Bleeding in Patients With Gastrointestinal Cancer Compared With Nongastrointestinal Cancer Treated With Apixaban, Rivaroxaban, or Enoxaparin for Acute Venous Thromboembolism

doi:10.1016/j.mayocp.2021.04.026

Mayo Clinic Proceedings

Volume 96, Issue 11, November 2021, Pages 2793-2805

https://doi.org/10.1016/j.mayocp.2021.04.026 Get rights and content

Abstract

Objective

To compare the bleeding risk in patients with gastrointestinal (GI) cancer with that in patients with non-GI cancer treated with anticoagulation for acute cancer-associated venous thromboembolism (Ca-VTE).

Patients and Methods

Consecutive patients with Ca-VTE seen at the Mayo Thrombophilia Clinic between March 1, 2013, and April 20, 2020, were observed prospectively to assess major bleeding and clinically relevant nonmajor bleeding (CRNMB).

Results

In the group of 1392 patients with Ca-VTE, 499 (35.8%) had GI cancer including 272 with luminal GI cancer (lower GI, 208; upper GI, 64), 176 with pancreatic cancer, and 51 with hepatobiliary cancer. The rate of major bleeding and CRNMB in patients with GI cancer was similar to that in 893 (64.2%) patients with non-GI cancer treated with apixaban, rivaroxaban, or enoxaparin. Apixaban had a higher rate of major bleeding in luminal GI cancer compared with the non-GI cancer group (15.59 vs 3.26 per 100 person-years; P=.004) and compared with enoxaparin in patients with luminal GI cancer (15.59 vs 3.17; P=.04). Apixaban had a lower rate of CRNMB compared with rivaroxaban in patients with GI cancer (3.83 vs 9.40 per 100 person-years; P=.03). Patients treated with rivaroxaban in the luminal GI cancer group had a major bleeding rate similar to that of patients with non-GI cancer (2.04 vs 4.91 per 100 person-years; P=.37).

Conclusion

Apixaban has a higher rate of major bleeding in patients with luminal GI cancer compared with patients with non-GI cancer and compared with enoxaparin in patients with luminal GI cancer. Rivaroxaban shows no increased risk of major bleeding in patients with GI cancer or luminal GI cancer compared with patients with non-GI cancer.

Trial Registration

ClinicalTrials.gov identifier: NCT03504007.

Section snippets

Patient Recruitment

Consecutive patients with acute Ca-VTE treated at the Thrombophilia Clinic, Gonda Vascular Center, Mayo Clinic Rochester between March 1, 2013, and April 20, 2020, were included in this study. The Thrombophilia Clinic’s highly organized system of prompt patient referral, guideline-supported patient care, and organized follow-up have been previously described.¹³^,¹⁴ Templated information about available Food and Drug Administration approved anticoagulants for Ca-VTE is provided by use of a

Patients

During the study period, 3471 patients with acute VTE were enrolled in our Thrombophilia Clinic standardized clinical practice, of whom 1392 (40.1%) had Ca-VTE. Within the group of Ca-VTE, there were 499 patients (35.8%) with GI cancer including 272 with luminal GI cancer (lower GI, 208; upper GI, 64), 176 with pancreatic cancer, and 51 with hepatobiliary cancer. Among 893 patients (64.2%) with non-GI cancer, the most common cancer type was genitourinary (n=291 [32.6%]), followed by hematologic

Discussion

The main finding of this study is that patients with GI cancer, as a whole group composed of luminal GI, pancreatic, and hepatobiliary cancers, do not have a higher rate of major bleeding and CRNMB compared with patients with non-GI cancers. This observation applies to therapy with apixaban, rivaroxaban, or enoxaparin. Treatment with apixaban was associated with a numerically higher rate of major bleeding, but the difference did not reach statistical significance (P=.1). However, in patients

Conclusion

In luminal GI cancer, apixaban used by experienced clinicians in a standardized system of therapeutic decision-making has a higher rate of major bleeding compared with enoxaparin and compared with patients with non-GI cancer treated with apixaban. Previous reports that patients with GI cancer treated with rivaroxaban have an increased risk of bleeding were not substantiated by this study.

