Kabrhel Christopher, Ali Ayman, Choi Jin G, Hur Chin
Center for Vascular Emergencies, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA.
Harvard Medical School, Boston, MA.
Acad Emerg Med. 2017 Oct;24(10):1235-1243. doi: 10.1111/acem.13242. Epub 2017 Sep 13.
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.
对于中度风险（次大面积）肺栓塞（PE）患者，围绕使用溶栓治疗的决策仍然具有挑战性。研究表明，全身溶栓治疗（静脉注射组织纤溶酶原激活剂[IV tPA]）可带来良好的临床结局，但严重出血和出血性中风的风险令人却步。导管定向溶栓（CDT）可能是一种更可取的策略，因为已证明其出血风险低于全身溶栓。然而，一项比较IV tPA、CDT和单纯抗凝治疗并进行长期随访的三臂随机对照研究成本高昂，不太可能开展。本研究的目的是使用决策模型来定量估计这三种策略之间的差异。
我们创建了一个个体水平的状态转换模型，以模拟接受IV tPA、CDT或单纯抗凝治疗的假设患者队列的长期结局。我们的模型纳入了临床随机对照试验和纵向研究数据，以了解每个研究组特定的患者特征和结局。基础病例是一名65岁的患者。此外，我们利用了麻省总医院肺栓塞反应团队发表的初步数据。通过确定性和概率敏感性分析解决模型输入的差异问题。我们的主要终点是质量调整生命年（QALY）。次要终点包括总成本和增量成本效益比（ICER）。
与单纯抗凝治疗（7.352[7.345 - 7.360]QALY）或IV tPA（7.343[7.336 - 7.351]QALY）相比，导管定向溶栓（平均，95%置信区间[CI]=7.388[7.381 - 7.396]QALY）为符合条件的患者带来了最长的长期效用。与单纯抗凝治疗相比，接受CDT的患者出血性中风风险升高；然而，单纯接受抗凝治疗的患者更有可能经历复发性PE相关的不良结局。随着年龄和性别的敏感性分析，结果保持稳定。我们评估联合方差的概率敏感性分析预测，以平均QALY衡量，在运行的98.4%中，CDT是最有效的策略，而全身溶栓在34.4%的时间里比单纯抗凝更受青睐。CDT与抗凝治疗相比的ICER为每获得一个QALY 317,042美元。
在我们的模型中，对于符合条件的患者，CDT为中度风险PE患者带来的QALY数量最多，尽管其成本相对较高，且单纯抗凝与CDT之间QALY的绝对差异较小。未来提供PE治疗患者纵向生活质量结局数据和CDT特征的研究将有助于增加模型输入、为假设提供信息并验证结果。
