Ensuring protection for patients with cancer-associated thrombosis

This is Gordon. Gordon is 44 years old and works as a journalist.

One year ago, just after Gordon and his wife had bought their first home, Gordon was diagnosed with lung cancer. Three months later, while he was still coming to terms with both the diagnosis and the demands of cancer treatment, Gordon developed a painful and swollen right leg. Compression ultrasound scans confirmed that Gordon had suffered a deep vein thrombosis (DVT).

For patients such as Gordon, a cancer diagnosis isn’t just associated with the burden of the malignant disease itself but also with that of cancer-associated thrombosis (CAT). Patient safety is a key consideration for physicians treating patients such as Gordon and must be balanced carefully against efficacy when making treatment choices.

What can we learn from clinical trial data in order to guide appropriate treatment choice?

Cancer-associated thrombosis is associated with a high burden of mortality and bleeding

The European Society for Medical Oncology (ESMO) has noted that many oncologists underestimate the prevalence of CAT and the impact that it has on patients such as Gordon.1 This is despite the fact that, alongside infection, thromboembolism represents the second highest cause of cancer outpatient mortality after progression of the cancer itself.2 The scale of this problem was emphasized by Professor Alok Khorana at the International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC) 2021: ‘the annual death rate for venous thromboembolism (VTE) is 47 times higher in the cancer population compared with the general population’.2 The risk of VTE recurrence is also more than 3 times greater in patients with cancer compared with those without cancer (Figure 1).4

Figure 1. The risk of recurrent VTE in patients with cancer receiving anticoagulation therapy.4
CI, confidence interval; HR, hazard ratio; VTE, venous thromboembolism

Additionally, patients such as Gordon are at an increased risk of experiencing fatal bleeding events compared with patients with VTE without cancer.5 The risk of bleeding can also vary depending upon the cancer site 6; therefore, there are many factors impacting upon patient safety beyond the prescribed treatment.

Efficacy and safety of rivaroxaban in cancer-associated thrombosis: The CALLISTO programme

A wealth of data exists that supports the use of rivaroxaban in a patient with CAT, such as Gordon, from both clinical trials and real-world studies. This includes CALLISTO, which was an international clinical research programme that investigated rivaroxaban for the treatment of CAT. CALLISTO recruited more than 3000 patients in total.7

As can be seen in Figure 2, the studies included in CALLISTO covered a wide range of clinical interest areas in CAT, including effectiveness, safety and patient satisfaction.7

Figure 2. The CALLISTO study programme of rivaroxaban in CAT 7
CAT, cancer-associated thrombosis; LMWH, low-molecular weight heparin; QoL, quality of life; VTE, venous thromboembolism

With regards to safety, results from the SELECT-D study demonstrated low rates of major bleeding with both rivaroxaban and dalteparin, and a similar low rate of fatal bleeding in both arms (Figure 3).8

Figure 3. Safety results from the SELECT-D trial8
GI, gastrointestinal

As Dr Jan Beyer-Westendorf (Director of Thrombosis Research, Dresden University) notes in the Thrombosis Adviser Podcast, if the primary cancer is resected, he would ‘offer the patient a NOAC as a first choice’, because parenteral agents are only preferable in patients who are at a high risk of bleeding, and patients tend to prefer the convenience of an oral agent.

Rivaroxaban for vulnerable patient populations: The EINSTEIN programme

Rivaroxaban has also been extensively studied in patients with VTE in the EINSTEIN clinical trial programme (Figure 4).

Figure 4. The EINSTEIN clinical trial programme of rivaroxaban in VTE9-12
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism

The EINSTEIN programme includes the EINSTEIN JUNIOR programme, which studied the use of body-weight adjusted rivaroxaban in paediatric patients with VTE.13 In a phase III open-label study included in the EINSTEIN JUNIOR programme, treatment with rivaroxaban resulted in low rates of recurrent VTE and clinically relevant bleeding (Figure 5).12 Findings are similar to those obtained in adult patients.12 Notably, in approximately 90% of these paediatric patients, the VTE was the result of an underlying condition, such as cancer, trauma or surgery, major organ disease, thrombophilia or infection, which is different from the distribution of risk factors in adults. Many children also presented with more than one of these VTE risk factors.12 Rivaroxaban is the only Factor Xa inhibitor that is approved for use in paediatric patients with VTE.

Figure 5. Primary efficacy and safety results of the EINSTEIN JUNIOR phase III study 12
CRNM, clinically relevant non-major; VKA, vitamin K antagonist; VTE, venous thromboembolism

The size of the EINSTEIN programme, and in particular EINSTEIN DVT and EINSTEIN PE, has allowed for pooled analyses to take place. In the EINSTEIN DVT/PE pooled analysis, rivaroxaban demonstrated similar efficacy to standard therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups such as fragile patients (based on age, renal function or low body weight), those with prior VTE, those with renal impairment, those with high or low body weight and those with cancer.13

Safety results for rivaroxaban present it as a compelling treatment option in CAT

The risk of bleeding is an important consideration when treating a patient such as Gordon with an anticoagulant. Thankfully, there is a wealth of data from clinical trial programmes indicating that rivaroxaban has a favourable safety profile in patients with CAT, providing that they do not have specific, patient-related factors predisposing them towards a high risk of bleeding.

References

Mandalà M, Falanga A, Roila F. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011;22 Suppl 6:vi85–92. Return to content
Khorana AA, Francis CW, Culakova E et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632–634. Return to content
Lyman GH, Eckert L, Wang Y et al. Venous thromboembolism risk in patients with cancer receiving chemotherapy: A real-world analysis. Oncologist 2013;18:1321–1329. Return to content
Prandoni P, Lensing AWA, Piccioli A et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484–3488. Return to content
Monreal M, Falga C, Valdes M et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: Findings from the RIETE registry. J Thromb Haemost 2006;4:1950–1956. Return to content
Angelini DE, Radivoyevitch T, McCrae KR, Khorana AA. Bleeding incidence and risk factors among cancer patients treated with anticoagulation. Am J Hematol 2019;94:780–785. Return to content
Bauersachs R, Khorana AA, Lee AYY, Soff G. Cancer-associated venous thromboembolism: Treatment and prevention with rivaroxaban. Res Pract Thromb Haemost 2020;4:532–549. Return to content
Young AM, Marshall A, Thirlwall J et al. Comparison of an oral Factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol 2018;36:2017–2023. Return to content
The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510. Return to content
The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–1297. Return to content
Weitz JI, Lensing AWA, Prins M et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017;376:1211–1222. Return to content
Male C, Lensing AWA, Palumbo JS et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: A randomised, controlled, phase 3 trial. Lancet Haematol 2020;7:e18–e27. Return to content
Cohen AT, Bauersachs R. Rivaroxaban and the EINSTEIN clinical trial programme. Blood Coagul Fibrinolysis 2019;30:85–95. Return to content

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