Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is commonly reported among patients with cancer and its incidence is increasing.1 The reason for the heightened risk of VTE is the hypercoagulable state caused by the cancer, a combination of the release of procoagulant factors, such as tissue factor, from malignant tissue, and also inflammation-driven activation of endothelial cells, platelets, and leukocytes.2 The occurrence of VTE is the second highest cause of death among cancer patients and is responsible for a two- to six-fold increase in the risk of mortality.3,4 Cancer patients with VTE also have a worse prognosis than those without VTE.5
Current guidelines recommend prophylaxis for hospitalised patients with cancer, with either low-molecular-weight heparin or low-dose aspirin.3,6 However, low-molecular-weight heparin is generally indicated in the postoperative setting, while most patients with cancer are now treated as outpatients in an effort to shorten hospital stays. The benefits of anticoagulation in these ambulatory patients has not been well defined. Vitamin K antagonists (VKAs), of which the most well-known is warfarin, have been used for many years in patients with cancer; however, patients with cancer have a higher risk of recurrent VTE despite sufficient anticoagulation with VKAs.7
The use of direct oral anticoagulants (DOACs), which directly inhibit factor Xa or thrombin, has become widespread in recent years, thanks to a number of factors. They can be taken orally, they do not require frequent dose adjustment, they do not require monitoring and they undergo minimal interactions with food and drugs.8 Five DOACs are currently approved for the prevention of VTE: dabigatran (Pradaxa®, Boehringer Ingelheim, Ingelheim am Rhein, Germany), rivaroxaban (Xarelto®, Janssen, Beerse, Belgium), apixaban (Equilis®, Bristol Myers-Squibb, New York, NY, US), edoxaban (Lixiana®, Daiichi Sankyo, Tokyo, Japan) and betrixanan (Bevyxxa®, Portola, South San Francisco, CA, US). To date, DOACs have been shown to be effective in patients with acute VTE in several clinical trials, which included hundreds of patients with either active cancer, a history of cancer, or a new occurrence of cancer during the course of the study.9–12 However, only subgroup analyses of larger studies (rivaroxaban and edoxaban)13,14 and the SELECT-D pilot trial (rivaroxaban)15 have investigated the efficacy and safety of DOACs in patients with cancer with acute VTE. Only one small phase II study has investigated the use of a DOAC (apixaban) for the prevention of VTE in patients with cancer.16 All DOACs were well tolerated in these studies and there was a low risk of major bleeding.
The CASSINI study was the first phase III study to assess DOACs for the prevention of VTEs in patients with cancer who are receiving systemic chemotherapy. Results were presented at the American Society of Hematology (ASH) Annual Meeting, which was held in San Diego, CA, US on 1–4 December 2018.17 The study enrolled 1,080 adult ambulatory patients with cancer who were planning to initiate a new systemic regimen within a week of initiating study treatment and were at increased risk for VTE (defined as a score ≥2 on the Khorana scale, which assigns risk for VTE based on cancer type, haemoglobin level, and pre-chemotherapy platelet and leukocyte counts). Patients were screened for DVT prior to study entry. Forty-nine patients had DVT at baseline and another 190 failed the screening for other reasons. Following screening, 841 participants were randomised 1:1 to receive rivaroxaban 10 mg once daily or placebo, for up to 180 days. Patients underwent ultrasound screening every 8 weeks to check for the presence of lower-extremity DVT. The study used an intention-to-treat population, which means that all participants were followed during the 180-day observation period, regardless of whether they took or prematurely discontinued the study treatment. The primary efficacy endpoint was a composite of DVT, PE, and VTE-related death during the 6-month observation period. The secondary endpoint was thrombotic risk during the on-treatment period. This was included to account for patients with cancer who changed therapeutic regimens or stopped anticoagulation.
The primary efficacy endpoint did not reach statistical significance across the 6-month period: the endpoint occurred in 25 of 420 rivaroxaban-treated patients (5.95%) and 37 of 421 placebo-treated patients (8.79%; hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.40–1.09; p=0.10). However, 38.7% of the events occurred in patients who had discontinued the study drug within the 6-month period. When the analysis was restricted to the on-treatment period, an average of 4.5 months, rivaroxaban was found to give a 60% reduction in the risk of DVT; the endpoint occurred in 2.62% of patients receiving rivaroxaban compared with 6.41% of those receiving placebo (HR=0.4; 95% CI 0.20–0.80; p=0.007).17
Major bleeding is a concern among people talking anticoagulant treatment, but the study met its primary safety endpoint of major bleeding and clinically relevant non-major bleeding. Major bleeding occurred in 1.98% of rivaroxaban-treated patients and in 0.99% of patients in the placebo group (HR: 1.96; 95% CI: 0.59–6.49; p=0.265). Clinically relevant non-major bleeding occurred in 2.72% and 1.98% of rivaroxaban and placebo groups, respectively (HR: 1.34; 95% CI: 0.54–3.32; p=0.53). Adverse events were comparable between groups.17
Although the study did not meet the primary efficacy endpoint, these findings are useful for informing future regulations regarding prevention of thrombotic events in ambulatory cancer patients. Of particular interest, the Khorana risk score cut-off of ≥2 identified cancer patients at high risk of thrombotic events both at baseline (4.5%) and during the study (8.8% with an additional 1.7% arterial events in the placebo group). This suggests that baseline screening should be considered in all patients starting treatment with systemic therapy.
These data have provided evidence that rivaroxaban is effective for the prevention of VTE in ambulatory patients with cancer. In a press release, lead investigator Alok A Khorana, MD, from Cleveland Clinic in Ohio commented: ‘In 2018, most of our cancer treatment takes place in the outpatient setting, so most of the clots occur in the outpatient setting. From a public health perspective, that is important because most of our [previous] efforts at preventing blood clots have focused on the inpatient setting.’18
References
1. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:484–90.
2. Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: Burden, mechanisms, and management. Thromb Haemost. 2017;117:219–30.
3. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189–204.
4. 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;5:632–4.
5. Chew HK, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458–64.
6. Mandala 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.
7. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484–8.
8. Adam SS, McDuffie JR, Ortel TL, et al. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med. 2012;157:796–807.
9. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.
10. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–52.
11. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764–72.
12. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375:534–44.
13. Prins MH, Lensing AW, Brighton TA, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol. 2014;1:e37–46.
14. Raskob GE, van Es N, Segers A, et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016;3:e379–87.
15. 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;36:2017–23.
16. Levine MN, Gu C, Liebman HA, et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10:807–14.
17. Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban thromboprophylaxis in high-risk ambulatory cancer patients receiving systemic therapy: results of a randomized clinical trial (CASSINI). Presented at: 61st American Society of Hematology Annual Meeting, San Diego, CA, US, 1–4 December 2018. Abstr LBA-1.
18. American Society of Hematology. Rivaroxaban Reduces Thrombotic Risk in Patients Undergoing Cancer Treatment. Available at: www.ashclinicalnews.org/on-location/ash-annual-meeting/rivaroxaban-reduces-thrombotic-risk-patients-undergoing-cancer-treatment/ (accessed 16 January 2019).
