What do we know about bleeding risk in patients with cancer?

Venous thromboembolism (VTE) is a well-recognized complication in patients with cancer, with an increase in risk by a factor of 4–9 compared with individuals without malignancies. [1] It is a relevant cause of morbidity and mortality in these patients. Therefore, individual risk assessment and primary prevention are desired. However, primary prophylactic anticoagulation is not generally recommended due to a concomitantly increased risk of bleeding in patients with cancer, especially in patients under anticoagulation. [2]

Incidence of bleeding

Notably, much less research has been conducted on bleeding risk in patients with cancer. As bleeding risk also seems to increase in cancer patients [3], it is highly relevant to consider an individual risk-benefit evaluation, including both thrombotic and bleeding risks.

Data on the baseline risk of bleeding, risk factors, and predictors are scarce.

Cancer patients undergoing anticoagulation have a higher bleeding risk than the general population. [3] It is known that Vitamin K antagonists (VKA) are associated with an increased recurrence but also augmented bleeding rate compared with low molecular weight heparin (LMWH). [4] Direct oral anticoagulant agents (DOAC) have also recently been implemented in the routine clinical treatment of cancer-associated thrombosis. [5] Both LMWH and DOAC can be used for primary thromboprophylaxis. [5]

Recently published randomized controlled trials comparing DOAC and LMWH reported rates of major bleeding of 4.3% and 3.3%, respectively. [6] In previous trials comparing LMWH with VKA, major bleeding rates were reported to be between 2.6–5.6% and 2.4–3.,6% and CRNMB rates at around 11% and 15%, respectively. [4]

The clinical trials comparing DOAC and LMWH showed that especially patients with gastrointestinal and genitourinary tumors had a higher bleeding rate, which led to the suggestion that LMWH treatment was preferred. [5, 6]

Bleeding risk in patients with cancer receiving anticoagulation therapy was mainly assessed in clinical studies, where the patient population is selected, and patients with significant comorbidities are not included. A recent multicenter observational study presented at the ICTHIC 2022 meeting reported that only about 45% of the included patients with cancer would have been eligible to participate in such a randomized controlled trial. [7] Therefore, real-life data regarding the bleeding risk in patients with cancer receiving these therapies would be of even greater value. The RIETE registry reported that of 3,805 patients with active cancer treated with an anticoagulation agent, 156 (4.1%) had major bleeding, of which 46 (29%) died. [8] Additionally, only one meta-analysis assessed the case-fatality rate of bleeding in patients with cancer after a VTE event and reported it to be significant at 8.9% per 100 patient-years of follow-up. [9]

Risk Factors for Bleeding and Assessment scores

Few risk factors or predictors for bleeding could be identified for cancer patients receiving anticoagulant treatment. These include age over 75, recent bleeding or anemia, liver dysfunction, kidney failure, severe thrombocytopenia, metastatic/advanced cancer, and intracranial lesions. [8, 10] Data also suggest that the risk of recurrent VTE and bleeding differs across different tumor types; it was reported that patients with prostate cancer had a higher bleeding risk vs. recurrent VTE risk than patients with lung (higher recurrent VTE risk) and breast and colorectal cancer (balanced risk). [11]

Another major concern is that patients with primary brain tumors and/or brain metastasis are at risk for intracranial bleeding. However, in patients undergoing therapeutic anticoagulation, those with brain metastasis showed no increased risk, unlike those with primary brain tumors. [12]

Earlier this year, de Winter et al. assessed whether existing bleeding risk scores could help identify patients with cancer at the highest bleeding risk. The authors have applied the -VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED scores to the patient population included in the HOKUSAI VTE Cancer study, which is an RCT comparing LMWH and DOAC for the treatment of cancer-associated VTE. However, the predictive performance of these scores was only poor to moderate. The authors further proposed a new score (“CAT-BLEED”) including age over 75 years, creatinine clearance, regionally advanced or metastatic cancer, genitourinary cancer, recent use of anticancer therapies associated with gastrointestinal toxicity, and gastrointestinal cancer as predictors, which, however, also performed modestly and needs to be externally validated. [13]

Conclusion

To conclude, data on the baseline risk of bleeding in this patient with cancer without anticoagulation are scarce. The risk of bleeding during anticoagulant therapy for cancer-associated VTE is still relatively high, and known bleeding risk assessment scores perform poorly. (13) This highlights the need for a clinical risk assessment tool to better assess bleeding risk in patients with cancer.

References

1. Mulder FI, Horváth-Puhó E, van Es N, van Laarhoven HWM, Pedersen L, Moik F, et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood. 2021;137(14):1959-69.
2. Trujillo-Santos J, Nieto JA, Ruíz-Gamietea A, López-Jiménez L, García-Bragado F, Quintavalla R, et al. Bleeding complications associated with anticoagulant therapy in patients with cancer. Thromb Res. 2010;125 Suppl 2:S58-61.
3. Yamashita Y, Morimoto T, Amano H, Takase T, Hiramori S, Kim K, et al. Anticoagulation Therapy for Venous Thromboembolism in the Real World- From the COMMAND VTE Registry. Circ J. 2018;82(5):1262-70.
4. Sobieraj DM, Baker WL, Smith E, Sasiela K, Trexler SE, Kim O, et al. Anticoagulation for the Treatment of Cancer-Associated Thrombosis: A Systematic Review and Network Meta-Analysis of Randomized Trials. Clin Appl Thromb Hemost. 2018;24(9_suppl):182s-7s.
5. Lyman GH, Carrier M, Ay C, Di Nisio M, Hicks LK, Khorana AA, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5(4):927-74.
6. Moik F, Posch F, Zielinski C, Pabinger I, Ay C. Direct oral anticoagulants compared to low-molecular-weight heparin for the treatment of cancer-associated thrombosis: Updated systematic review and meta-analysis of randomized controlled trials. Res Pract Thromb Haemost. 2020;4(4):550-61.
7. Petit B, Saudet S, Poenou G, Zarrat E, Machuron T, Accassat S, et al. PO-41 Cancer-associated thrombosis: how many patients seen in clinical practice would be eligible to a randomized controlled trial? 11th ICTHIC; Bergamo2022.
8. Trujillo-Santos J, Nieto JA, Tiberio G, Piccioli A, Di Micco P, Prandoni P, et al. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost. 2008;100(3):435-9.
9. Abdulla A, Davis WM, Ratnaweera N, Szefer E, Ballantyne Scott B, Lee AYY. A Meta-Analysis of Case Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding in Patients with Cancer. Thromb Haemost. 2020;120(4):702-13.
10. Kamphuisen PW, Lee AYY, Meyer G, Bauersachs R, Janas MS, Jarner MF, et al. Clinically relevant bleeding in cancer patients treated for venous thromboembolism from the CATCH study. J Thromb Haemost. 2018;16(6):1069-77.
11. Mahe I, Chidiac J, Bertoletti L, Font C, Trujillo-Santos J, Peris M, et al. The Clinical Course of Venous Thromboembolism May Differ According to Cancer Site. Am J Med. 2017;130(3):337-47.
12. Zwicker JI, Karp Leaf R, Carrier M. A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic anticoagulation. J Thromb Haemost. 2016;14(9):1736-40.
13. de Winter MA, Dorresteijn JAN, Ageno W, Ay C, Beyer-Westendorf J, Coppens M, et al. Estimating Bleeding Risk in Patients with Cancer-Associated Thrombosis: Evaluation of Existing Risk Scores and Development of a New Risk Score. Thromb Haemost. 2021.