Comparison of rivaroxaban and low molecular weight heparin in the treatment of cancer-associated venous thromboembolism: a Swedish national population-based register study.

BACKGROUND: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk. OBJECTIVES: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT. METHODS: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated. RESULTS: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67). CONCLUSIONS: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding. TRIAL REGISTRATION NUMBER: NCT05150938 (Registered 9 December 2021).

Comparison of Clinical Outcomes in Patients with Active Cancer Receiving Rivaroxaban or Low-Molecular-Weight Heparin: The OSCAR-UK Study.

BACKGROUND: In most patients with cancer-associated venous thromboembolism (CT), essentially those not at high risk of bleeding, guidelines recommend treatment with direct oral anticoagulants as an alternative to low-molecular-weight heparins (LMWHs). Population-based studies comparing these therapies are scarce. OBJECTIVES: To compare the risk of venous thromboembolism (VTE) recurrences, significant bleeding, and all-cause mortality in patients with CT receiving rivaroxaban or LMWHs. PATIENTS/METHODS: Using UK Clinical Practice Research Datalink data from 2013 to 2020, we generated a cohort of patients with first CT treated initially with either rivaroxaban or LMWH. Patients were observed 12 months for VTE recurrences, significant bleeds (major bleeds or clinically relevant nonmajor bleeding requiring hospitalization), and all-cause mortality. Overlap weighted sub-distribution hazard ratios (SHRs) compared rivaroxaban with LMWH in an intention-to-treat analysis. RESULTS: The cohort consisted of 2,259 patients with first CT, 314 receiving rivaroxaban, and 1,945 LMWH, mean age 72.4 and 66.9 years, respectively. In the 12-month observational period, 184 person-years following rivaroxaban and 1,057 following LMWH, 10 and 66 incident recurrent VTE events, 20 and 102 significant bleeds, and 10 and 133 deaths were observed in rivaroxaban and LMWH users, respectively. The weighted SHR at 12 months for VTE recurrences in rivaroxaban compared with LMWH were 0.80 (0.37-1.73); for significant bleeds 1.01 (0.57-1.81); and for all-cause mortality 0.49 (0.23-1.06). CONCLUSION: Patients with CT, not at high risk of bleeding, treated with either rivaroxaban or LMWH have comparable effectiveness and safety outcomes. This supports the recommendation that rivaroxaban is a reasonable alternative to LMWH for the treatment of CT.

Cancer and the Risk of Perioperative Arterial Ischemic Events.

BACKGROUND AND AIMS: Most cancer patients require surgery for diagnosis and treatment. This study evaluated whether cancer is a risk factor for perioperative arterial ischemic events. METHODS: The primary cohort included patients registered in the National Surgical Quality Improvement Program (NSQIP) between 2006-2016. The secondary cohort included Healthcare Cost and Utilization Project (HCUP) claims data from 11 U.S. states between 2016-2018. Study populations comprised patients who underwent inpatient (NSQIP, HCUP) or outpatient (NSQIP) surgery. Study exposures were disseminated cancer (NSQIP) and all cancers (HCUP). The primary outcome was a perioperative arterial ischemic event, defined as myocardial infarction or stroke diagnosed within 30 days after surgery. RESULTS: Among 5,609,675 NSQIP surgeries, 2.2% involved patients with disseminated cancer. The perioperative arterial ischemic event rate was 0.96% among patients with disseminated cancer versus 0.48% among patients without (HR, 2.01; 95% CI, 1.90-2.13). In Cox analyses adjusting for demographics, functional status, comorbidities, surgical specialty, anesthesia type, and clinical factors, disseminated cancer remained associated with higher risk of perioperative arterial ischemic events (HR, 1.37; 95% CI, 1.28-1.46). Among 1,341,658 surgical patients in the HCUP cohort, 11.8% had a diagnosis of cancer. A perioperative arterial ischemic event was diagnosed in 0.74% of patients with cancer versus 0.54% of patients without cancer (HR, 1.35; 95% CI, 1.27-1.43). In Cox analyses adjusted for demographics, insurance, comorbidities, and surgery type, cancer remained associated with higher risk of perioperative arterial ischemic events (HR, 1.31; 95% CI, 1.21-1.42). CONCLUSIONS: Cancer is an independent risk factor for perioperative arterial ischemic events.

