50,000 per QALY gained to define cost-effectiveness. Results Compared to LMWH, DOACs were less costly (mean costs: $8,477 vs. $33,917 per year) and similarly effective (mean QALY: 0.616 vs. 0.622). The incremental cost-effectiveness ratio was $4,479,374 per QALY gained with LMWH, indicating that DOACs are cost-effective (Table 1). In threshold analyses, LMWH therapy only became cost-effective when DOAC recurrent VTE risk increased to at least 72% (relative risk vs. LMWH, 6.19) or DOAC clinically relevant bleeding increased to at least 39% (relative risk vs. LMWH, 10.09). Scenarios Recurrent VTE, % Major bleed, % Mean difference DOAC − LMW ICER DOAC LMWH Relative Risk DOAC LMWH Relative Risk Cost QALY Base case 8.1 11.6 0.71 6.8 4.0 1.75 −$25,440 (−26,496, −24,274) −0.006 (−0.019, 0.008) $4,479,374 DOAC outcome rate threshold at which LMWH becomes cost-effective* Recurrent VTE 71.5 11.7 6.19 – – – −$6,064 (−7,534, −4,627) −0.121 (−0.136, −0.108) $49,886 Major Bleed – – – 38.9 4.0 10.09 −$2,192 (−3,400, −704) −0.044 (−0.056, −0.030) $49,878 DOAC = direct oral anticoagulant, ICER = incremental cost-effectiveness ratio, LMWH = low-molecular-weight heparin, VTE = venous thromboembolism. Values are mean (95% Uncertainty Interval). Uncertainty was derived from 1,000 stochastic model iterations. *Represents the minimum increased risk with DOAC that would result in LMWH achieving an ICER &lt;$50K per QALY gained. Conclusion In this simulation study, DOACs were a cost-effective oral alternative to LMWH for the treatment of CA-VTE. For LMWH to be cost-effective, DOAC event rates needed to be far higher than what is likely to be observed in clinical practice. Acknowledgement/Funding Agency for Health Research and Quality R18HS026156

The Role of Direct Oral Anticoagulants in Cancer-Associated Venous Thromboembolism

Abstract Patients with cancer are at increased risk for developing venous thromboembolism due to disease-related and treatment-related risk factors. Low-molecular-weight heparins are the standard of care for prevention and treatment of venous thromboembolism in patients with cancer; however, direct oral anticoagulants offer a convenient dosing option for patients who have compelling reasons to avoid low-molecular-weight heparin.