Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study

Kraaijpoel, Noémie; Nisio, Marcello Di; Mulder, Frits I.; Es, Nick van; Beyer‐Westendorf, Jan; Carrier, Marc; García, David; Grosso, Michael; Kakkar, Ajay K.; Mercuri, Michele; Middeldorp, Saskia; Rojas‐Hernandez, Cristhiam M.; Santamaría, A.; Schwocho, Lee; Segers, Annelise; Verhamme, Peter; Wang, Tzu‐Fei; Weitz, Jeffrey I.; Zhang, George; Zwicker, Jeffrey I.; Büller, Harry R.; Raskob, Gary E.

doi:10.1055/s-0038-1667001

Cited by 166 publications

(160 citation statements)

References 14 publications

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“…There are reports of a higher incidence of gastrointestinal bleeding in patients with colorectal cancer treated with DOACs, without a statistically significant difference, in one study, 44 whereas in the recent Hokusai VTE Cancer Study the entire excess of major bleeding with edoxaban occurred in patients with gastrointestinal cancer. 45 The percentage of patients with this type of cancer in two RCTs that compared a DOAC with a VKA and provided relevant results was <10%, which may well explain the superior safety of the former agents in this comparison (Fig. 4B), 27,31 and the seemingly discrepant results of the comparison of DOACs with LMWH.…”

Section: Totalmentioning

confidence: 90%

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

Kirkilesis

Kakkos

Tsolakis

2019

European Journal of Vascular and Endovascular Surgery

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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.

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Section: Totalmentioning

confidence: 90%

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

Kirkilesis

Kakkos

Tsolakis

2019

European Journal of Vascular and Endovascular Surgery

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“…Pancreatic cancers may require higher doses of anticoagulant prophylaxis for most effective prophylactic strategy as assessed by LMWH prophylaxis studies . Similarly, gastroesophageal cancers may pose higher risk of bleeding on DOAC . Finally, AVERT used a “modified” Khorana score that allowed additional cancer types across both study arms (15 patients with multiple myeloma and 24 patients with primary brain tumor).…”

Section: Discussionmentioning

confidence: 99%

“…21,22 Similarly, gastroesophageal cancers may pose higher risk of bleeding on DOAC. 23 Finally, AVERT used a "modified" Khorana score that allowed additional cancer types across both study arms (15 patients with multiple myeloma and 24 patients with primary brain tumor).…”

Section: Discussionmentioning

confidence: 99%

Direct oral anticoagulant for the prevention of thrombosis in ambulatory patients with cancer: A systematic review and meta‐analysis

Kuderer

García

et al. 2019

Journal of Thrombosis and Haemostasis

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Background It is unclear if direct oral anticoagulant (DOAC) is efficacious and safe for prophylaxis of venous thromboembolism (VTE) in ambulatory patients with cancer. Methods We performed a systematic review using EMBASE, MEDLINE, and CENTRAL. Inclusion criteria included adult ambulatory patients with cancer, prophylactic use of DOAC, and randomized controlled trials. Exclusion criteria included pediatric patients, inpatient or postoperative setting, therapeutic indication of DOAC, or non‐phase III randomized controlled trial. Two authors screened/reviewed articles and abstracted the data. Meta‐analysis was performed using random‐effects model. Efficacy outcome included overall and symptomatic VTE incidence during the first 6 months. Safety outcomes included major bleeding and clinically relevant non‐major bleeding (CRNMB) incidence during the on‐treatment period. Subgroup analysis was performed for intermediate‐ and high‐risk Khorana score. Results A total of 202 records were identified and 28 full‐text articles were assessed. Two studies with 1415 participants were included for meta‐analysis. For DOAC vs placebo, the relative risks for overall and symptomatic VTE incidence by 6 months were 0.56 (0.35‐0.89) and 0.58 (0.29‐1.13), respectively. The relative risks for major bleeding and CRNMB while on‐treatment were 1.96 (0.80‐4.82) and 1.28 (0.74‐2.20), respectively. Patients with high‐risk Khorana score (3+) derived the largest absolute risk reduction of VTE. Conclusions Low‐dose DOAC reduces the rate of overall VTE in higher risk cancer patients starting systemic chemotherapy. It may reduce the rate of symptomatic VTE but increase the likelihood of bleeding.

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“…The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. 5 In the SELECT-D trial, patients received rivaroxaban or dalteparin for 6 months. 4 Using rivaroxaban reduced the 6-month VTE recurrence rate compared with dalteparin (hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.19-0.99).…”

Section: And the Anticoagulation Therapy In Selected Cancer Patients mentioning

confidence: 99%

“…At 12 months, the recurrent VTE rate was higher in the dalteparin arm than in the edoxaban arm and the rate of major bleeding was significantly lower with dalteparin compared with edoxaban. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer . In the SELECT‐D trial, patients received rivaroxaban or dalteparin for 6 months .…”

Section: Introductionmentioning

confidence: 99%

Treatment of cancer‐associated venous thromboembolism: 12‐month outcomes of the placebo versus rivaroxaban randomization of the SELECT‐D Trial (SELECT‐D: 12m)

Marshall

Levine

Hill

et al. 2020

Journal of Thrombosis and Haemostasis

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Background The Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT‐D) trial demonstrated reduction in recurrent venous thromboembolism (VTE) but increased bleeding with rivaroxaban compared with dalteparin for treatment of acute VTE in cancer patients, at 6 months. Uncertainty remains around optimal duration of anticoagulation. Objectives To assess VTE recurrence and bleeding, with anticoagulation or not, beyond 6 months. Patients/Methods In SELECT‐D, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis (RDVT) or index pulmonary embolism (PE) were eligible for randomization to a further 6 months of rivaroxaban or placebo. Patients with no RDVT stopped anticoagulation. Primary outcome was VTE recurrence at 12 months. The second randomization closed prematurely because of low recruitment when 92 of the planned 300 patients were recruited. Results Ninety‐two of 136 eligible patients were randomized to rivaroxaban or placebo. The cumulative VTE recurrence after 6 months from the second randomization was 14% with placebo and 4% with rivaroxaban (hazard ratio, 0.32; 95% confidence interval [CI], 0.06‐1.58). The major and clinically relevant non‐major bleeding rates were 0% and 0% with placebo; and 5% (95% CI, 1‐18) and 4% (95% CI, 1‐17) with rivaroxaban. In an exploratory analysis, 7 (15%) of 46 placebo patients with RDVT or an index PE experienced recurrent VTE compared to none in the 35 patients in the RDVT‐negative cohort (P = .03). Conclusion The SELECT‐D trial was underpowered to detect a statistically significant reduction in recurrent VTE with extended anticoagulation. The absence of RDVT and/or index PE, defined a population at low risk of recurrence.

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Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study

Cited by 166 publications

References 14 publications

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

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

Direct oral anticoagulant for the prevention of thrombosis in ambulatory patients with cancer: A systematic review and meta‐analysis

Treatment of cancer‐associated venous thromboembolism: 12‐month outcomes of the placebo versus rivaroxaban randomization of the SELECT‐D Trial (SELECT‐D: 12m)

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