What evidence supports the use of oral factor Xa inhibitors for VTE prevention in patients with cancer?

Background                                        

Venous thromboembolism (VTE) is a leading cause of death in cancer patients.¹ The incidence of VTE is up to 6.5-fold higher in patients with cancer versus those without cancer and cancer accounts for about 18% of all VTE cases. Risk factors for VTE in cancer patients include general patient risk factors (active/advanced cancer, cancer type, and medical comorbidities), treatment-related risk factors (major surgery, central intravenous [IV] catheter use, certain chemotherapy regimens, and exogenous hormonal therapy), and other risk factors (smoking, obesity, and activity level).² The Khorana score is a predictive model that seeks to quantify the risk of chemotherapy-associated VTE, as summarized in the Table.^2,3

Table. Khorana risk score for chemotherapy-associated VTE.^2,3

Both the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) have authored guidelines on the prevention of cancer-related VTE.^2,4 The more recent of these was released by ASCO in August 2019.⁴ This organization states that ambulatory cancer patients with a high risk of VTE (defined as a Khorana risk score ≥2 before starting a new chemotherapy regimen) may receive apixaban, rivaroxaban, or a low molecular weight heparin (LMWH) for prophylaxis. The NCCN guideline recommends LMWH, unfractionated heparin, warfarin, or aspirin for VTE prophylaxis in the same population, with a high risk of VTE defined as a Khorana risk score of ≥3.² Both organizations endorse an individualized approach based on risk for both VTE and bleeding.^2,4

The updated ASCO guideline contains the first recommendation for the use of direct-acting oral anticoagulants (DOACs) for VTE prophylaxis in ambulatory patients with cancer.⁴ Prior studies suggested that DOACs may be effective and safe compared to traditional agents for secondary prevention of recurrent VTE, but until recently prospective studies in the setting of primary prevention were lacking.^5-7 This article summarizes 2 recent randomized trials that studied the efficacy and safety of rivaroxaban and apixaban versus placebo for VTE prophylaxis in high risk ambulatory patients with cancer.^8,9

Literature Summary

Rivaroxaban

In a phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial (CASSINI), 841 ambulatory cancer patients at high risk of VTE (Khorana score of ≥2) were randomized to rivaroxaban 10 mg (n=420) or placebo (n=421) orally once daily for 180 days.⁸ The primary efficacy endpoint was the composite of objectively confirmed symptomatic or asymptomatic proximal deep vein thrombosis (DVT) in a lower limb, symptomatic DVT in a lower limb or distal DVT in a lower limb, symptomatic or incidental pulmonary embolism, and death from VTE. The primary safety endpoint was the occurrence of major bleeding as defined by the International Society on Thrombosis and Hemostasis (ISTH) including bleeding leading to transfusion or to a decrease in the hemoglobin level of ≥2 g/dL.¹⁰ At baseline, 68.5% and 24.0% of patients had a Khorana score of 2 or 3, respectively, and the most prevalent cancer types were pancreatic (33%), gastric or gastroesophageal (20.9%), and lung (15.9%).⁸ During the observation period (180 days), the primary efficacy endpoint occurred in 6% of the rivaroxaban group and 8.8% of the placebo group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.40 to 1.09; p=0.10). During the intervention (on-treatment) period, the primary efficacy endpoint occurred in 2.6% of the rivaroxaban group and 6.4% of the placebo group (HR, 0.40; 95% CI, 0.20 to 0.80). The rate of major bleeding was 2.0% in the rivaroxaban group and 1.0% in the placebo group (HR, 1.96; 95% CI, 0.59 to 6.49). One fatal bleed occurred in the rivaroxaban group. The authors concluded that the benefit of rivaroxaban for VTE prophylaxis in high-risk ambulatory patients was limited to the intervention period.

Apixaban

In another phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial (AVERT), 574 ambulatory cancer patients with a newly diagnosed cancer or progression of known cancer and who were initiating a new course of chemotherapy and were at high risk of thromboembolism (Khorana score ≥2) were randomized to apixaban (n=291) 2.5 mg twice daily or placebo (n=283) twice daily for 180 days.⁹ The primary efficacy outcome was a composite of the first episode of objectively documented symptomatic or incidentally detected proximal deep vein thrombosis of the lower or upper limbs, any nonfatal symptomatic or incidental pulmonary embolism, or pulmonary embolism-related death within 180 days. The primary safety endpoint was the occurrence of major bleeding defined by the ISTH including bleeding that resulted in decrease in hemoglobin level of ≥2 g/dL, led to transfusion of ≥2 units of packed red blood cells, occurred in a critical site, or contributed to death.¹⁰ At baseline, 65.5% and 25.4% of patients had a Khorana score of 2 or 3, respectively, and the most prevalent cancer types were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%).⁹ The primary efficacy endpoint occurred in 4.2% of the apixaban group and 10.2% of the placebo group (HR, 0.41; 95% CI, 0.26 to 0.65; p<0.001). During the intervention (on-treatment) period, the primary efficacy endpoint occurred in 1.0% of the apixaban group and 7.3% of the placebo group (HR, 0.14; 95% CI, 0.05 to 0.42). Major bleeding occurred in 3.5% of the apixaban group and 1.8% of the placebo group (HR, 2.00; 95% CI, 1.01 to 3.95; p=0.046). The authors concluded that apixaban reduced the risk of VTE and increased major bleeding in high-risk patients with cancer who were initiating chemotherapy.

