Rivaroxaban Versus Low-molecular-weight Heparin for Venous Thromboembolism in Advanced Upper Gastrointestinal Tract and Hepatopancreatobiliary Cancer

Abstract

Background/Aim: The aim of this study was to examine the efficacy and safety of direct oral anticoagulants for cancer-associated venous thromboembolism (VTE) in patients with active cancer. Patients and Methods: This study included patients with advanced unresectable/metastatic upper gastrointestinal (GI) or hepatopancreatobiliary (HPB) cancers with high risks of VTE and bleeding. Results: No significant differences were noted in potential bleeding factors between the rivaroxaban (n=105) and low-molecular-weight heparin (LMWH) (n=69) groups. Rivaroxaban exhibited similar risk of recurrent/aggravated VTE compared with LMWH (p=0.625) but increased risk of major bleeding (17.4% vs. 7.6%; p=0.072), clinically relevant bleeding (31.9% vs. 14.3%; p=0.019), and total bleeding (40.6% vs. 19%; p=0.010). The multivariate analysis regarded rivaroxaban as a significant factor for major bleeding (p=0.043) and clinically relevant bleeding (p=0.043). Conclusion: Rivaroxaban exhibits comparable efficacy but increases bleeding risks compared with LMWH in patients with active unresectable/metastatic upper GI tract or HPB cancers, requiring extra caution of higher major bleeding risks.As cancer-associated venous thromboembolism (VTE) might cause a delay or discontinuation of anticancer treatments (1), optimal management of VTE is essential in patients with cancer. The anticoagulation treatment in cancer-associated VTE is especially challenging in balancing the risks of recurrent VTE and bleeding during anticoagulation (2, 3). Randomized phase III trials have established that long-term low-molecular-weight heparins (LMWHs), such as dalteparin, correlated with better or similar efficacy and safety than vitamin K antagonists (VKAs) maintenance in patients with cancer (4-6). Accordingly, LMWH has been preferred over VKA for the treatment of cancer-associated thrombosis (7-9).Owing to convenience in administration and monitoring, direct oral anticoagulants (DOACs), including factor Xa inhibitors and thrombin inhibitors, have emerged with expectation to replace oral VKAs or LMWHs, as prophylactic and therapeutic anticoagulation options. In two large randomized studies comparing rivaroxaban, an oral factor Xa inhibitor, with enoxaparin followed by VKA maintenance for the treatment of deep-vein thrombosis (DVT) (EINSTEIN-DVT) and pulmonary embolism (EINSTEIN-PE), rivaroxaban demonstrated noninferior efficacy with similar risk for bleeding (10, 11). Other DOACs, including apixaban (12), edoxaban (13), and dabigatran (14), also showed noninferior efficacy and a similar or lower bleeding risk in patients with VTE compared with an oral VKA. However, these studies were not cancer-specific, and only <10% of patients had cancer, including cancer history only. Although a subgroup analysis of EINSTEIN-DVT and EINSTEIN-PE and a meta-analysis comparing DOAC and VKA in patients with cancer exhibited similar efficacy and safety between DOAC and VKA, these studies examined not only patients with cancer during anticoagulation but also patients whose c...

Epidemiology, Prevention, Diagnosis, and Management of Venous Thromboembolism in Gastrointestinal Cancers

“…Recio-Boiles et al demonstrated increased major bleeding with rivaroxaban compared with LMWH (21.5 vs. 5%, p ¼ 0.04). 18,19 These results were consistent with the increased risk of bleeding in the small subgroup of patients with esophageal or GE junction cancers in the SELECT-D trial. 16 Most recently, the Caravaggio trial randomized 1,155 patients with cancer and acute DVT to dalteparin at standard dosing or apixaban 10 mg by mouth twice daily for 7 days followed by 5 mg by mouth twice daily, both to complete 6 months of treatment.…”

“…14 Clinical trials of direct-acting oral anticoagulants (DOACs) have recently raised the question of increased risk of bleeding when patients with GI malignancies and VTE are treated with DOACs. [15][16][17][18][19] In addition to this bleeding risk, patients with cancer and VTE have a higher risk of VTE recurrence compared with patients without cancer with 12-month cumulative incidence up to 20.7%. 10,13,20 Regarding mortality in patients with cancer-associated VTE, a Dutch study found that among patients diagnosed with cancer at the time of VTE, the rate of 1 year overall survival (OS) was 12% compared with 36% in matched cancer controls resulting in a hazard ratio (HR) of 2.20.…”

“direct Oral Anticoagulants Versus Low-molecular-weight Heparin for Acute Treatment of Venous Thromboembolism in Patients With Gastrointestinal Cancer: a Systematic Review and Meta-analysis”

“…Similarly, among non-luminal GI cancer patients, major bleeding was not signi cantly different between groups, but the patients who received DOACs showed a trend towards more major bleeding with a pooled RR of 1.83 (95% CI: 0.6-5.56, P = 0.29, I 2 = 0%) (Fig. 3B) [11,22,24].…”

“…The number of patients enrolled in this study according to the type of GI cancer was 361 with upper GI cancer (cancer of the esophagus and/or stomach), 567 with lower GI cancer (cancer of colon and/or rectum), 483 hepato-biliary-pancreatic cancer (hepatocellular carcinoma, cholangiocarcinoma, cancer of the gallbladder, and/or pancreatic cancer), and 7 neuroendocrine tumors. GI cancer patients were further subdivided into the following three groups: group 1-928 patients with luminal GI cancer (cancer of the esophagus, stomach, colon, and/or rectum) [11,[20][21][22][23][24]; group 2-483 patients with non-luminal GI cancer (hepatocellular carcinoma, cancer of the gallbladder, and/or pancreatic cancer) [11,[20][21][22][23][24]; and, group 3-7 patients with neuroendocrine tumor [23]. The follow-up time in all studies was 6 months [11,[20][21][22][23][24].…”

“…A subgroup analysis evaluating major bleeding events in patients with luminal and non-luminal GI cancer revealed a trend toward non-statistically signi cant increased major bleeding in patients with luminal GI cancer treated with DOACs with a pooled RR of 1.58 (95% CI: 0.67-3.72, P = 0.30, I 2 = 49%) (Fig. 3A) [11,22,24]. Similarly, among non-luminal GI cancer patients, major bleeding was not signi cantly different between groups, but the patients who received DOACs showed a trend towards more major bleeding with a pooled RR of 1.83 (95% CI: 0.6-5.56, P = 0.29, I 2 = 0%) (Fig.…”