primary prophylaxis with direct oral anticoagulants (DOACs) for transwomen taking estrogen is not cost-effective Free

Introduction: Gender affirming hormonal therapy (GAHT), particularly estrogen-based regimens, is a vital part of gender-affirming care for transwomen (TW). Estrogen is known to increase venous thromboembolism (VTE) risk, particularly oral estradiol. While exogenous estrogen exposure in the general population is typically time-limited (e.g. premenopausal women taking estrogen-progestin contraception), TW often undergo lifelong GAHT, potentially sustaining elevated VTE risk. Current guidelines recommend anticoagulation in the setting of VTE, but do not address primary prophylaxis for high-risk individuals on long-term GAHT. We hypothesized that the reduction in VTE risk with low-dose direct oral anticoagulant (DOAC) prophylaxis could offset the harms of bleeding and the expense of developing a thrombotic event or complication, while avoiding potential interruptions in GAHT. We sought to test this hypothesis by determining the cost-effectiveness of low-dose DOAC prophylaxis in adults older than 18 years of age starting GAHT.

Methods:In this independent analysis free of industry influence, we built a Markov cohort model to evaluate the cost-effectiveness of low-dose DOAC prophylaxis versus no prophylaxis for TW aged 18 or older without a prior VTE. Our analysis was conducted from the US societal perspective over a lifetime time-horizon. TW without a personal history of VTE were assumed to start DOAC prophylaxis (i.e. apixaban 2.5mg BID or rivaroxaban 10mg daily) with oral GAHT (i.e. 2mg daily of oral estradiol). Transition probabilities were informed from the largest ambi-directional cohort in the Kaiser Permanente health plans of TW individuals matched with non-TW general population with an average follow-up of 3.6 years (maximum 14 years), funded by the Patient-Centered Outcomes Research Institute. The age- and biological sex-specific baseline bleeding risk was derived from a large prospective cohort study conducted in a general population without major risk factors. Bleeding risk associated with low-dose and full-dose DOAC was derived from the multicenter randomized RENOVE and AMPLIFY-EXT trials. The relative risk reduction of VTE incidence with DOAC prophylaxis was conservatively assumed to be 0.5 based on expert opinion. Effectiveness was measured in quality-adjusted life-years (QALYs) and was informed from published literature for the following disease- and treatment-specific complications: 1) major bleeding excluding intracranial hemorrhage (ICH), 2) intracranial hemorrhage, 3) deep venous thrombosis (DVT), 4) pulmonary embolism (PE), 5) post-thrombotic syndrome (PTS), and 6) chronic thromboembolic pulmonary hypertension (CTEPH). Age-, biological sex-, and disease-specific background mortality were employed. Costs for were sourced from the largest single health insurer in the United States, the Centers for Medicare & Medicaid Services, alongside VTE-specific comorbidity attributable costs on the baseline of age-specific annual healthcare expenses informed from the United States Medical Expenditure Panel Survey. For societal costs, we considered productivity losses due to premature mortality. The primary outcome was the incremental cost-effectiveness ratio (ICER) in USD/QALY across all accepted willingness-to-pay (WTP) thresholds in the US. The secondary outcomes were threshold analyses for maximum cost-effective DOAC price. We concluded with probabilistic sensitivity analyses that captured uncertainty in all parameters simultaneously over 10,000 Monte Carlo iterations.

Results: In the base-case, DOAC prophylaxis versus standard of care (SOC) accrued 22.97 and 22.82 QALYs across the lifespan at costs of $497,000 and $329,000, respectively. The ICER for DOAC prophylaxis was $1,099,000/QALY (95% credible interval $687,000-1,830,000/QALY). In deterministic sensitivity analyses, the model result was most sensitive to the baseline risk of VTE, VTE risk reduction with prophylaxis, and DOAC cost. No parameter variation changed which strategy is cost-effective. In probabilistic analyses, DOAC prophylaxis was not favored over SOC in 100% of 10,000 Monte Carlo iterations across all accepted WTP thresholds. Threshold analysis indicated that DOAC prophylaxis would become cost-effective at a price reduction of 86%.

Conclusions:At known TW-specific VTE rates and current DOAC pricing, DOAC prophylaxis is not a cost-effective strategy for adult TW patients receiving GAHT.