Sequential Multiple Assessment Randomized Trial of Exercise for PAD: SMART Exercise for PAD

PAD运动序贯多项评估随机试验：PAD智能运动 有监督的运动疗法(SET)，包括每周在中心进行3次跑步机运动 在医护人员在场的情况下，是腿部周围残障人士的一线治疗 动脉疾病(PAD)。然而，去SET中心旅行是一种负担。截至2018年，仅有1.3%的 有医疗保险和症状性PAD的患者已登记入SET。居家锻炼更方便 而且比设定的负担要轻。然而，指南建议对PAD进行家庭锻炼。 临床试验已经确定了基于家庭的运动干预的三个特征，这三个特征是高度 对患有PAD的人有效：1)纳入行为改变方法；2)定期与教练联系， 3)运动强度在运动中引起腿部缺血症状。最近我们在《美国医学会杂志》上报道了 包括这些显著和有意义的特征的家庭锻炼干预 与注意控制组相比，改善了在PAD中步行6分钟的时间。然而，没有一项随机试验 直接将SET与对PAD患者进行高效的家庭运动干预进行比较。此外, 45%的PAD患者没有对运动做出有意义的反应，运动的定义是未能改善6分钟的步行 距离增加了20米(这是一个有临床意义的改善)。这一现象发生在两个被监控者身上 和居家锻炼。我们的第二阶段试验表明，富含硝酸盐的甜菜根汁会增加血浆 亚硝酸盐、肢体灌注和运动强度显著降低了对运动的无反应率， 与PAD中的安慰剂相比。因此，我们将使用序贯多项评估随机试验 (SMART)解决两个主要障碍，以从港口及机场管理局的演习中获益：第一，建议 有监督的演习。第二，缺乏对PAD运动无反应的治疗。 在PAD的智能锻炼中，250名PAD参与者将被随机分配到家庭锻炼或 设定为12周(第一阶段)。在12周的随访中，参与者将被归类为“响应者”(&>20米 改善6分钟步行)或“无效”(&lt；6分钟步行改善20米)。在13周内- 24(第二阶段)，所有参与者将继续他们最初分配的锻炼条件(设定或在家)， 无反应者将被重新随机分为甜菜根汁增强组或安慰剂组，同时 继续他们原来的练习。我们将检验两个主要假设。首先，我们是否以家庭为基础 运动干预提高了6分钟步行的效果，超过了12周的随访(主要目标1)。第二, 甜菜根汁生物强化运动能否改善PAD患者的6分钟步行能力 12周后对运动无反应(主要目标2)。在次要和探索性目标中，我们将确定 为所有PAD患者最大限度地增加步行距离的最佳锻炼策略，从而 改善数百万因PAD致残的老年人的行动能力。

Sequential Multiple Assessment Randomized Trial of Exercise for PAD: SMART Exercise for PAD Supervised exercise therapy (SET), consisting of treadmill exercise conducted 3 times/week at a center in the presence of healthcare personnel, is first line therapy for people disabled by lower extremity peripheral artery disease (PAD). However, travelling to a center for SET is burdensome. As of 2018, only 1.3% of patients with Medicare and symptomatic PAD had enrolled in SET. Home-based exercise is more accessible and less burdensome than SET. Yet, guidelines recommend SET over home-based exercise for PAD. Clinical trials have identified three characteristics of home-based exercise interventions that are highly effective for people with PAD: 1) incorporation of behavioral change methods; 2) regular contact with a coach, and 3) an exercise intensity that elicits ischemic leg symptoms during exercise. Recently we reported in JAMA that a home-based exercise intervention that included these characteristics significantly and meaningfully improved 6-minute walk in PAD, compared to an attention control group. However, no randomized trials have directly compared SET to a highly effective home-based exercise intervention for people with PAD. In addition, 45% of people with PAD do not meaningfully respond to exercise, defined as failure to improve six-minute walk distance by > 20 meters (a clinically meaningful improvement). This phenomenon occurs for both supervised and home-based exercise. Our Phase II trial showed that nitrate-rich beetroot juice, which increases plasma nitrite, limb perfusion, and exercise intensity, significantly reduced rates of non-response to exercise, compared to placebo, in PAD. Therefore, we will use a Sequential Multiple Assessment Randomized Trial (SMART) to address two major barriers to benefit from exercise for PAD: First, the recommendation for supervised exercise. Second, the lack of treatment for non-response to exercise in PAD. In SMART Exercise for PAD, 250 participants with PAD will be randomized to home-based exercise or SET for 12 weeks (Stage I). At 12-week follow-up, participants will be classified into ‘responders’ (> 20 meter improvement in 6-minute walk) or ‘non-responders’ (< 20 meter improvement in 6-minute walk). In weeks 13- 24 (Stage II), all participants will continue their originally assigned exercise condition (SET or home-based), and non-responders will be re-randomized to either augmentation with beetroot juice or placebo while continuing their original exercise. We will test two primary hypotheses. First, whether our home-based exercise intervention improves 6-minute walk more than SET at 12-week follow-up (Primary Aim #1). Second, whether biologic augmentation of exercise with beetroot juice improves 6-minute walk in PAD patients unresponsive to exercise after 12 weeks (Primary Aim #2). In Secondary and Exploratory Aims, we will identify the optimal exercise strategy to maximize gains in walking distances for all patients with PAD, thereby improving mobility in the millions of older people disabled by PAD.