Rivaroxaban Versus Low-Molecular-Weight Heparins in a Broad Cohort of Patients With Cancer-Associated Venous Thromboembolism: An Analysis of the OSCAR-US Program.

Cancer-associated venous thromboembolism (CAT) guidelines recommend direct oral anticoagulants as alternatives to low-molecular-weight heparin (LMWH) in most patients. This study compared the effectiveness and safety of rivaroxaban versus LMWH for a broad CAT cohort. The cohort study used electronic health data from January 2012 to December 2020 to evaluate patients with active cancer experiencing acute venous thromboembolism (VTE) and treated with rivaroxaban or LMWH. Propensity score-overlap weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE, bleeding-related hospitalization, and all-cause mortality were calculated. In total, 4935 patients were identified (27.9% on rivaroxaban and 72.1% on LMWH). The cancer types included gastrointestinal (29.4%), genitourinary (26.2%), lung (24.0%), breast (19.7%), and hematologic (14.4%). Rivaroxaban was associated with a reduction in recurrent VTE versus LMWH among all patients with cancer (HR = 0.78; 95%CI = 0.61-0.99) at 3 months. No differences in bleeding-related hospitalization or all-cause mortality were observed. Directionally similar results to those at 3 months were observed at 6 months for all outcomes. In conclusion, we observed fewer recurrent VTE cases and no increase in bleeding-related hospitalizations with rivaroxaban versus LMWH at 3 months in this patient cohort with various cancer types.

Rivaroxaban versus Apixaban for Treatment of Cancer-Associated Venous Thromboembolism in Patients at Lower Risk of Bleeding.

This retrospective study, utilizing U.S. electronic health record (EHR) data from January 2013 to December 2020, sought to assess whether rivaroxaban and apixaban had similar effectiveness and safety in the treatment of cancer-associated venous thromboembolism (VTE) in patients with a cancer type not associated with a high risk of bleeding. We included adults diagnosed with active cancer, excluding esophageal, gastric, unresected colorectal, bladder, noncerebral central nervous system cancers and leukemia, who experienced VTE and received a therapeutic VTE dose of rivaroxaban or apixaban on day 7 post-VTE, and were active in the EHR ≥12 months prior to the VTE. Primary outcome was the composite of recurrent VTE or any bleed resulting in hospitalization at 3 months. Secondary outcomes included recurrent VTE, any bleed resulting in hospitalization, any critical organ bleed, and composites of these outcomes at 3 and 6 months. Inverse probability of treatment-weighted Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). We included 1,344 apixaban and 1,093 rivaroxaban patients. At 3 months, rivaroxaban was found to have similar hazard to apixaban for developing recurrent VTE or any bleed resulting in hospitalization (HR: 0.87; 95% CI: 0.60-1.27). No differences were observed between cohorts for this outcome at 6 months (HR: 1.00; 95% CI: 0.71-1.40) or for any other outcome at 3 or 6 months. In conclusion, patients receiving rivaroxaban or apixaban showed similar risks of the composite of recurrent VTE or any bleed resulting in hospitalization in patients with cancer-associated VTE. This study was registered at www.clinicaltrials.gov as #NCT05461807. Key Points Rivaroxaban and apixaban have similar effectiveness and safety for treatment of cancer-associated VTE through 6 months.Clinicians should therefore consider patient preference and adherence when choosing the optimal anticoagulant.

Effectiveness and Safety of Rivaroxaban and Low Molecular Weight Heparin in Cancer-Associated Venous Thromboembolism.

