Effectiveness and Safety of Rivaroxaban in Treatment of Venous Thromboembolism in Cancer Patients

Introduction

Patients with active cancer have a high risk for venous thromboembolism (VTE). The current treatment of choice for cancer-associated thrombosis is low molecular weight heparin (LMWH). Evidence for the efficacy and safety of the target-specific oral anticoagulants in the prevention and treatment of cancer-associated thrombosis is limited. In the EINSTEIN trials, comparing rivaroxaban to LMWH plus a vitamin K antagonist, only a small number of patients with active cancer received treatment with rivaroxaban (6.8% [n=118] in EINSTEIN-DVT¹ and 4.7% [n=114] in EINSTEIN-PE²). The use of rivaroxaban over LMWH for cancer-associated thrombosis is not recommended by the current guidelines.³However, due to the parenteral route of administration and high cost burden of LMWH, some cancer patients at our institution have received rivaroxaban for cancer-associated thrombosis.

Method

An observational chart review was performed to determine the effectiveness and safety of rivaroxaban for the treatment of VTE in cancer patients by observing recurrent VTE and bleeding events. For the effectiveness endpoint, patients who received rivaroxaban for less than one month were excluded from the study. For the safety analysis, patients who received at least one dose of rivaroxaban were included in the study.

 Result

A total of 92 cancer patients with VTE who received rivaroxaban at Huntsman Cancer Institute were selected for the study. Median age was 60 years old and 54% (n=50) were male. Average estimated creatinine clearance at the initiation of rivaroxaban was 96.2 mL/min (range 31.8-241 mL/min, Cockcroft-Gault). Thirty-eight patients (41%) were treated for DVT (deep venous thromboses), 32 patients (35%) had PE (pulmonary embolism), and 19 patients (21%) had both DVT and PE.

A total of 20 patients (21.7%) had a bleeding event while on therapy (see table). Ten patients (10.8%) experienced a major bleed and the median time to major bleeding was 4.4 months (IQR 2.4-11.6 months). One patient had a fatal intracranial bleed. Four patients (4.3%) had critical bleeding and 5 patients (5.4%) had a clinically relevant bleeding with ≥ 2g/dL drop in hemoglobin level and/or required ≥2 units of red blood cell transfusion. Pharmacodynamic interactions may have contributed to 3 major bleeds, including one patient on aspirin, another on ibuprofen, and the third patient on both aspirin and clopidogrel at the time of bleeding. Seven patients were taking rivaroxaban 20 mg daily at the time of the major bleed. The median platelet count at the time of bleeding was 170k/µL (IQR 108-333k/µL). One patient had a platelet count of 17 k/µL and was admitted with sepsis at the time of bleed. Ten patients (10.8%) experienced minor symptomatic bleeds and the median time to bleeding was 2.5 months (IQR 0.73-4.8 months).

Only 4 patients (4.3%) experienced recurrent VTE while on rivaroxaban. Two patients had recurrent DVT. Two patients developed recurrent PE and both were admitted to the hospital for parenteral anticoagulation. The median time to recurrent VTE was 5.7 months (IQR 2.5-11 months). The median platelet count at the time of recurrence was 120 k/µL (range 26-216k/µL). One patient had a known thrombophilia, Factor V Leiden mutation.

Conclusion

These data suggest that rivaroxaban may be a safe and acceptable alternative to LMWH for the treatment and secondary prevention of cancer-associated thrombosis.

	Huntsman Cancer Institute (n=92)	EINSTEIN-DVT1 (Cancer sub-group, n=118)	EINSTEIN-PE2 (Cancer sub-group, n=114)	CLOT trial4 (n=336)
Major bleeding	10.8% (n=10)	14.4% (n=17)	12.3% (n=14)	14% (n=47)
Clinically relevant non-major bleeding	10.8% (n=10)
Recurrent DVT	2.2% (n=2)	3.4% (n=4)	n/a	4.2% (n=14)
Recurrent PE	2.2% (n=2)	n/a	1.8% (n=2)	3.9% (n=13)

References:

1. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med.2010;363(26):2499–2510.

2. Büller HR, Prins MH, Lensin AWA, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N. Engl. J. Med.2012;366(14):1287-1297.

3. NCCN Clinical Practice Guidelines in Oncology. Cancer-Associated Venous Thromboembolic Disease, v2.2014. www.nccn.org.

4. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N. Engl. J. Med. 2003;349(2):146–153.