Ensor Joie, Riley Richard D, Jowett Sue, Monahan Mark, Snell Kym Ie, Bayliss Susan, Moore David, Fitzmaurice David
Public Health, Epidemiology and Biostatistics, School of Health and Population Sciences, University of Birmingham, Birmingham, UK.
Research Institute of Primary Care and Health Sciences, Keele University, Staffordshire, UK.
Health Technol Assess. 2016 Feb;20(12):i-xxxiii, 1-190. doi: 10.3310/hta20120.
Unprovoked first venous thromboembolism (VTE) is defined as VTE in the absence of a temporary provoking factor such as surgery, immobility and other temporary factors. Recurrent VTE in unprovoked patients is highly prevalent, but easily preventable with oral anticoagulant (OAC) therapy. The unprovoked population is highly heterogeneous in terms of risk of recurrent VTE.
The first aim of the project is to review existing prognostic models which stratify individuals by their recurrence risk, therefore potentially allowing tailored treatment strategies. The second aim is to enhance the existing research in this field, by developing and externally validating a new prognostic model for individual risk prediction, using a pooled database containing individual patient data (IPD) from several studies. The final aim is to assess the economic cost-effectiveness of the proposed prognostic model if it is used as a decision rule for resuming OAC therapy, compared with current standard treatment strategies.
Standard systematic review methodology was used to identify relevant prognostic model development, validation and cost-effectiveness studies. Bibliographic databases (including MEDLINE, EMBASE and The Cochrane Library) were searched using terms relating to the clinical area and prognosis. Reviewing was undertaken by two reviewers independently using pre-defined criteria. Included full-text articles were data extracted and quality assessed. Critical appraisal of included full texts was undertaken and comparisons made of model performance. A prognostic model was developed using IPD from the pooled database of seven trials. A novel internal-external cross-validation (IECV) approach was used to develop and validate a prognostic model, with external validation undertaken in each of the trials iteratively. Given good performance in the IECV approach, a final model was developed using all trials data. A Markov patient-level simulation was used to consider the economic cost-effectiveness of using a decision rule (based on the prognostic model) to decide on resumption of OAC therapy (or not).
Three full-text articles were identified by the systematic review. Critical appraisal identified methodological and applicability issues; in particular, all three existing models did not have external validation. To address this, new prognostic models were sought with external validation. Two potential models were considered: one for use at cessation of therapy (pre D-dimer), and one for use after cessation of therapy (post D-dimer). Model performance measured in the external validation trials showed strong calibration performance for both models. The post D-dimer model performed substantially better in terms of discrimination (c = 0.69), better separating high- and low-risk patients. The economic evaluation identified that a decision rule based on the final post D-dimer model may be cost-effective for patients with predicted risk of recurrence of over 8% annually; this suggests continued therapy for patients with predicted risks ≥ 8% and cessation of therapy otherwise.
The post D-dimer model performed strongly and could be useful to predict individuals' risk of recurrence at any time up to 2-3 years, thereby aiding patient counselling and treatment decisions. A decision rule using this model may be cost-effective for informing clinical judgement and patient opinion in treatment decisions. Further research may investigate new predictors to enhance model performance and aim to further externally validate to confirm performance in new, non-trial populations. Finally, it is essential that further research is conducted to develop a model predicting bleeding risk on therapy, to manage the balance between the risks of recurrence and bleeding.
This study is registered as PROSPERO CRD42013003494.
The National Institute for Health Research Health Technology Assessment programme.
特发性首次静脉血栓栓塞症（VTE）被定义为在没有诸如手术、制动及其他临时因素等诱发因素情况下发生的VTE。特发性患者的复发性VTE非常普遍，但口服抗凝剂（OAC）治疗很容易预防。在复发性VTE风险方面，特发性人群具有高度异质性。
该项目的首要目标是回顾现有的预后模型，这些模型根据复发风险对个体进行分层，从而有可能实现个性化治疗策略。第二个目标是通过使用包含来自多项研究的个体患者数据（IPD）的汇总数据库，开发并外部验证一种用于个体风险预测的新预后模型，以加强该领域的现有研究。最终目标是评估如果将所提出的预后模型用作恢复OAC治疗的决策规则，与当前标准治疗策略相比的经济成本效益。
使用标准的系统评价方法来识别相关的预后模型开发、验证和成本效益研究。使用与临床领域和预后相关的术语检索文献数据库（包括MEDLINE、EMBASE和Cochrane图书馆）。由两名评审员独立使用预定义标准进行评审。对纳入的全文文章进行数据提取和质量评估。对纳入的全文进行批判性评价，并对模型性能进行比较。使用来自七项试验的汇总数据库中的IPD开发一种预后模型。采用一种新颖的内部 - 外部交叉验证（IECV）方法来开发和验证一种预后模型，并在每项试验中反复进行外部验证。鉴于IECV方法表现良好，使用所有试验数据开发最终模型。使用马尔可夫患者水平模拟来考虑使用决策规则（基于预后模型）决定是否恢复OAC治疗的经济成本效益。
系统评价识别出三篇全文文章。批判性评价发现了方法学和适用性问题；特别是，所有三个现有模型均未进行外部验证。为解决此问题，寻求具有外部验证的新预后模型。考虑了两个潜在模型：一个用于治疗停止时（D - 二聚体前），一个用于治疗停止后（D - 二聚体后）。在外部验证试验中测量的模型性能显示这两个模型均具有良好的校准性能。D - 二聚体后模型在区分度方面表现明显更好（c = 0.69），能更好地区分高风险和低风险患者。经济评估表明，基于最终的D - 二聚体后模型的决策规则对于每年复发预测风险超过8%的患者可能具有成本效益；这表明对于预测风险≥8%的患者继续治疗，否则停止治疗。
D - 二聚体后模型表现出色，可用于预测个体在长达2 - 3年的任何时间的复发风险，从而有助于患者咨询和治疗决策。使用该模型的决策规则在告知治疗决策中的临床判断和患者意见方面可能具有成本效益。进一步的研究可以调查新的预测因素以提高模型性能，并旨在进一步进行外部验证以确认在新的非试验人群中的性能。最后，必须进行进一步研究以开发一种预测治疗期间出血风险的模型，以平衡复发风险和出血风险。
本研究注册为PROSPERO CRD42013003494。
英国国家卫生研究院卫生技术评估计划。