Limitations

In both the CASSINI and AVERT trials, Khorana scores were used to select patients at high risk for VTE.^8.9 The Khorana score cutoff used in these trials (≥2) was lower than the score for high risk that was established in the original validation study (≥3), which has led to inclusion of the lower score in the ASCO guideline and potential confusion among clinicians about the optimal score cutoff to use in clinical practice.^3,4,8,9 The AVERT study used a modified Khorana score with points assigned or brain tumor (2 points), myeloma (1 point), and kidney cancer (1 point), and the CASSINI study modified the Khorana score by allowing 1 point for kidney cancer.^8,9 These modifications may limit external validity. In general, the Khorana score has shortcomings such as not taking into account the chemotherapy regimen, which could have an effect on the risk of thrombosis. Additionally, the Khorana score does not perform well with some cancer types, including lung cancer (which was a common cancer type in both trials).^8,9,11

The CASSINI trial did not find a difference in the primary composite outcome between rivaroxaban and placebo during the 180-day observation period, likely because the sample size was too small for the absolute difference in rates between groups.⁸ Several common cancer types were underrepresented in these trials (including colorectal, breast, and prostate); therefore, the external validity of these trials might be limited in patients with these cancer types.¹² Although risk of bleeding were low, long-term (beyond 6 months) safety and efficacy of these therapies are unknown.^8,9 Furthermore, the mortality benefit of apixaban and rivaroxaban in this patient population remains unclear since neither trial was powered to detect a difference in mortality.

Discussion

Despite their limitations, the CASSINI and AVERT trials have influenced clinical practice guidelines.^4,8,9 Both apixaban and rivaroxaban are listed in the latest ASCO guideline as options for VTE prophylaxis in ambulatory patients with cancer and high VTE risk (which is defined in the guideline using the trial-specific Khorana score cutoff of ≥2).⁴ A statement from the ISTH also supports the use of apixaban or rivaroxaban for VTE prophylaxis in patients with cancer and a Khorana score ≥2.¹³ Consistent with these recommendations, a recent meta-analysis of 24 randomized controlled trials concluded that the risk of VTE in patients with cancer who received prophylaxis with factor Xa inhibitors was reduced compared to placebo (relative risk, 0.39; 95% CI, 0.24 to 0.63; p<0.001).¹⁴ However, LMWH continues to be a guideline-recommended prophylactic option and may be preferred by some clinicians due to more clinical experience with its use.^2,3,13

References

1. Ay C, Kamphuisen PW, Agnelli G. Antithrombotic therapy for prophylaxis and treatment of venous thromboembolism in patients with cancer: review of the literature on current practice and emerging options. ESMO Open. 2017;2(2):e000188.
2. National Comprehensive Cancer Network. Clinical Practice Guidelines for Cancer-Associated Venous Thromboembolic Disease. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Version 1.2019. Accessed August 21, 2019.
3. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907.
4. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update [published online ahead of print August 5, 2019]. J Clin Oncol. 2019;JCO1901461. doi: 10.1200/JCO.19.01461.
5. Yan YD, Zhang C, Shen L, et al. Net clinical benefit of non-vitamin K antagonist oral anticoagulants for venous thromboembolism prophylaxis in patients with cancer: a systematic review and trade-off analysis from 9 randomized controlled trials. Front Pharmacol. 2018;9:575.
6. Alzghari SK, Seago SE, Garza JE, et al. Retrospective comparison of low molecular weight heparin vs. warfarin vs. oral Xa inhibitors for the prevention of recurrent venous thromboembolism in oncology patients: The Re-CLOT study. J Oncol Pharm Pract. 2018;24(7):494-500.
7. Xing J, Yin X, Chen D. Rivaroxaban versus enoxaparin for the prevention of recurrent venous thromboembolism in patients with cancer: A meta-analysis. Medicine (Baltimore). 2018;97(31):e11384.
8. Khorana AA, Soff GA, Kakkar AK, et al; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380(8):720-728.
9. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380(8):711-719.
10. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694.
11. Kuderer NM, Poniewierski MS, Culakova E, et al. Predictors of venous thromboembolism and early mortality in lung cancer: results from a global prospective study (CANTARISK). Oncologist. 2017;23(2):247-255.
12. Agnelli G. Direct oral anticoagulants for thromboprophylaxis in ambulatory patients with cancer. N Engl J Med. 2019;380(8):781-783.
13. Wang TF, Zwicker JI, Ay C, et al. The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: guidance from the SSC of the ISTH [published online ahead of print July 15, 2019]. J Thromb Haemost. doi: 10.1111/jth.14564.
14. Barbarawi M, Zayed Y, Kheiri B, et al. The role of anticoagulation in venous thromboembolism primary prophylaxis in patients with malignancy: A systematic review and meta-analysis of randomized controlled trials. Thromb Res. 2019;181:36-45.

Prepared by:
Parzhak Karimi
PharmD Candidate, Class of 2019
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

September 2019

The information presented is current as of August 8, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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