Systemic Thrombolysis, Catheter-Directed Thrombolysis, and Anticoagulation for Intermediate-risk Pulmonary Embolism: A Simulation Modeling Analysis.

Abstract

Decision making around the use of thrombolysis for patients with intermediate-risk (submassive) pulmonary embolism (PE) remains challenging. Studies indicate favorable clinical outcomes with systemic thrombolytics (intravenous tissue plasminogen activator [IV tPA]), but the risk of major bleeding and hemorrhagic stroke is a deterrent. Catheter-directed thrombolysis (CDT) may be a preferable strategy, as it has been shown to have a lower risk of bleeding than systemic thrombolysis. However, a three-arm randomized control study comparing IV tPA, CDT, and anticoagulation alone, with long-term follow up, would be costly and is unlikely to be performed. The aim of this study was to use decision modeling to quantitatively estimate the differences between the three strategies. We created an individual-level state-transition model to simulate long-term outcomes of a hypothetical patient cohort treated with IV tPA, CDT, or anticoagulation alone. Our model incorporated clinical randomized controlled trial and longitudinal study data to inform patient characteristics and outcomes specific to each study arm. The base case was a 65-year-old patient. Additionally, we utilized preliminary data published by the Pulmonary Embolism Response Team at the Massachusetts General Hospital. Variance in model inputs was addressed with deterministic and probabilistic sensitivity analyses. Our primary endpoint was quality-adjusted life-years (QALYs). Secondary endpoints included total cost and incremental cost-effectiveness ratios (ICERs). Catheter-directed thrombolysis (mean, 95% confidence interval [CI]= 7.388 [7.381-7.396] QALYs) resulted in the most long-term utility for eligible patients compared to anticoagulation alone (7.352 [7.345-7.360] QALYs) or IV tPA (7.343 [7.336-7.351] QALYs). Patients receiving CDT had an elevated risk of hemorrhagic stroke in comparison to anticoagulation alone; however, patients treated with anticoagulation alone were more likely to experience recurrent PE associated adverse outcomes. Results were stable with sensitivity analyses varying age and sex. Our probabilistic sensitivity analysis assessing joint variance predicts CDT to be the most effective strategy, when measured by mean QALYs, in 98.4% of runs, while systemic thrombolysis was favored over anticoagulation alone 34.4% of the time. The ICER of CDT compared to anticoagulation was $317,042 per QALY gained. In our model, for those eligible, CDT results in the largest number of QALYs for patients with intermediate-risk PE, although it is relatively expensive and the absolute difference in QALYs between anticoagulation alone and CDT is small. Future studies that provide data on longitudinal quality-of-life outcomes of patients treated for PE and characteristics of CDT would be beneficial to augment model inputs, inform assumptions, and validate results.