Exercise therapy for peripheral artery disease in 2022: Progress and a prediction

Supervised exercise therapy (SET), typically consisting of walking for exercise on a treadmill in the presence of an exercise physiologist or nurse, is first-line therapy for walking disability in people with symptomatic lower-extremity peripheral artery disease (PAD). Over the past approximately 30 years, more than 30 randomized clinical trials including more than 1500 participants with PAD have consistently demonstrated benefits of SET on improved treadmill walking distance and/or 6-minute walk distance in PAD. ¹ However, many critically important questions regarding supervised exercise remain unanswered, ranging from the absence of a clear understanding of the biologic pathways that mediate the effects of ischemia-inducing walking exercise on improved walking performance to the lack of sufficient information regarding methods to ensure that all patients with PAD have access to this highly effective therapy. In honor of Dr William R Hiatt (1950–2020), a former president of the Society for Vascular Medicine, Editor of Vascular Medicine, and a physician scientist whose groundbreaking work in PAD included early investigations of SET for PAD, this issue of the Journal is dedicated to articles focused on exercise therapy. This editorial highlights some articles of this special issue and speculates about future scientific breakthroughs regarding exercise therapy for PAD.

In this issue of Vascular Medicine, two original research investigations describe preliminary results of novel exercise interventions for PAD.^2,3 Identifying novel forms of exercise is important for patients with PAD who prefer an alternative to walking exercise or who are unable to participate in walking exercise due to extreme ischemic leg symptoms or frailty. Lanzi and colleagues report a pilot study of descending stair walking as an alternative form of exercise for people with PAD. ² Whereas climbing stairs is associated with muscle shortening and contraction, descending stair walking lengthens leg muscles while simultaneously inducing positive adaptations to improve muscle strength and function. Among nine people with PAD, compared to a single bout of stair climbing, a single bout of descending stair walking was associated with less leg ischemia, measured by calf muscle tissue oxygen saturation (StO₂), and less claudication pain. Salisbury and colleagues studied the effects of 12 weeks of total body recumbent stepping, compared to traditional treadmill exercise training, in a pilot randomized clinical trial of 19 people with PAD. ³ Total recumbent stepping exercise is a low-impact aerobic exercise, consisting of pushing pedals (i.e. ‘stepping’) while in a reclined position. At 12-week follow-up, there was no significant difference in 6-minute walk improvement between total body recumbent stepping and supervised treadmill exercise (+47.1 vs +40.5 m, p = 0.68). ³ A nonexercise control group was not included. Further definitive studies with larger sample sizes are needed to assess whether descending stair walking and recumbent stepping exercise are effective forms of exercise that significantly improve walking performance in people with PAD.

For most adults, sitting occupies most waking time. In this issue of the Journal, two studies in people without PAD demonstrated associations of prolonged uninterrupted sedentary time and fewer breaks during sedentary time with more adverse flow-mediated dilation (FMD) and microvascular or macrovascular function.^4–6 A systematic review reported that better aerobic fitness and regular exercise training were associated with more favorable measures of low-flow-mediated constriction, a measure of endothelial vasodilator function and of the decline in conduit artery diameter that occurs during the distal ischemic period of the FMD test. ⁶ Whether these vascular associations contribute to the biologic pathway for the association of greater sedentary time with higher rates of cardiovascular events requires further study.

Although the Center for Medicare and Medicaid Services (CMS) insurance has covered SET for people with symptomatic PAD since 2017, growing evidence documents low participation rates. ⁷ Reasons for low participation remain unclear. Altin and colleagues described the real-world experience of male veteran patients referred to SET prior to lower-extremity revascularization. ⁸ Of 76 patients with PAD referred for exercise, 37 (48.7%) completed all 36 sessions of prescribed SET and improved their exercise capacity (from a mean of 3.4 to 5.5 metabolic equivalents), whereas 14 (18%) pursued self-directed exercise, and 25 (32.9%) declined any exercise therapy. ⁸ The most common reasons for declining exercise therapy were inadequate transportation, inconvenience, and the copayment costs. ⁸ Further studies should confirm these preliminary findings in a large and diverse group of patients with PAD and identify interventions to overcome these challenges to SET participation.

