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

项目摘要 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 (PAD)与没有PAD的人相比，有更大的功能障碍和更快的功能下降速度。 然而，很少有治疗方法可以改善PAD患者的功能或预防其功能下降。 间歇性气动加压（IPC）是一种非侵入性干预，由空气泵组成 在可充气的袖带内，缠绕在脚、脚踝和小腿上，每天佩戴两个小时。每 20秒后，袖带快速充气，然后快速放气。在放气过程中，动脉血回流到 动静脉压力梯度产生剪切应力并刺激一氧化氮的产生。初步 有证据表明，IPC可改善PAD患者的下肢血流量和步行耐力 并且在干预完成后，益处持续长达12个月。然而，证据有限， 样本量小、失访率高、缺乏盲法和缺乏假对照。临床实践 指南没有提到IPC作为PAD的治疗选择。需要进行明确的随机试验。 步行锻炼是PAD的一线治疗。然而，许多PAD患者不能或不愿意 锻炼的因此，在PAD患者中，我们将确定IPC是否增加了运动的益处， 步行耐力以及单独IPC是否与假手术对照相比改善步行耐力。我们将 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 +运动组; B组：IPC +“不运动”对照组; C组：假对照+运动组; D：假手术对照+“不运动”对照。IPC和假干预将持续6个月。在 我们的主要具体目标是，我们将确定IPC结合运动是否能改善6分钟步行 在6个月随访时与单独运动相比，以及单独IPC是否改善了6个月时的6分钟步行。 月随访，与假手术对照组相比。在次要目标中，我们将确定IPC的益处是否 在IPC干预后6个月，通过在12个月随访时重新测量研究结果， 完成我们还将通过测量IPC影响步行能力的机制， MRI测量的小腿肌肉灌注、体力活动（使用ActiGraph测量）和小腿肌肉的变化 血管生成、肌肉再生、线粒体生物发生、线粒体活性的活检测量，以及 自噬基于IPC增加一氧化氮丰度并促进 血管舒张的骨骼肌远离下肢，我们将确定是否IPC改善 通过测量肱动脉血流介导的舒张的变化，测定全身内皮功能。 如果有或没有运动的IPC干预改善了功能表现， PAD的功能下降，这种非侵入性和耐受性良好的干预将对 预防行动能力丧失，提高大量且不断增加的PAD患者的生活质量。

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.