Background: Direct-acting oral anticoagulants (DOACs) are alternatives to low molecular weight heparin (LMWH) in most cancer-associated thrombosis (CAT) patients. Objectives: This study sought to compare the effectiveness and safety of rivaroxaban and LMWH for venous thromboembolism (VTE) treatment in patients with an active cancer type not associated with a high risk of DOAC bleeding. Methods: An analysis of electronic health records from January 2012 to December 2020 was performed. Patients were adults, had active cancer, experienced an index CAT event, and were treated with rivaroxaban or LMWH. Patients with cancers with an established high risk of bleeding on DOACs were excluded. Baseline covariates were balanced using propensity score-overlap weighting. HRs with 95% CIs were calculated. Results: We identified 3,708 CAT patients treated with rivaroxaban (29.5%) or LMWH (70.5%). The median (25th-75th percentiles) time on anticoagulation was 180 (69-365) and 96 (40-336) days for rivaroxaban and LMWH patients. At 3 months, rivaroxaban was associated with a 31% reduced risk of recurrent VTE vs LMWH (4.2% vs 6.1%; HR: 0.69; 95% CI: 0.51-0.92). No difference in bleeding-related hospitalizations or all-cause mortality was observed (HR: 0.79; 95% CI: 0.55-1.13 and HR: 1.07; 95% CI: 0.85-1.35, respectively). Rivaroxaban reduced the recurrent VTE risk (HR: 0.74; 95% CI: 0.57-0.97) but not bleeding-related hospitalizations or all-cause mortality at 6 months. At 12 months, no difference was observed between cohorts for any of the previously mentioned outcomes. Conclusions: Among active cancer patients experiencing VTE and not at high risk of bleeding on DOACs, rivaroxaban was associated with a reduced risk of recurrent VTE versus LMWHs at 3 and 6 months but not 12 months. (Observational Study in Cancer-Associated Thrombosis for Rivaroxaban-United States Cohort [OSCAR-US]; NCT04979780).

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update.

PURPOSE: To conduct an update of the ASCO venous thromboembolism (VTE) guideline. METHODS: After publication of potentially practice-changing clinical trials, identified through ASCO's signals approach to updating, an updated systematic review was performed for two guideline questions: perioperative thromboprophylaxis and treatment of VTE. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) published between November 1, 2018, and June 6, 2022. RESULTS: Five RCTs provided information that contributed to changes to the 2019 recommendations. Two RCTs addressed direct factor Xa inhibitors (either rivaroxaban or apixaban) for extended thromboprophylaxis after surgery. Each of these postoperative trials had important limitations but suggested that these two oral anticoagulants are safe and effective in the settings studied. An additional three RCTs addressed apixaban in the setting of VTE treatment. Apixaban was effective in reducing the risk of recurrent VTE, with a low risk of major bleeding. RECOMMENDATIONS: Apixaban and rivaroxaban were added as options for extended pharmacologic thromboprophylaxis after cancer surgery, with a weak strength of recommendation. Apixaban was also added as an option for the treatment of VTE, with high quality of evidence and a strong recommendation.Additional information is available at www.asco.org/supportive-care-guidelines.

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.

Clinical care pathway for the evaluation of patients with suspected VITT after ChAdOx1 nCoV-19 vaccination.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adenoviral vector vaccination. In British Columbia (BC), Canada, a provincial clinical care pathway was developed to guide clinicians in evaluating for VITT among patients who present with thrombocytopenia or thrombosis symptoms within 4 to 28 days after adenoviral vector vaccine exposure. All patients had enzyme-linked immunosorbent assay (ELISA) testing for platelet factor 4 (PF4) antibodies, and all cases with positive PF4-ELISA or d-dimer levels ≥2.0 mg/L fibrinogen equivalent units (FEU) had further testing for platelet-activating PF4 antibodies using a modified serotonin release assay (SRA). Between 1 May and 30 June 2021, 37% of 68 patients investigated for VITT had thrombosis, but only 3 had VITT confirmed by PF4-ELISA and SRA. Platelet counts, d-dimer levels, and ELISA optical density values were significantly different between those with and without VITT. Three patients had thrombocytopenia and thrombosis with d-dimer levels >4.0 mg/L FEU but had negative PF4-ELISA and SRA results. Patients with VITT were treated successfully with IV immunoglobulin, nonheparin anticoagulants, and corticosteroids. Our pathway demonstrated that thrombosis is common among patients investigated for VITT and that PF4-ELISA testing is necessary to confirm VITT in those presenting with thrombosis and thrombocytopenia.

Cancer-associated venous thromboembolism.

