Betrixaban for first-line venous thromboembolism prevention in acute medically ill patients with risk factors for venous thromboembolism

ABSTRACT

Introduction: Compared to other direct oral anticoagulants, betrixaban has a longer half-life, smaller peak-trough variance, minimal renal clearance, and minimal hepatic Cytochrome P (CYP) metabolism. The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial evaluated the efficacy and safety of extended duration betrixaban compared to standard duration enoxaparin in acutely ill hospitalized patients.

Areas covered: This article describes the role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely ill medical patients. This article provides a consolidated summary of the primary APEX study findings as well as prespecified and exploratory substudies. This article also provides a review of the results of studies in which other direct factor Xa inhibitors have been evaluated in an extended duration regimen in this patient population.

Expert commentary: While previous agents have demonstrated that extended duration VTE prophylaxis can be efficacious, betrixaban is the first agent to demonstrate efficacy without an increase in major bleeding. The totality of the data from the APEX trial supports extended duration betrixaban for VTE prophylaxis in the acute medically ill patient population. As such, betrixaban has been approved in the USA for extended VTE prophylaxis in at-risk acute medically ill patients.     

Travel-related thromboembolism: mechanisms and avoidance

Evidence regarding the existence of travel-related venous thrombosis and pulmonary embolism is building. Research suggests that travel of all kinds increases the risk by two- to four-fold. Risks are not restricted to air travel alone. For travelers without any known risk factors, the risk of experiencing venous thromboembolism is likely to be very low. However, risks increase significantly in the presence of known risk factors, such as age over 60 years, thrombophilic disorders, varicose veins, history of thromboembolism, obesity, women taking oral contraceptives and travel duration over 12 h. A combination of one or more of these risk factors raises the probability of developing travel-related thromboembolism. Possible contributing factors, such as cramped sitting (with suppressed leg venous flow), moderate hypoxia, low humidity in the aircraft and dehydration, are discussed. Depending on the risk profile of individuals, the use of graduated compression stockings and/or pharmacological interventions (low-molecular-weight heparins are preferred) may be recommended.     

Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups

Background: New oral anticoagulants for thromboprophylaxis after hip or knee arthroplasty have been given as fixed‐dose regimens. Objective: To evaluate the consistency of the antithrombotic efficacy and bleeding risk of apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily after knee or hip arthroplasty across the clinical characteristics of age, gender, body weight, body mass index (BMI) and creatinine clearance. Methods: The pooled results of the ADVANCE‐2 (knee arthroplasty) and ‐3 (hip arthroplasty) randomized trials were used to evaluate if treatment had a statistically significantly different effect (P < 0.10) on major venous thromboembolism (VTE) and bleeding for the characteristics of age, gender, body weight, BMI and creatinine clearance. Both univariate analysis and multivariate logistic regression were used. Results: Univariate analyses identified statistically significant interactions for age and major VTE (P = 0.09); for both age (P = 0.07) and body weight (P = 0.07) and the outcome of major bleeding; and for creatinine clearance (P = 0.03) and the composite outcome of major and clinically relevant non‐major bleeding. Estimates of these possible differences were not precise, with wide 95% confidence intervals (CIs) that included a zero difference for several subgroups. Multivariate logistic regression analysis did not detect a statistically significant interaction for any outcomes. Conclusions: This analysis found no convincing evidence that age, weight, gender, BMI or creatinine clearance influenced the balance of benefit to risk for apixaban compared with enoxaparin. Because only 5% of patients had a creatinine clearance between 30 and 50 mL min^?1, further data are needed in such patients.     

Venous Thromboembolism During Chemotherapy for Testicular Cancer: A Population-Based Study

AimsVenous thromboembolism (VTE) is a potential complication among germ cell tumour patients. We evaluated the incidence rate, timing and factors associated with VTE among patients with germ cell cancer in routine practice.Materials and methodsThe Ontario Cancer Registry was linked to electronic records of treatment to identify all cases of testicular cancer treated in Ontario during 2000–2010. Administrative databases were used to identify VTE in the 3 months before and 5 years after orchiectomy. We explored patient-, disease- and treatment-related factors associated with VTE among all patients as well as those with detailed chemotherapy records available.ResultsDuring 2000–2010, 2650 patients underwent orchiectomy for testicular cancer; among this cohort, 920 (33%) received chemotherapy. The VTE rate was 8% (69/920) among patients treated with chemotherapy and 0.6% (11/1730) among those without chemotherapy. Among the patients treated with chemotherapy who had VTE, 13% (9/69) occurred in the month before starting chemotherapy, 62% (42/69) in the first 3 months after starting and 25% thereafter. For patients who received three and four cycles, VTE rates were 8% (21/258) and 16% (19/121), respectively. In adjusted analyses, the only factor independently associated with VTE was increasing number of cycles (odds ratio 3.91 for four cycles, odds ratio 1.63 for three cycles (P = 0.022) compared with one to two cycles).ConclusionThis population-based study confirms findings from institutional case series regarding the high rate of VTE among patients with germ cell tumours treated with chemotherapy. Future studies should evaluate the extent to which VTE prophylactic strategies might mitigate this risk.     

