Longitudinal Systemic Bevacizumab Therapy Produces Cost Savings and Improves Quality-Adjusted Life Expectancy in the Care of Patients with Hereditary Hemorrhagic Telangiectasia with Moderate-to-Severe Bleeding

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is the second-most-common hereditary bleeding disorder worldwide, afflicting 1 in 5000 or 1.4 million persons. Unlike peer disorders hemophilia and von Willebrand disease, there are no FDA or EMA-approved therapies. The current standard-of-care (SOC) consists of red blood cell (RBC) transfusion, IV iron supplementation, and local hemostatic procedures (i.e., nasal, gastrointestinal). However, bleeding pathophysiology is amenable to vascular endothelial growth factor inhibition, and IV bevacizumab has shown great promise as a disease-modifying therapeutic. The multisite, international InHIBIT-Bleed study employed a pre- versus post-bevacizumab design and was the largest clinical study of HHT (n=238). InHIBIT-Bleed demonstrated that longitudinal systemic bevacizumab significantly improved clinical symptoms, raised hemoglobin levels, and nearly abrogated IV iron infusion and RBC transfusion need for patients with HHT. Although bevacizumab is an expensive biologic agent with a financial barrier to access, we hypothesized that reduction in health resource utilization and improvement in transfusion dependence will improve quality-of-life for patients with HHT at costs commensurate with added clinical value. Accordingly, we conducted the first cost-effectiveness analysis of bevacizumab therapy in HHT.

Methods: For this independent analysis free of industry influence, we built a Markov simulation of adult patients with HHT to examine the cost-effectiveness of bevacizumab added to SOC versus SOC alone, over a lifetime time-horizon and across accepted willingness-to-pay (WTP) thresholds. Costs were assessed in 2023 US dollars. We employed study data for pre- and post-bevacizumab that included descriptive statistics for 1) hemostatic procedures, 2) hospitalizations, 3) emergency department visits, 4) RBC transfusions, and 5) iron infusions. Treatment-specific patient time and lost wages were also accounted for across IV infusions, emergency department visits, hospitalizations, and hemostatic procedures. Probabilities of RBC- and iron-related adverse events were sourced from hemovigilance reports, the 2015 National Blood Collection and Utilization Survey and 2008-2017 World Health Organization's VigiBase. Ferric carboxymaltose was used as the base-case iron supplement, and a scenario analysis examined ferumoxytol. Effectiveness was calculated in QALYs, and employed age-adjusted utilities derived using HHT-specific EQ-5D index values, with the 2019 Global Burden of Disease Study used to account for the degree of anemia improvement reported with bevacizumab. The primary outcome was the incremental cost-effectiveness ratio (ICER), or incremental net monetary benefit (iNMB) if intervention was found to be cost-saving. The secondary outcome was the aggregated patient time spent receiving HHT-specific care. We concluded by conducting deterministic and probabilistic sensitivity analyses, capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo iterations.

Results: In the base-case, bevacizumab versus SOC cost $959,000 and $1,533,000 while accruing 24.1 and 21.8 QALYs, respectively. The iNMB with bevacizumab was $916,000 [95% credible interval $454,000-$1,994,000] and $1,004,000 [95% CI $473,000-$2,237,000] from the US health system and societal perspectives, respectively, at a WTP of $150,000/QALY. Bevacizumab also saves patients 125 hours per year lived. Deterministic sensitivity analysis revealed that no parameter variance changes the model result. In probabilistic sensitivity analysis bevacizumab was favored in 100.0% of 10,000 Monte Carlo iterations: saving cost with increased QALYs in 99.6% and cost-effective in the remaining 0.4% of iterations (Figure 1). Similar cost-savings were found in the scenario analysis with ferumoxytol.

Conclusion: By reducing the need for hemostatic procedures, hospitalizations, emergency visits, RBC transfusions, and iron infusions, bevacizumab is, unusually, a cost-saving intervention that also improves the quality-adjusted life expectancy of patients with HHT. Bevacizumab also saves patient time spent on receiving HHT-specific care. Collecting long-term follow-up data to evaluate continued response to bevacizumab will help assess its value versus future advances in the care of patients with HHT.