Cancer-associated thrombosis (including venous thromboembolism (VTE) and arterial events) is highly consequential for patients with cancer and is associated with worsened survival. Despite substantial improvements in cancer treatment, the risk of VTE has increased in recent years; VTE rates additionally depend on the type of cancer (with pancreas, stomach and primary brain tumours having the highest risk) as well as on individual patient's and cancer treatment factors. Multiple cancer-specific mechanisms of VTE have been identified and can be classified as mechanisms in which the tumour expresses proteins that alter host systems, such as levels of platelets and leukocytes, and in which the tumour expresses procoagulant proteins released into the circulation that directly activate the coagulation cascade or platelets, such as tissue factor and podoplanin, respectively. As signs and symptoms of VTE may be non-specific, diagnosis requires clinical assessment, evaluation of pre-test probability, and objective diagnostic testing with ultrasonography or CT. Risk assessment tools have been validated to identify patients at risk of VTE. Primary prevention of VTE (thromboprophylaxis) has long been recommended in the inpatient and post-surgical settings, and is now an option in the outpatient setting for individuals with high-risk cancer. Anticoagulant therapy is the cornerstone of therapy, with low molecular weight heparin or newer options such as direct oral anticoagulants. Personalized treatment incorporating risk of bleeding and patient preferences is essential, especially as a diagnosis of VTE is often considered by patients even more distressing than their cancer diagnosis, and can severely affect the quality of life. Future research should focus on current knowledge gaps including optimizing risk assessment tools, biomarker discovery, next-generation anticoagulant development and implementation science.

How I treat and prevent venous thrombotic complications in patients with lymphoma.

Venous thromboembolism (VTE) is a common complication occurring in 5% to 10% of patients with lymphoma. As the complexity of lymphoma management has increased with novel therapies, so too has the treatment of VTE. Therapeutic options for the treatment of cancer-associated VTE have expanded from only warfarin and low-molecular-weight heparins (LMWHs) to include the direct oral anticoagulants (DOACs) apixaban, edoxaban and rivaroxaban. There have been no head-to-head trials comparing different DOACs in this setting, and randomized trials comparing a DOAC with LMWH dalteparin differ in trial design and results. Drug-drug interactions, drug-specific side effects, and patient selection are important considerations when prescribing anticoagulant therapy. In all patients, the relative risks of thrombosis and bleeding, the availability of the anticoagulant, and the life expectancy of the patient are vital elements in selecting the most appropriate anticoagulant (which can vary over time) for the individual patient. We describe the intricacies and challenges of treating thrombotic complications in patients with lymphoma with an emphasis on evidence and guideline-based care.

Cancer-Associated ThrOmboSIs - Patient-Reported OutcoMes With RivarOxaban (COSIMO) - Baseline characteristics and clinical outcomes.

BACKGROUND: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolic events, which contribute to significant morbidity and mortality. Direct oral anticoagulants may provide a convenient treatment option for these patients. OBJECTIVES: To assess clinical characteristics and outcomes of patients with active cancer changing to rivaroxaban after ≥4 weeks of standard therapy for the treatment of venous thromboembolism (VTE) in clinical practice. This analysis focused on secondary outcomes of Cancer-associated thrOmboSIs - Patient-reported outcoMes with rivarOxaban (COSIMO). PATIENTS: COSIMO was a multinational, prospective, noninterventional, single-arm cohort study. Overall, 505 patients received at least one dose of rivaroxaban; 96.6% changing from low-molecular-weight heparin, 1.6% from a vitamin K antagonist, and 1.8% from fondaparinux. RESULTS: Most patients had solid tumors (n = 449; 88.9%) and approximately half of these patients had metastases. The qualifying venous thromboembolic event was deep vein thrombosis (DVT) in 45.3% of patients, pulmonary embolism (PE) in 37.2% of patients, DVT with PE in 9.7% of patients, and catheter-associated DVT in 7.5% of patients. Approximately 75.1% of patients received rivaroxaban for at least 3 months; 150 (29.7%) patients received concomitant chemotherapy during the study. VTE recurrence, major bleeding, nonmajor bleeding, and major adverse cardiovascular events occurred in 18 (3.6%), 18 (3.6%), 81 (16.0%), and 12 (2.4%) patients, respectively. CONCLUSIONS: In patients with CAT who changed to rivaroxaban treatment after ≥4 weeks of standard therapy, the observed incidence proportions of recurrent VTE and bleeding events were in keeping with the recognized effectiveness and safety profile of rivaroxaban for the treatment of CAT.