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Cited by (19)

Editorial commentary: A one-fits-all approach to cancer-associated thrombosis – Are we there yet?
2023, Trends in Cardiovascular Medicine
Effectiveness and Safety of Rivaroxaban and Low Molecular Weight Heparin in Cancer-Associated Venous Thromboembolism
2023, JACC: CardioOncology
Direct-acting oral anticoagulants (DOACs) are alternatives to low molecular weight heparin (LMWH) in most cancer-associated thrombosis (CAT) patients.
This study sought to compare the effectiveness and safety of rivaroxaban and LMWH for venous thromboembolism (VTE) treatment in patients with an active cancer type not associated with a high risk of DOAC bleeding.
An analysis of electronic health records from January 2012 to December 2020 was performed. Patients were adults, had active cancer, experienced an index CAT event, and were treated with rivaroxaban or LMWH. Patients with cancers with an established high risk of bleeding on DOACs were excluded. Baseline covariates were balanced using propensity score–overlap weighting. HRs with 95% CIs were calculated.
We identified 3,708 CAT patients treated with rivaroxaban (29.5%) or LMWH (70.5%). The median (25th-75th percentiles) time on anticoagulation was 180 (69-365) and 96 (40-336) days for rivaroxaban and LMWH patients. At 3 months, rivaroxaban was associated with a 31% reduced risk of recurrent VTE vs LMWH (4.2% vs 6.1%; HR: 0.69; 95% CI: 0.51-0.92). No difference in bleeding-related hospitalizations or all-cause mortality was observed (HR: 0.79; 95% CI: 0.55-1.13 and HR: 1.07; 95% CI: 0.85-1.35, respectively). Rivaroxaban reduced the recurrent VTE risk (HR: 0.74; 95% CI: 0.57-0.97) but not bleeding-related hospitalizations or all-cause mortality at 6 months. At 12 months, no difference was observed between cohorts for any of the previously mentioned outcomes.
Among active cancer patients experiencing VTE and not at high risk of bleeding on DOACs, rivaroxaban was associated with a reduced risk of recurrent VTE versus LMWHs at 3 and 6 months but not 12 months. (Observational Study in Cancer-Associated Thrombosis for Rivaroxaban-United States Cohort [OSCAR-US]; NCT04979780)
Influence of primary cancer site on clinical outcomes of anticoagulation for associated venous thromboembolism
2023, Thrombosis Research
Citation Excerpt :
Current guidelines recommend anticoagulation therapy for a minimum of 6 months or until the patient is declared cancer-free, irrespective of cancer location [7,8]. The recent finding of a higher risk of bleeding in patients with gastrointestinal and genitourinary cancers treated with direct oral anticoagulants [9–11] highlights the impact of specific cancer locations on the outcome of anticoagulation. Previous studies have also revealed different rates of VTE recurrence and bleeding complications in anticoagulated patients with cancers at different sites, but these data are limited and inconsistent [5,12,13].
The outcome of anticoagulation for cancer-associated venous thromboembolism (Ca-VTE) differs according to cancer location, but data are limited and inconsistent.
Patients with acute venous thromboembolism (VTE) enrolled between 03/01/2013 and 04/30/2021 were followed prospectively to assess VTE recurrence, major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and death.
There were 1702 (45.3 %) patients with Ca-VTE including: gastrointestinal (n = 340), pancreatic (n = 223), hematologic (n = 188), genitourinary (n = 163), lung (n = 139), ovarian (n = 109), breast (n = 97), renal (n = 75), prostate (n = 73), hepatobiliary (n = 70), brain (n = 57), and other cancers (n = 168); 2057 VTE patients had no cancer (NoCa-VTE). Hepatobiliary cancer had the highest VTE recurrence (all rates 100 person-years) of all cancers and higher compared to NoCa-VTE (13.69, p = 0.01), while the MB rate, although numerically higher (15.91), was not different (p = 0.09). Another 3 cancers had higher VTE recurrence but similar MB rates compared to NoCa-VTE: genitourinary [(9.59, p = 0.01) and (7.03, p = 1.0)], pancreatic [(9.74, p < 0.001) and (5.47, p = 1.00)], and hematologic [(5.29, p = 0.05) and (3.59, p = 1.0)]. Renal cancer had the highest rate of MB among all cancers and was higher than that of NoCa-VTE (16.49; p < 0.001), with no difference in VTE recurrence (1.62; p = 1.0). VTE recurrence and MB rates were not significantly different between NoCa-VTE and gastrointestinal, lung, breast, prostate, and brain cancers. CRNMB rates were similar and mortality higher in Ca-VTE patients, except for prostate and breast cancer, compared to NoCa-VTE.
Significant differences in clinical outcomes indicate that anticoagulation strategies may need to be tailored to the primary cancer location.
A review of latest clinical practice guidelines for the management of cancer-associated thrombosis
2022, Best Practice and Research: Clinical Haematology
Citation Excerpt :
Of note, the CARAVAGGIO [48] trial included a smaller proportion of patients with upper GI cancer (4% in the apixaban arm and 5.4% in the dalteparin arm) as compared to HOKUSAI-VTE CANCER (6.3% in the edoxaban arm and 4.0% in the dalteparin arm) [45] and SELECT-D (7% in the rivaroxaban arm and 12% in the dalteparin arm) [46]. In contrast, a recent observational study reported that major bleeding tended to occur more frequently in patients with luminal GI cancers receiving apixaban (7.1 per 100 person years at 6 months) compared to those receiving enoxaparin (2.8 per 100 person-years at 6 months, p = 0.16) [64]. The risk of clinically relevant nonmajor bleeding was significantly higher with DOACs in the HOKUSAI-VTE CANCER [45] (HR 1.38, 95% CI 0.98–1.94), SELECT-D [46] (HR 3.76, 95% CI 1.63–8.69), and CARAVAGGIO [48] (HR 1.42, 95% CI 0.88–2.30) trials, due to bleeding mainly occurring in the GI or genitourinary (GU) tracts with DOACs.
The management of cancer-associated thrombosis (CAT) poses unique challenges to healthcare professionals. While low‐molecular weight heparins (LMWHs) have long been the gold standard for both the primary and secondary prevention of CAT, results from large randomized controlled trials assessing the benefit of direct oral anticoagulants (DOACs) in both settings have resulted in some paradigm shifts. Herein, we review and compare recommendations from the latest authoritative clinical practice guidelines (CPGs) for the management of CAT and summarize the most recent evidence on available treatment options. A rigorous methodology was used to select high quality CPGs and compare the recommendations across CPGs. Only CPGs focusing on the management of CAT developed by a multidisciplinary international working group and issued or endorsed by national or international scientific societies, or government organizations were eligible for inclusion. The quality of selected CPGs was assessed using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) tool. Four CPGs met the inclusion criteria, including the International Initiative on Thrombosis and Cancer (ITAC), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), and the National Comprehensive Cancer Network (NCCN).
Cancer-associated non-bacterial thrombotic endocarditis—Clinical series from a single institution
2024, American Journal of Hematology
The effectiveness of atorvastatin for the prevention of deep vein thrombosis in cancer patients undergoing chemotherapy: A randomised controlled trial: open label
2023, Thrombosis Journal

