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

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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.