Bronas and Regensteiner reviewed the history of scientific investigation of exercise training for people with PAD over an approximately 75-year period, beginning with the 1940s and 1950s. ⁹ They discuss that the earliest recommended therapies for PAD-related disability were bed rest and physical activity avoidance. Bronas and Regensteiner trace the history of exercise therapy for PAD through the late 20th and early 21st centuries, when initial small clinical trials, often with fewer than 40 PAD participants, first documented the functional benefits of supervised exercise but eschewed home-based exercise as ineffective. They review results of more recent randomized trials documenting that home-based exercise can meaningfully improve walking performance in PAD when programs incorporate behavioral change methods.^1,9 Progress in exercise therapy for PAD over the past 75 years may be best illustrated by contrasting the recommendation of ‘bed rest’ for treating disabling claudication in the 1950s to the recent findings from a multicentered randomized clinical trial of 305 participants, which demonstrated that inducing ischemic leg symptoms during walking exercise was necessary to achieve objective improvement in walking performance. ¹⁰ Specifically, the LITE multicentered randomized clinical trial of 305 participants with PAD demonstrated that, compared to a nonexercise control group, home-based exercise that induced ischemic leg symptoms significantly and meaningfully improved the 6-minute walk distance and maximal treadmill walking time, whereas home-based walking exercise conducted without ischemic leg symptoms had no effect on these outcomes. ¹⁰ Thus, recommendations for medical therapies to improve disability in PAD have completely reversed course, from a bed rest prescription in the 1950s to randomized trial evidence 70 years later demonstrating that inducing ischemic leg symptoms during exercise is necessary to improve objectively measured walking performance in a home-based exercise intervention for PAD.^9,10

Bronas and Regensteiner’s review emphasizes that future studies of exercise therapy for PAD should include adequate representation of women and minority populations. ⁹ Importantly, some recent randomized trials of exercise for PAD have successfully included large proportions of participants who were women or underrepresented minorities.^{10 –12} For example, the LITE randomized trial of 305 participants with PAD included 146 (47.9%) women and 181 (59.3%) participants who were Black. ¹⁰ Although clinical trials have shown no differences in the benefits of exercise by sex or race,^10,12 recent evidence suggests that uptake of supervised exercise in the US is better in people who are White. ⁷ Overcoming barriers to SET and ensuring adequate access to SET for patients with PAD who represent ethnic minorities is an important area for future research and health policy.

What major new discoveries may be identified in the next 15–20 years? This writer predicts that home-based walking exercise will supersede supervised treadmill exercise as the most effective and most widely recommended and implemented noninvasive therapy for walking limitations due to PAD. To date, home-based exercise interventions have been highly heterogeneous. Over time, randomized trials have identified components of highly potent home-based exercise interventions, including behavioral change principles and frequent communication, such as by telephone, with a coach. As scientific study further refines characteristics of the most potent home-based exercise interventions, home-based exercise has the potential to overcome supervised exercise as the most effective medical therapy for walking disability in PAD. In support of this prediction, randomized clinical trials have already documented that, compared to an attention control group, home-based exercise interventions can improve the 6-minute walk distance by a mean of 42–53 meters, whereas supervised treadmill exercise improves the 6-minute walk distance by only 15–30 meters. ¹ However, no definitive multicentered randomized trials have directly compared supervised treadmill exercise to a highly effective home-based exercise intervention for the primary outcome of an improved 6-minute walk distance. Home-based exercise is safe, as described by a systematic review by Waddell and colleagues in this issue of the Journal. ¹³ Home-based walking exercise is also more convenient, does not require regular transportation, and because coaching contact is remote and typically less frequent than SET, is likely to be less costly than SET. Based on progress over the past 70 years, there is reason to remain highly optimistic that exercise therapy for PAD in the coming years will be even more effective and personalized, with greater uptake by all patients with PAD. Our friend and colleague, William R Hiatt, MD, would be pleased.