Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Cost-utility analysis of apixaban compared with usual care for primary thromboprophylaxis in ambulatory patients with cancer.

BACKGROUND: Apixaban (2.5 mg) taken twice daily has been shown to substantially reduce the risk of venous thromboembolism (VTE) compared with placebo for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE. We aimed to compare the health system costs and health benefits associated with primary thromboprophylaxis using apixaban with those associated with the current standard of care (where no primary thromboprophylaxis is given), from the perspective of Canada's publicly funded health care system in this subpopulation of patients with cancer over a lifetime horizon. METHODS: We performed a cost-utility analysis to estimate the incremental cost per quality-adjusted life-year (QALY) gained with primary thromboprophylaxis using apixaban. We obtained baseline event rates and the efficacy of apixaban from the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial on apixaban prophylaxis. We estimated relative risk for bleeding, risk of complications associated with VTE treatment, mortality rates, costs and utilities from other published sources. RESULTS: Over a lifetime horizon, apixaban resulted in lower costs to the health system (Can$7902.98 v. Can$14 875.82) and an improvement in QALYs (9.089 v. 9.006). The key driver of cost-effectiveness results was the relative risk of VTE as a result of apixaban. Results from the probabilistic analysis showed that at a willingness to pay of Can$50 000 per QALY, the strategy with the highest probability of being most cost-effective was apixaban, with a probability of 99.87%. INTERPRETATION: We found that apixaban is a cost-saving option for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE.

Arterial Thrombosis in Patients with Cancer.

Patients with cancer are at increased risk of arterial thromboembolic disease due to the presence of risk factors common to both the development of cancer and arterial thrombosis, the cancer itself, and the treatments provided to treat cancer. We review here the epidemiology and pathophysiology of arterial thromboembolic disease in cancer, along with its prevention and treatment strategies. We also propose a generalized approach for the management of arterial thromboembolic disease in this patient population.

Anticoagulation management and related outcomes in patients with cancer-associated thrombosis and thrombocytopenia: A systematic review and meta-analysis.

BACKGROUND: Patients with cancer have an increased risk of both venous thromboembolism (VTE) requiring anticoagulation and thrombocytopenia. The optimal management is unclear. We performed a systematic review and meta-analysis to evaluate the outcomes in these patients. METHODS: We searched MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials from inception to February 5, 2022. Studies assessing adult patients with cancer-associated thrombosis and platelet count <100 × 109/L were included. Three anticoagulation management strategies were reported: full dose, modified dose, or no anticoagulation. The primary efficacy outcome was recurrent VTE, and the primary safety outcome was major bleeding. The incidence rates of thrombotic and bleeding outcomes by anticoagulation management strategies were descriptive, and were pooled using random effects model and expressed as events per 100 patient-months with associated 95 % confidence intervals (CI). RESULTS: We included 19 observational cohort studies (N = 1728 patients) in the systematic review, with 10 included in the meta-analysis (N = 707 patients). Approximately 90 % of patients had hematological malignancies, with low-molecular-weight heparin being the main anticoagulant. The rates of recurrent VTE and bleeding complications were high regardless of management strategies - recurrent VTE on full dose: 2.65/100 patient-months (95 % CI 1.62-4.32), modified dose: 3.51/100 patient-months (95 % CI 1.00-12.39); major bleeding on full dose: 4.45/100 patient-months (95 % CI 2.80-7.06), modified dose: 4.16/100 patient-months (95 % CI 2.24-7.74). There was serious risk of bias in all studies. CONCLUSIONS: Patients with cancer-associated thrombosis and thrombocytopenia have high risks of both recurrent VTE and major bleeding, but current literature is significantly limited to guide the best management.

Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. OBJECTIVES: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE. METHODS: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. RESULTS: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%). CONCLUSIONS: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.

Evidence-Based Minireview: Mortality and thrombosis in patients receiving prothrombin complex concentrates or andexanet alfa for the management of direct oral factor Xa inhibitor-associated major bleeding.

A 77-year-old man with atrial fibrillation and a CHA2DS2Vasc score of 6 for hypertension, age, diabetes, and previous stroke is brought to the emergency department with decreased level of consciousness. He is anticoagulated with rivaroxaban (a direct oral factor Xa inhibitor [FXaI]) and received his last dose about 4 hours before presentation. Urgent computed tomography of the head shows intracerebral hemorrhage. Because of his previous stroke, the patient's family is concerned about treating the bleed with pharmacological agents that may increase the risk of stroke. What are the risks of thrombosis and mortality related to the use of prothrombin complex concentrates (PCCs) and andexanet alfa for patients with direct oral FXaI-associated major bleeding?

