Supplementary Material for: Early Decline in Six-Minute Walk Distance from the Time of Diagnosis Predicts Clinical Worsening in Pulmonary Arterial Hypertension

Background: The six-minute walk distance (6MWD) is commonly used to assess pulmonary arterial hypertension (PAH). However, the role of 6MWD in predicting outcomes in PAH is controversial. Clinical worsening is being increasingly considered as a clinically meaningful end point in PAH. Objectives: We aimed to investigate whether early longitudinal changes in 6MWD (Δ6MWD) in meters and percent predicted (%pred) from the time of diagnosis predict clinical worsening of PAH. Methods: One hundred patients with group I PAH were retrospectively assessed. 6MWD was calculated using American (%pred US) or Canadian (%pred CAN) reference equations. Δ6MWD at 6 months were recorded. Clinical worsening was defined as either: development of right heart failure, hospital admission for PAH, referral for lung transplantation or initiation of prostanoids after oral therapy failed. Optimal 6-month differences in 6MWD to detect worsening were defined with receiver operating characteristics (ROC) analysis. Results: Progressors, i.e. patients with clinical worsening, and nonprogressors showed significant differences in Δ6MWD. The most clinically significant declines in 6MWD at 6 months were ≥35 m, ≥8%pred US and ≥6%pred CAN. ROC and Cox proportional hazard analyses showed equivalent results for 6MWD %pred and meters. Six-month declines in 6MWD predicted worsening with a high specificity (94%) but a low sensitivity (33%). Conclusions: Early declines in 6MWD (within the first 6 months) predict future clinical worsening of PAH with high specificity. Δ6MWD may still be part of a comprehensive assessment of a patient's clinical status. However, given the poor sensitivity, a decline in 6MWD should be used with other clinical tools to make an appropriate assessment of the progression of PAH.

Background: 六分钟步行距离（6MWD）是评估肺动脉高压（PAH）的常用手段，但6MWD在预测PAH患者预后中的作用尚存争议。临床恶化正日益被视为PAH具有临床意义的终点事件。
Objectives: 本研究旨在探讨诊断早期以米为单位的6MWD纵向变化量（Δ6MWD）及预测百分比（%pred），是否可用于预测PAH患者的临床恶化情况。
Methods: 本研究回顾性评估了100例I型肺动脉高压患者。6MWD的预测百分比分别采用美国（%pred US）和加拿大（%pred CAN）的参考方程进行计算。记录患者6个月时的6MWD变化量（Δ6MWD）。临床恶化的定义为：出现右心衰竭、因PAH住院、接受肺移植转诊，或口服治疗失败后启动前列腺素类药物治疗。采用受试者工作特征（ROC）分析确定用于识别病情恶化的最佳6个月6MWD变化阈值。
Results: 病情进展组（即出现临床恶化的患者）与非进展组的Δ6MWD存在显著差异。6个月时6MWD最具临床意义的下降幅度分别为≥35米、≥8%pred US及≥6%pred CAN。ROC分析与Cox比例风险分析结果显示，以米为单位的6MWD和以预测百分比表示的6MWD具有同等的预测价值。6个月内6MWD下降预测病情恶化的特异性较高（94%），但敏感性较低（33%）。
Conclusions: 发病早期（前6个月内）的6MWD下降可高特异性地预测PAH患者未来的临床恶化情况。Δ6MWD仍可作为患者临床状况综合评估的组成部分之一。但鉴于其敏感性较差，6MWD下降需结合其他临床工具，才能对PAH的病情进展做出恰当评估。