Postpartum thromboembolism: Severe events might be preventable using a new risk score model

Background:

Pregnancy-related venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality. A new risk assessment model for VTE in relation to pregnancy has been introduced in Sweden. We wished to determine the proportion of preventable VTE cases if the model had been in use and make a brief cost-benefit analysis.

Methods:

A hospital-based retrospective case-control study of all postpartum thromboembolic instances of deep venous thrombosis and pulmonary embolisms during a 16-year period. Large anamnestic risk factors at the time of delivery were assessed. We correlated the findings with the new Swedish guidelines for thromboprophylaxis.

Results:

We found 37 cases of postpartum VTE during the study period. Nineteen of all VTE cases (51%) and eight out of eleven of cases of pulmonary embolism (73%) had two or more large anamnestic risk factors, ie, they would have been subjected to thromboprophylaxis if the new guidelines had been used. The cost of each preventable VTE was lower than treating a VTE.

Conclusion:

Approximately one-half of postpartum VTE cases and 70% of pulmonary emboli cases have at least two large risk factors and might be preventable using the new algorithm. From the perspective of the health care system the new recommendations appears to be cost-effective.     

Anticoagulation

The increasing incidence of thrombosis in hospitalized patients in the 21st century is due to improved awareness by clinicians and more sophisticated forms of imaging. Thromboprophylaxis is now an imperative in the NHS of the UK and this combined with new, improved and safer forms of anticoagulation means that post-operative deaths from venous thromboembolic disease should become a thing of the past. In the following paper the authors review the up-to-date literature with emphasis on the newer anticoagulants that do not require blood test monitoring. We fully accept that this is a developing field and that the recognized indications for certain of these agents will change with the accumulation of further evidence.     

Thromboprophylaxis in patients with lower limb immobilisation – review of current status

The risk for venous thromboembolism (VTE) associated with lower limb immobilisation is unclear, owing to of a lack of evidence from studies in this patient group. However, six small, randomised control trials (RCTs), totalling 1536 patients, compared low molecular weight heparin (LMWH) with controls and showed a significant reduction in asymptomatic deep vein thrombosis (DVT) from 17·1% to 9·8%, with very low bleeding rates. This is likely to be an underestimate of the real risk reduction as most trials excluded high-risk patients from randomisation. There have been no other controlled trials in cast-immobilised patients using alternative prophylactic measures. Together with the RCTs, other cohort studies have identified risk factors that increase the risk for VTE in lower limb immobilisation. In summary, patients in lower limb cast (or brace) immobilisation should be risk assessed and those deemed high risk for VTE should receive prophylactic LMWH for at least the duration of cast immobilisation.     

Selection of medical patients for prophylaxis of venous thromboembolism based on analysis of the benefit–hazard ratio

Background:  Medical patients may benefit from anticoagulant prophylaxis of venous thromboembolism (VTE), but assessment of thrombotic risk is complex. I describe a method for estimating the minimum thrombotic risk required to ensure that a reasonable benefit–hazard ratio is maintained.
Methods:  An equation was derived relating baseline VTE risk and a minimum acceptable benefit–hazard ratio ( R ), defined as 'pulmonary embolus (PE) alone', 'PE or symptomatic proximal deep venous thrombosis (DVT)', or 'PE or any symptomatic DVT' prevented per major bleeding. The equation was used to estimate the relative risk (RR) of thromboembolism required for net benefit (main outcome measure). The PREVENT study was the primary data source, backed by data from two meta-analyses.
Results:  For R ranging from 3 to 10, the RR required for net beneficial prophylaxis was 6.5–21.6 (PE alone); 3.0–9.9 (PE or symptomatic proximal DVT); and 2.3–7.6 (PE or any symptomatic DVT), respectively. These RR are possible only in the presence of risk factors of high weighting. Sensitivity analysis showed that the findings were robust to changes in baseline assumptions related to thrombosis and bleeding rates.
Conclusion:  A method for risk assessment for medical thromboprophylaxis has been developed. The results suggest that only a minority of medical patients with high RR should receive prophylaxis.     

妊娠相关静脉血栓栓塞症防治策略及中国实践

妊娠期和产褥期是静脉血栓栓塞症(VTE)明确的危险因素。妊娠相关VTE主要根据临床症状和体征、加压超声、肺通气/灌注扫描和CT肺动脉造影确诊。其防治首选低分子肝素,少数特殊患者使用普通肝素优于低分子肝素,溶栓治疗或放置下腔静脉滤器应严格把握指征。其中VTE的分娩期处理极具挑战性,需要产科、麻醉科、新生儿科以及血液科多科协作。近年来中国的VTE发生率有增高趋势,但缺乏实际的发病率数据以及有关VTE防治策略的研究,因此建立适合中国孕产妇的防治策略并采取多学科协作诊治的方式尤为重要。