What's new in the prevention and treatment of cancer-associated thrombosis?

Venous thromboembolism (VTE) is a common complication in ambulatory cancer patients receiving chemotherapy. Current clinical guidelines recommend against the use of routine primary thromboprophylaxis in unselected ambulatory cancer patients. The Khorana score is a risk assessment tool derived and prospectively validated for the identification of cancer patients at high risk of thrombotic complications. Recently, 2 randomized, controlled trials have assessed the use of low-dose direct oral Xa inhibitors, apixaban and rivaroxaban, for the prevention of cancer-associated thrombosis in ambulatory patients at intermediate to high risk of VTE (Khorana score ≥2). Taken together, these trials have shown that low-dose direct oral Xa inhibitors reduce the risk of VTE in this patient population without a significant increase in major bleeding. These results should encourage clinicians to consider the use of primary thromboprophylaxis in ambulatory cancer patients at intermediate to high risk of VTE who do not have any apparent risk factors for bleeding. The direct oral Xa inhibitors have also been assessed in the acute management of cancer-associated thrombosis. Current evidence suggests that these drugs are a convenient, effective, and safe option for the management of acute VTE in many cancer patients. Low-molecular weight heparin, however, may continue to be the treatment of choice depending on the presence of bleeding risk factors, the type of cancer, drug-drug interactions, and patient preferences.

Efficacy and safety of Xa inhibitors for the treatment of cancer-associated venous thromboembolism.

INTRODUCTION: Cancer patients with cancer-associated thrombosis (CAT) are at an elevated risk of recurrent venous thromboembolism (VTE) and of major bleeding while receiving treatment with anticoagulation. Recently, Xa inhibitors have been assessed in cancer patients for the treatment of CAT, providing clinicians and patients with more treatment options. AREAS COVERED: In this narrative review, the authors evaluate the evidence regarding the efficacy and safety of edoxaban, rivaroxaban, and apixaban in the treatment of CAT. EXPERT OPINION: Xa inhibitors are an effective, safe, and convenient option for the treatment of CAT. Overall, they may be associated with a lower risk of recurrent VTE in cancer patients. Certain subgroups of cancer patients may be at increased risk of major bleeding while on treatment with Xa inhibitors, when compared to low-molecular-weight-heparin (LMWH). The current published data suggests an increase in gastrointestinal (GI) major bleeding in patients with GI malignancies. Other patient, treatment, and cancer characteristics may also be associated with a higher risk of major bleeding. Therefore, when assessing the appropriateness of Xa inhibitors for the treatment of CAT, the clinician must take into consideration the known interactions of these drugs, the individualized bleeding risk, and the patient's preferences, in order to make the best possible anticoagulation therapy recommendation.

Risk of major bleeding during extended oral anticoagulation in patients with first unprovoked venous thromboembolism: a systematic review and meta-analysis protocol.

BACKGROUND: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) remains controversial. Deciding to stop or continue anticoagulant therapy indefinitely after completing 3 to 6 months of initial treatment requires balancing the long-term risk of recurrent VTE if anticoagulation is stopped against the long-term risk of major bleeding if anticoagulation is continued. However, knowledge of the long-term risk for major bleeding events during extended anticoagulation in this patient population is limited. We plan to conduct a systematic review and meta-analysis to quantify the risk for major bleeding events during extended oral anticoagulation in patients with first unprovoked VTE. METHODS: Electronic databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials will be systematically searched with the assistance of an information specialist (from inception to March 1, 2019) to identify randomized controlled trials and prospective cohort studies reporting major bleeding during extended oral anticoagulation in patients with first unprovoked VTE, who have completed at least 3 months of initial anticoagulant therapy. Study selection, risk of bias assessment, and data extraction will be performed independently by at least two investigators. The number of major bleeding events and person-years of follow-up will be used to calculate the rate (events per 100 person-years) with its 95% confidence interval for each study cohort, during clinically relevant time periods of extended anticoagulant therapy. Results will be pooled using random effect meta-analysis. DISCUSSION: The planned systematic review and meta-analysis will provide reliable estimates of the risk for major bleeding events during extended anticoagulation. This information will help inform patient prognosis and assist clinicians with balancing the risks and benefits of treatment to guide management of unprovoked VTE. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128597 .

Apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients receiving chemotherapy: Rational and design of the AVERT trial.

