INTERmittent pneumatic ComprEssion for Disability rEversal in PAD: the INTERCEDE Trial

项目总结 我们和其他人的工作已经确定，患有下肢外周动脉疾病的人 与没有PAD的人相比，PAD有更大的功能损害和更快的功能衰退率。 然而，很少有治疗方法改善PAD患者的功能或防止其功能下降。 间歇性气动加压(IPC)是一种非侵入性干预，由一个空气泵组成 在充气袖口内，包裹在脚、脚踝和小腿上，每天戴两个小时。每个 20秒后，袖口迅速膨胀，紧随其后的是快速通缩。在通货紧缩期间，动脉血液回流到 动静脉压力梯度产生切应力并刺激一氧化氮的产生。初步 有证据表明，IPC改善了PAD患者的下肢血流和步行耐力 而且在干预完成后，这种好处可以持续长达12个月。然而，证据受到以下因素的限制 样本量小，随访率高，无盲法，无假对照。临床实践 指南没有提到IPC是PAD的一种治疗选择。需要一项明确的随机试验。 步行锻炼是PAD的一线治疗方法。然而，许多PAD患者不能或不愿意 锻炼身体。因此，在患有PAD的人中，我们将确定IPC是否增加了运动的好处 步行耐力，以及与假对照组相比，IPC是否单独提高了步行耐力。我们会 对230名PAD参与者进行随机试验(2 x 2析因设计)，随机分为四组： A组：IPC+运动；B组：IPC+“不运动”对照；C组：假手术+运动； D组：假手术对照组+“不运动”对照组。IPC和Sham干预措施将提供六个月的时间。在……里面 我们的主要具体目标是，我们将确定IPC结合锻炼是否能改善6分钟的步行 在6个月的随访中，与单独锻炼相比，单独进行IPC是否提高了6-6分钟的步行 随访1个月，与假手术对照比较。在次要目标中，我们将确定IPC的好处 坚持在12个月的随访中重新评估研究结果，在IPC干预后6个月 完成。我们还将通过测量来描述IPC影响步行能力的机制 MRI测量的小腿肌肉血流灌注、体力活动(用肌动图测量)和小腿肌肉的变化 血管生成、肌肉再生、线粒体生物生成、线粒体活性和 自噬。基于临床前证据，IPC增加了一氧化氮的丰度并促进了 远端骨骼肌的血管扩张，我们将确定IPC是否有改善 通过测量肱动脉血流介导的扩张的变化来衡量系统内皮功能。 如果运动和不运动的IPC干预改善了功能表现，并防止 PAD的功能下降，这种非侵入性和耐受性良好的干预将对 在越来越多的PAD患者中，防止行动不便并提高生活质量。

PROJECT SUMMARY Our work and that of others has established that people with lower extremity peripheral artery disease (PAD) have greater functional impairment and faster rates of functional decline than people without PAD. However, few therapies improve functioning or prevent functional decline in people with PAD. Intermittent pneumatic compression (IPC) is a non-invasive intervention, consisting of an air pump inside inflatable cuffs that are wrapped around the feet, ankles, and calves and worn for two hours daily. Every 20 second, the cuffs rapidly inflate, followed by rapid deflation. During deflation, arterial blood return into the arteriovenous pressure gradient generates shear stress and stimulates nitric oxide production. Preliminary evidence suggests that IPC improves lower extremity blood flow and walking endurance in people with PAD and that benefits persist for up to 12 months after intervention completion. However, evidence is limited by small sample sizes, high loss to follow-up, lack of blinding, and lack of sham controls. Clinical practice guidelines do not mention IPC as a therapeutic option in PAD. A definitive randomized trial is needed. Walking exercise is first-line therapy for PAD. However, many PAD patients are unable or unwilling to exercise. Therefore, in people with PAD, we will determine whether IPC augments the benefits of exercise on walking endurance and whether IPC alone improves walking endurance compared to sham control. We will conduct a randomized trial (2 x 2 factorial design) of 230 PAD participants randomized to one of four groups: Group A: IPC + exercise; Group B: IPC + “no exercise” control; Group C: sham control + exercise; and Group D: sham control + “no exercise” control. The IPC and sham interventions will be delivered for six months. In our primary specific aims, we will determine whether IPC combined with exercise improves the 6-minute walk at 6-month follow-up compared to exercise alone and whether IPC alone improves the 6-minute walk at 6- month follow-up, compared to sham control. In secondary aims, we will determine whether benefits of IPC persist by re-measuring study outcomes at twelve-month follow-up, six months after the IPC intervention is completed. We will also delineate mechanisms by which IPC affects walking performance, by measuring changes in MRI-measured calf muscle perfusion, physical activity (measured with ActiGraph), and calf muscle biopsy measures of angiogenesis, muscle regeneration, mitochondrial biogenesis, mitochondrial activity, and autophagy. Based on preclinical evidence that IPC increases nitric oxide abundance and promotes vasodilation in skeletal muscle distant from the lower extremities, we will determine whether IPC improves systemic endothelial function, by measuring changes in brachial artery flow-mediated dilation. If the IPC intervention with and without exercise improves functional performance and prevents functional decline in PAD, this non-invasive and well tolerated intervention will have a major impact on preventing mobility loss and improving quality of life in the large and growing number of people with PAD.