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: Grant Support: This work was partially supported by the discretionary fund from Gonda Vascular Center, Mayo Clinic Rochester.

: Potential Competing Interests: Robert D. McBane has a Research Grant from Bristol Myers Squibb. All remaining authors have declared no conflicts of interest.

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Original articleBleeding in Patients With Gastrointestinal Cancer Compared With Nongastrointestinal Cancer Treated With Apixaban, Rivaroxaban, or Enoxaparin for Acute Venous Thromboembolism

Abstract

Objective

Patients and Methods

Results

Conclusion

Trial Registration

Section snippets

Patient Recruitment

Patients

Discussion

Conclusion

J Thromb Haemost

J Thromb Haemost

Mayo Clin Proc

Chest

J Thromb Haemost

Oral apixaban for the treatment of acute venous thromboembolism

N Engl J Med

Apixaban for extended treatment of venous thromboembolism

N Engl J Med

Oral rivaroxaban for symptomatic venous thromboembolism

N Engl J Med

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism

N Engl J Med

Rivaroxaban or aspirin for extended treatment of venous thromboembolism

N Engl J Med

Original article
Bleeding in Patients With Gastrointestinal Cancer Compared With Nongastrointestinal Cancer Treated With Apixaban, Rivaroxaban, or Enoxaparin for Acute Venous Thromboembolism