Recurrent Venous Thromboembolism (VTE), Major Bleeding (MB), and Associated Cost of Treatment with Low Molecular Weight Heparin (LMWH) or Direct Oral Anticoagulant (DOAC) in High Risk Patients with Gastrointestinal (GI) Malignancies: Retrospective Real-World Analysis at a Comprehensive Cancer Center
Authors: Recio Boiles Alejandro , McBride Ali , Babiker Hani M. , Alsaid Nimer , Abraham Ivo , Elquza Emad 
Published: October 2019

Abstract
Introduction:
Cancer patients who experienced a venous thromboembolism (VTE) are at high risk for poor clinical outcomes; hence VTE recurrence prevention is salient. Low molecular weight heparin (LMWH) has been the preferred treatment for cancer-related VTE; however, direct oral anticoagulants (DOACs) have been prescribed empirically in cancer due to patient convenience. Although the recent HOKUSAI and SELECT-D trials have confirmed the non-inferiority of DOACs to LMWH in the management of recurrent VTE in cancer patients, there remain a continued safety concern for major bleeds (MB). Recurrent VTE and MB complications during anticoagulation treatment of GI cancer (GICA) patients are increased as compared to other cancer types. The incremental health care costs associated with VTE recurrences and MB episodes are significant and steadily increasing. In this retrospective analysis, we aimed (1) to evaluate for differences in the VTE recurrence rate and MB events based on anticoagulation therapy (LMWH or DOAC) prescribed with a prior VTE and (2) to calculate the associated healthcare costs for six months of treatment.
Methods:
We reviewed the medical records of patients with biopsy-proven GICA and imaging documented VTE treated with DOAC or LMWH from November 2013 to February 2017. Patients were excluded if anticoagulation was given for another treatment indication or cancer diagnosis. Adverse events of recurrent VTE and MB criteria were defined per the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Costs of LMWH and DOAC t was sourced from Medicare Reimbursement 2018. Hospital admission and adjusted 6-month ambulatory cots were sourced from Economic Evaluations of Anticoagulation Outcomes in the U.S. by Amin et al 2015. Costs were inflation-adjusted to 2018 cost levels using the Medical Care component of the Consumer Price Index. The Chi-squared test was used for overall and the Fisher exact test for pairwise comparisons of the proportions of patients experiencing VTE and MB events.
Results:
Our analysis included 106 patients on enoxaparin (N=40), rivaroxaban (N=37) and apixaban (N=29). Recurrent VTE outcomes at 6 months were 3 (7.5%) for enoxaparin, 1 (2.7%) for rivaroxaban, and 2 (6.8%), for apixaban (all p=n.s.) (Table 1). Major bleeding events at 6 months were 2 (5%) for enoxaparin, 2 (6.8%) for apixaban, and a significantly higher 8 (21.6%) for rivaroxaban (overall p=0.048; v. LMWH pairwise p=0.042; all other p=n.s.). The estimated composite costs associated with the observed recurrent VTE event rates were $173,130 for enoxaparin, $57,710 for rivaroxaban, and $115,420 for apixaban. The estimated composite costs associated with the observed MB event rates were $117,146 for enoxaparin and apixaban, versus $468,558 for rivaroxaban. The estimated total 6-months healthcare costs for recurrent VTE, MB and prescriptions were $293,784 for enoxaparin, $529,336 for rivaroxaban, and $235,634 for apixaban.
Conclusion:
Our real-world retrospective analysis corroborates a non-inferiority of DOACs to LMWH in preventing recurrent VTE in GICA patients at 6 months but a higher incidence of MB in rivaroxaban v. LMWH treated patients. The higher MB rate for rivaroxaban mainly accounts for the higher overall costs of this DOAC v. LMWH and apixaban. In absolute total costs, apixaban prevails over LMWH and rivaroxaban, and LMWH prevails over rivaroxaban in cost-efficiency in this analysis of anticoagulation in selected high-risk GICA patients. Rivaroxaban significantly increases medical costs, mainly driven by the total number of major bleed adverse events in GICA patients, confirming previously published evidence. The subpopulation of GICA patients at high risk of VTE/MB warrants an additional prospective clinical trial for primary safety major bleed outcomes of DOACs with an accompanying cost-effectiveness analysis. This may eventually reduce the healthcare economic burden.

Disclosures
Abraham: Sandoz: Consultancy.