Treatment Algorithm in Cancer-Associated Thrombosis: Updated Canadian Expert Consensus.

Patients with cancer-associated thrombosis (CAT) are at high risk of recurrent venous thromboembolism (VTE) and major bleeding complications. Risks vary significantly between individuals based on cancer status, treatment, and other characteristics. To facilitate the evidence-based management of anticoagulant therapy in this patient population, a committee of 11 Canadian clinical experts updated a consensus-based algorithm for the acute and extended treatment of symptomatic and incidental CAT that was developed in 2018. Following a systematic review of the literature, updates to the algorithm were discussed during an online teleconference, and the algorithm was subsequently refined based on feedback from committee members. Clinicians using this treatment algorithm should consider bleeding risk, type of cancer, and drug-drug interactions, as well as patient and clinician preferences, in tailoring anticoagulation for patients with CAT. Anticoagulant therapy should be adapted as the patient's cancer status and management change over time.

American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.

BACKGROUND: Venous thromboembolism (VTE) is a common complication among patients with cancer. Patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The guideline development process was supported by updated or new systematic evidence reviews. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess evidence and make recommendations. RESULTS: Recommendations address mechanical and pharmacological prophylaxis in hospitalized medical patients with cancer, those undergoing a surgical procedure, and ambulatory patients receiving cancer chemotherapy. The recommendations also address the use of anticoagulation for the initial, short-term, and long-term treatment of VTE in patients with cancer. CONCLUSIONS: Strong recommendations include not using thromboprophylaxis in ambulatory patients receiving cancer chemotherapy at low risk of VTE and to use low-molecular-weight heparin (LMWH) for initial treatment of VTE in patients with cancer. Conditional recommendations include using thromboprophylaxis in hospitalized medical patients with cancer, LMWH or fondaparinux for surgical patients with cancer, LMWH or direct oral anticoagulants (DOAC) in ambulatory patients with cancer receiving systemic therapy at high risk of VTE and LMWH or DOAC for initial treatment of VTE, DOAC for the short-term treatment of VTE, and LMWH or DOAC for the long-term treatment of VTE in patients with cancer.

Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes.

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

Anticoagulation Treatment in Cancer-Associated Venous Thromboembolism: Assessment of Patient Preferences Using a Discrete Choice Experiment (COSIMO Study).

INTRODUCTION: Clinical guidelines recommend anticoagulation therapy for the treatment of cancer-associated venous thromboembolism (VTE), but little is known about preferences. Therefore, the objective of this discrete choice experiment (DCE) was to elucidate patient preferences regarding anticoagulation convenience attributes. METHODS: Adult patients with cancer-associated VTE who switched to direct oral anticoagulants were included in a single-arm study (COSIMO). Patients were asked to decide between hypothetical treatment options based on a combination of the following attributes: route of administration (injection/tablet), frequency of intake (once/twice daily), need for regular controls of the international normalized ratio (INR) at least every 3 to 4 weeks (yes/no), interactions with food/alcohol (yes/no), and distance to treating physician (1 vs. 20 km) as an additional neutral attribute. DCE data were collected by structured telephone interviews and analyzed based on a conditional logit regression. RESULTS: Overall, 163 patients (mean age 63.7 years, 49.1% female) were included. They strongly preferred oral administration compared with self-injections (importance of this attribute for overall treatment decisions: 73.8%), and a treatment without dietary restrictions (11.8%). Even if these attributes were less important (7.2% and 6.5%, respectively), patients indicated a preference for a shorter distance to the treating physician and once-daily dosing compared with twice-daily intake. "Need for regular controls of INR at least every 3 to 4 weeks" showed no significant impact on the treatment decision (0.7%). CONCLUSION: This study showed that treatment-related decision making in cancer-associated VTE, assuming comparable effectiveness and safety of anticoagulant treatments, is predominantly driven by "route of administration," with patients strongly preferring oral administration.