Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta‐analysis of the literature

Summary. Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta‐analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60–2.41%; I) antenatally and 1.90% (95% CI 0.80–3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88–3.49%; I² 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy‐related VTE, but the optimal dosing regimens remain uncertain.     

Venous thromboembolism in cancer patients receiving neoadjuvant chemotherapy: a systematic review and meta‐analysis

Essentials

• Cancer patients are at risk for venous thromboembolism (VTE).
• The risk of VTE in less advanced stage cancer on neoadjuvant chemotherapy is unclear.
• In over 7800 patients, we found a 7% pooled incidence of VTE during neoadjuvant therapy.
• Highest VTE rates were observed in patients with bladder and esophageal cancer.

Summary

Background

Venous thromboembolism (VTE) is a frequent complication in cancer patients receiving adjuvant treatment. The risk of VTE during neoadjuvant chemo‐radiotherapy remains unclear.

Objectives

This systematic review evaluated the incidence of VTE in patients with cancer receiving neoadjuvant treatment.

Methods

MEDLINE and EMBASE databases were searched from inception to October 2017. Search results were supplemented with screening of conference proceedings of the American Society of Clinical Oncology (2009–2016) and the International Society of Thrombosis and Haemostasis (2003–2016). Two review authors independently screened titles and abstracts, and extracted data onto standardized forms.

Results

Twenty‐eight cohort studies (7827 cancer patients, range 11 to 1398) were included. Twenty‐five had a retrospective design. Eighteen cohorts included patients with gastrointestinal cancer, representing over two‐thirds of the whole study population (n = 6002, 78%). In total, 508 of 7768 patients were diagnosed with at least one VTE during neoadjuvant treatment, for a pooled VTE incidence of 7% (95% CI, 5% to 10%) in the absence of substantial between‐study heterogeneity. Heterogeneity was not explained by site of cancer or study design characteristics. VTE presented as pulmonary embolism in 22% to 96% of cases (16 cohorts), and it was symptomatic in 22% to 100% of patients (11 cohorts). The highest VTE rates were observed in patients with bladder (10.6%) or esophageal (8.4%) cancer.

Conclusions

This review found a relatively high incidence of VTE in cancer patients receiving neoadjuvant therapy in the presence of some between‐study variation, which deserves further evaluation in prospective studies.

     

Reduced‐dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta‐analysis

Essentials

• In venous thromboembolism (VTE), benefits of extended treatment are balanced by bleeding risks.
• This is a meta‐analysis of reduced‐dose direct oral anticoagulants (DOACs) in extended treatment.
• Reduced‐dose DOACs are as effective as full anticoagulation with bleeding risks similar to placebo.
• Reduced‐dose DOACs are an attractive option for patients in the extended phase of VTE treatment.

Summary

Background

Extended‐duration anticoagulation is beneficial for preventing recurrent venous thromboembolism (VTE). Reduced‐dose direct oral anticoagulants (DOACs) may be preferable if they preserve efficacy and cause less bleeding. We conducted a systematic review and meta‐analysis of trials comparing reduced‐dose DOACs with full‐dose DOACs and aspirin or placebo in the extended phase of VTE treatment.

Methods

A literature search was conducted by use of the MEDLINE, EMBASE and CINAHL databases, supplemented by hand‐searching. One thousand three hundred and ninety‐nine titles were screened, with data from accepted studies being extracted by two independent reviewers. Major outcomes analyzed included recurrent VTE and major and clinically relevant non‐major bleeding events, presented as risk ratios (RRs) and 95% confidence intervals (CI).

Results

Two trials met the prespecified inclusion criteria. Data from 5847 patients were analyzed for efficacy outcomes, and from 5842 patients for safety outcomes. Reduced‐dose DOACs were as effective as full‐dose treatment in preventing recurrent VTE at 1 year (RR 1.12 [95% CI 0.67–1.87]), and more effective than aspirin or placebo (RR 0.26 [95% CI 0.14–0.46]). Rates of major or clinically relevant non‐major bleeding events were similar between patients receiving reduced‐dose DOACs and and those receiving aspirin or placebo (RR 1.19 [95% CI 0.81–1.77]). There was a trend towards less bleeding when reduced‐dose and full‐dose DOACs were compared (RR 0.74 [95% CI 0.52–1.05]).