Patients with active cancer have a heightened risk of venous thromboembolism (VTE). This risk is further increased by the initiation of chemotherapy. Although previous studies have suggested that the use of parenteral thromboprophylaxis in all ambulatory cancer patients receiving chemotherapy significantly decreases the rate of VTE, current clinical practice guidelines do not recommend routine use of thromboprophylaxis in this patient population. A major criticism of these studies has been the inclusion of patients at lower risk for VTE, which may have diluted the potential beneficial effect of the parenteral thromboprophylaxis. It is therefore imperative to appropriately risk stratify ambulatory cancer patients using a validated scoring system (e.g. Khorana risk score) in order to identify those most likely to benefit from thromboprophylaxis. Direct oral anticoagulants, such as apixaban, may offer a convenient and safe option for thromboprophylaxis. As such, AVERT will randomize 574 ambulatory cancer patients receiving chemotherapy who are at high-risk for VTE (as defined by a Khorana score of ≥2) to Apixaban 2.5 mg BID versus placebo. The primary study outcome will be the first episode of objectively documented symptomatic or incidental VTE (deep vein thrombosis and/or pulmonary embolism) within the first 6 months (180 days ±â€¯3) following initiation of the blinded study drug for both intervention and placebo groups. The secondary safety outcomes include major bleeding, clinically relevant non-major bleeding, and overall survival rates. This study will hopefully offer evidence regarding the benefit of apixaban in ambulatory patients at high risk for VTE receiving chemotherapy.

A simple method to identify patients on long-term warfarin who may derive the most benefit from new oral anticoagulants.

In many countries, new oral anticoagulants are only covered for patients with suboptimal anticoagulation control on vitamin K antagonists (VKAs). The quality of VKA management is often reported using the time in therapeutic range (TTR). We sought to predict a TTR 65% or less using a surrogate measure [number of changes in VKA dose and number of international normalized ratio (INR) tests] that could be easily determined by primary care physicians. This cross-sectional study included consecutive patients whose VKA therapy was managed in a specialized anticoagulation clinic. Patients were dichotomized according to their TTR in the past 6 months (TTR > or ≤ 65%). The ability of the number of INR tests and VKA dose changes to predict TTR group was assessed using receiver-operating characteristics (ROC) curve analysis. The analyses included 1381 patients with a median age of 63 years. The mean TTR was 81% (interquartile range 70-90) and 17.4% of patients had a TTR 65% or more. Based on the ROC curve, patients were stratified according to whether they had either 3 or more dose changes or 9 or more INR tests within the last 6 months. The sensitivity to identify patients with TTR 65% or less was 87% and the specificity was 63%. The number of dose changes and the number of INR tests might be used as indicators of TTR; they could offer a simple way for clinicians to identify patients who are good candidates for the new oral anticoagulants. However, external validation studies in different clinical settings are needed to confirm these findings.

Estimating quality of life in acute venous thrombosis.

IMPORTANCE: Future funding for new treatments in venous thromboembolism will be guided by cost-utility analyses. There is little available information on the utility of acute venous thromboembolism, limiting the validity of economic analyses. OBJECTIVE: To measure the quality of life in the health states relating to thromboembolism cost-utility analyses. DESIGN: A prospective cohort study. SETTING: A single-center, university-affiliated thrombosis clinic. PARTICIPANTS: Two hundred sixteen thrombosis clinic patients with a history of lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE). EXPOSURES: Participants consented to take a standard gamble interview. Each participant rated the quality of life in acute DVT, acute PE, and bleeding complication health states. MAIN OUTCOMES AND MEASURES: The standard gamble measured quality of life (utility value) for acute DVT, acute PE, major intracranial bleeding event, minor intracranial bleeding event, and gastrointestinal bleeding event. RESULTS: Two hundred fifteen responses were included in the analysis. Twenty-six percent had experienced both PE and DVT; 54%, DVT alone; and 20%, PE alone. Forty-two percent had experienced more than 1 episode of thrombosis, and 23% had had cancer-associated thrombosis. We found the median utility for acute DVT was 0.81 (interquartile range [IQR], 0.55-0.94); acute PE, 0.75 (IQR, 0.45-0.91); major intracranial bleeding event, 0.15 (IQR, 0.00-0.65); minor intracranial bleeding event, 0.75 (IQR, 0.55-0.92); and gastrointestinal bleeding event, 0.65 (IQR, 0.15-0.86). The median length of symptoms for DVT or PE was 1 week (IQR, <1-3 weeks). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest published study on utilities in which the participants had personal experience of venous thromboembolism. We present unique information for economic analyses but have also identified future challenges for research in this area. Our summary results differ from those previously published, and we found wide variation in individual responses.