Editor's Choice – A Systematic Review and Meta-Analysis of the Efficacy and Safety of Anticoagulation in the Treatment of Venous Thromboembolism in Patients with Cancer

Abstract

WHAT THIS PAPER ADDS This meta-analysis provides complete evidence for the relative efficacy and safety of all major anticoagulant types in the treatment of cancer related venous thromboembolism, pointing out the often insufficient and moderate quality information in the existing literature, which highlights the need for further investigations. Data from previous studies showing that low molecular weight heparins (LMWHs) are more effective than, and equally safe as vitamin K antagonists (VKAs) are confirmed. However, anti-Xa agents are more effective and much safer than VKAs. In a direct comparison, direct oral anticoagulants are better but less safe than LMWHs, although the moderate quality of the evidence calls for further research results that are eagerly awaited.Objective/Background: The aim was to review the relative efficacy and safety of anticoagulation for managing venous thromboembolism (VTE) in patients with cancer. Methods: A systematic review and meta-analysis was carried out. On 17 May 2018 the MEDLINE and Scopus databases were searched for randomised controlled trials (RCTs). Eligible RCTs had to be performed in patients with cancer exclusively or to report results on a subset of patients with cancer. The main study outcomes (efficacy/recurrent VTE and safety/bleeding events) were expressed as risk ratios (RR) with a 95% confidence interval (CI). The quality of evidence was assessed following the GRADE method. Results: Twenty-three RCTs with 6980 patients were identified. Low molecular weight heparins (LMWHs) were more effective than vitamin K antagonists (VKAs) in preventing recurrent VTE (RR 0.58, 95% CI 0.45e0.75) and deep vein thrombosis (RR 0.44, 95% CI 0.29e0.69) but not pulmonary embolism (PE), bleeding, or overall mortality. Direct oral anticoagulants (DOACs) were more effective than VKAs in preventing recurrent VTE (RR 0.65, 95% CI 0.45e0.95) but not DVT, PE, overall mortality, or bleeding. However, anti-Xa DOACs were more effective (RR for VTE 0.64, 95% CI 0.42e0.97) and caused less bleeding than VKAs, although major bleeding was reduced only with DOACs not requiring initial parenteral anticoagulation (RR 0.45, 95% CI 0.21e0.97). In a direct comparison, DOACs were more effective than LMWHs in preventing VTE recurrence (RR 0.64, 95% CI 0.45e0.90) but caused more major bleeding (RR 1.75, 95% CI 1.10e2.77), with no difference in fatal bleeding and overall mortality. Quality of evidence, where sufficient, was mostly moderate or high. Conclusion: Compared with VKAs, LMWHs and DOACs are more effective in treating VTE, but the former caused less bleeding. DOACs are more effective than LMWHs in preventing VTE recurrence but may carry a higher risk of major bleeding, pending additional information by ongoing trials.

Editor's Choice – European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis

“…A recent meta-analysis identified 23 RCTs with 6 980 patients. 365 LMWHs were more effective than VKAs in preventing recurrent VTE (RR 0.58, 95% CI 0.45 e 0. In the first open label, non-inferiority trial, the Hokusai VTE Cancer Investigators randomly assigned 1 050 patients with cancer who had acute symptomatic or incidental VTE to receive either LMWH for at least five days followed by oral edoxaban (60 mg once daily) or subcutaneous dalteparin (200 IU/Kg for one month reduced to 150 IU/kg, once daily).…”

“…Heterogeneity: Chi 2 = 4.05, df = 3 (p = .26); I 2 = 26% Test for overall effect: Z = 3.50 (p = .0005) Test for subgroup differences: Chi 2 = 1.03, df = 2 (p = .60); I 2 = 0% edoxaban), UFH, or VKAs are acceptable therapeutic options for principal anticoagulation. 365,369 See also sections 2.3.3, 4.6 for patients with renal impairment, and 4.7 for patients with extreme body weight. In general, for patients with CAVT, anticoagulation should be continued for as long as the cancer is active, considering that rates of late recurrence, after two to three years, are generally much lower than observed in the first two years.…”

“…This is owing to the safety profile of the DOACs, particularly anti-Xa DOACs not requiring initial parenteral anticoagulation with heparin (i.e., rivaroxaban or apixaban). 365 Management of recurrent VTE in patients with cancer follows the principles provided elsewhere in the document, with additional consideration of mechanical compression from tumour masses. 372…”

An epidemic of redundant meta‐analyses

“…At the time the search was ended (October 6, 2020), 46 records were identified, of which 26 were discarded on title and abstract ( n = 24) or full‐text ( n = 2). The 20 remaining meta‐analyses were published in nonpredatory peer‐reviewed journals: five studies pooled the data of two RCTs, 6‐10 four studies pooled the data of three RCTs, 11‐14 and 11 studies pooled the data of four RCTs 15‐25 . The main characteristics of the 20 meta‐analyses are described in Table 1 and the results of the 20 meta‐analyses for efficacy and safety endpoint are shown Figure 1.…”

The Current Status of Direct Oral Anticoagulants in Cancer-Related Venous Thromboembolism Treatment

“…Основа этому подходу была заложена в 2003 г. публикацией исследования CLOT, в котором применение далтепарина в дозе 200 МЕ/кг массы тела на протяжении первого месяца и 150 МЕ/кг массы тела в течение последующих 5 мес в сравнении с традиционным применением АВК позволило уменьшить риск рецидива ВТЭО на 52% без влияния на показатели кровотечения и смертности [27]. Последующие мета-анализы подтвердили названную тенденцию: применение НМГ в сравнении с АВК позволяет снизить риск возникновения повторного тромботического события на 42-44% и не влияет на вероятность кровотечения и летального исхода [28,29] [6]).…”