Conclusions

Extended‐duration treatment of VTE with reduced‐dose DOACs may be as efficacious as full‐dose treatment, with rates of major bleeding being similar to those in patients receiving treatment with aspirin or placebo, but further long‐term studies are needed.

     

Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta‐analysis

See also Watson HG. RVO – Real value obscure. This issue, pp 1116–8; Le Gal G, Carrier M, Kovacs MJ, Betancourt MT, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Delluc A, White RH, Vickars L, Rodger M. Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study. This issue, pp 1126–32. Summary. Background: Residual vein obstruction (RVO) detected on compression ultrasonography of the leg after a few months of anticoagulation therapy might be able to identify patients with deep vein thrombosis (DVT) at high risk of having a recurrent venous thromboembolism (VTE). Aim: To determine whether RVO is associated with an increased risk of recurrent events in patients with DVT. Patients and Methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. We selected 14 articles (nine prospective cohort studies and five randomized controlled trials) that included patients with DVT who had an assessment for RVO with the use of compression ultrasonography. Two reviewers independently extracted data onto standardized forms. Results: Overall, the presence of RVO was not associated with an increased risk of recurrent VTE (odds ratio [OR] 1.24, 95% confidence interval [CI] 0.9–1.7) in patients with unprovoked DVT who stopped oral anticoagulation therapy at the time of RVO assessment. However, RVO was significantly associated with recurrent VTE in patients with any (unprovoked or provoked) DVT (OR 1.5, 95% CI 1.1–2.0). Conclusions: RVO was associated with a modestly increased risk of recurrent VTE in patients with DVT (unprovoked and provoked). However, RVO did not seem to be a predictor of recurrent VTE in patients with unprovoked DVT following anticoagulation discontinuation. Further prospective studies are needed to assess the role of RVO in patients with unprovoked DVT.     

Prevention of venous thromboembolism: a key patient safety priority

Summary.  It is more than 50 years since the first publication of a study showing that symptomatic and fatal venous thromboembolism could be reduced with the use of thromboprophylaxis. Furthermore, it is 23 years since the first evidence-based guidelines recommended routine use of thromboprophylaxis for most hospitalized patients. However, despite the overwhelming evidence that thromboprophylaxis safely and inexpensively reduces thromboembolic complications associated with acute illness and surgery, there continue to be large gaps in the provision of this key patient safety intervention and even larger gaps in the provision of optimal thromboprophylaxis. The implementation of quality improvement strategies, both at the national level and in local hospitals, are able to increase awareness of thromboembolic risks, to increase adherence to thromboprophylaxis guidelines, and to decrease both clinically important thromboembolic events and hospital costs. Therefore, the objective is for every hospitalized patient to receive appropriate thromboprophylaxis based on their thromboembolic and bleeding risks.     

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.     

Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta‐analysis

Summary. Background: Whether patients with unprovoked venous thromboembolism (VTE) have a higher risk of arterial cardiovascular events than the general population and patients with provoked VTE is a matter of debate. Objective: To perform a systematic review and a meta‐analysis aimed at assessing the risk of arterial cardiovascular events in patients with unprovoked VTE as compared with both patients with provoked VTE and controls. Methods: A systematic search was performed. Studies reporting on (i) patients with confirmed VTE, (ii) a follow‐up of at least 6 months and (iii) the incidence of arterial cardiovascular events (acute myocardial infarction and ischemic stroke) were included in the systematic review. Those studies reporting separate incidences of cardiovascular events in patients with unprovoked and provoked VTE or patients with unprovoked VTE and controls were included in the incidence rate meta‐analysis. Results: Overall, 17 studies were included in the systematic review. The weighted mean incidence of arterial cardiovascular events was 0.46% [95% confidence interval (CI) 0.34–0.59] and 0.35% (95% CI 0.24–0.49) per patient‐year in patients with unprovoked and provoked VTE, respectively. Six studies were included in the meta‐analysis. The risk of arterial cardiovascular events appeared to be higher in patients with unprovoked VTE than in controls [incidence rate ratio (IRR) 1.87, 95% CI 1.32–2.65] and than in patients with provoked VTE (IRR 1.86, 95% CI 1.19–2.89). Conclusions: Patients with unprovoked VTE have a higher risk of arterial cardiovascular events than patients with provoked VTE over long‐term follow‐up.