What does the future hold for structured exercise training for people with PAD? Ideas from two Masters of the Society for Vascular Medicine

In 1997, we were introduced at the annual meeting of the Society for Vascular Medicine (and Biology). This meeting began a long and wonderful friendship, as well as a close professional relationship, based on our mutual interest in the role of exercise in treating peripheral artery disease (PAD). Given this mutual interest, we worked together on a number of excellent projects over the years including the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program ¹ beginning in 1998, The Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) multicenter NIH trial ² beginning in 2008, and most recently, a high profile scientific statement from the American Heart Association focused on optimal exercise programs for patients with PAD ³ published in 2019, among others. Sadly, the scientific statement was the final paper on which we worked together with William R Hiatt, MD, whose groundbreaking work gave rise to the growth of the field of exercise training for PAD and whose untimely loss in 2020 inspired these thoughts.

We both benefited extensively from being mentored by Dr Hiatt, given his tremendous leadership and innovative thought in the field of exercise therapy for PAD. In this piece, we focus on some of the remaining significant knowledge gaps in the field of PAD and exercise, with the hope that this work will go forward, inspired by the pioneering work of Dr Hiatt and others.

In 1990, Dr Hiatt and colleagues published one of the first rigorously designed randomized clinical trials evaluating the efficacy of supervised exercise therapy (SET) for patients with symptomatic PAD. ⁴ The exercise intervention consisted of intermittent treadmill walking at an intensity that would elicit moderately severe ischemic symptoms within 10 minutes, followed by rest, until symptoms subsided over a period of 12 weeks, three times per week. These exercise–rest cycles were repeated during each 60-minute session. Results demonstrated significant improvement in several outcomes including pain-free and peak treadmill walking times, peak oxygen consumption, and change in skeletal muscle function. The structure of this intervention served as a model for many studies that followed, and since that time a wealth of evidence supporting SET as well as other forms of structured exercise therapy for patients with PAD has emerged. However, despite all the evidence we now have, there remain many gaps in our understanding of how, for whom, and under what conditions exercise improves walking performance in patients with PAD. Of the many remaining questions to be asked and answered, we discuss four key gaps:

Gap #1: Elucidation of the physiological and biological mechanisms of improvement

As noted above, Dr Hiatt’s studies and those of others demonstrated changes in skeletal muscle function and change in central cardiovascular conditioning resulting from structured treadmill exercise training.^5,6 This indicates that there could be multiple potential mechanisms of improvement. The prevailing thinking is that it is necessary to exercise at an intensity high enough to induce moderately severe ischemic symptoms, and that this will stimulate improvement in skeletal muscle metabolism. However, the research in this area is mixed, with some studies showing improvement, some harm, and some showing no benefit from this type of exercise. ⁶ It could be that the intensity of exercise also gives an aerobic stimulus sufficient to increase central cardiovascular conditioning (i.e., peak VO₂), and that is part of the mechanism of improvement. ⁵ Given the pathophysiological complexities of PAD, it may also be that the response to a given exercise intervention may differ depending on disease severity, lesion location, large versus small vessel arterial disease, or other underlying risk factors. Dr Hiatt’s early studies were conducted at the VA Medical Center in Denver. They included primarily white men and excluded individuals with diabetes, citing concerns that glycemic control might affect the response to exercise training.^4,7 Almost 60% of participants were current smokers, whereas only 30–40% are current smokers in more recently published clinical trials.^{8 –10} These more recent trials also included approximately 40% of participants with diabetes,^8,10,11 as well as a range of other risk factors. Well-designed studies that test the various potential mechanisms of improvement in subgroups of the PAD population are needed to address this gap in evidence.

Gap #2: Identification, delineation, and utilization of effective home-based or community-based exercise intervention

The safety and effectiveness of the center-based SET model for symptomatic patients with PAD are well established, although problems with uptake persist. ¹² As noted in the review article by Bronas and Regensteiner in this issue of Vascular Medicine, barriers to SET have limited its utilization even though its strong effectiveness makes it a desirable treatment.^13,14 In addition, SET is reimbursable by third party payers. In a Cochrane analysis, the authors noted, based on moderate- and high-quality data, that SET improves walking ability significantly more in terms of peak walking distance and pain-free walking distance compared with home-based exercise training or advice about walking. Determining the place of home-based exercise training versus center-based programs for PAD is still an area which needs further development, particularly to determine its role in the clinical setting. ¹⁵ There are significant barriers to home-based exercise programs including lack of supervision, possible lack of a safe environment in which to exercise, and lack of reimbursement. However, researchers including McDermott et al. and Gardner et al. have demonstrated the effectiveness of these programs in many domains.^8,10,16 Recently, McDermott and colleagues showed that among patients with PAD, low-intensity home-based exercise was significantly less effective than high-intensity home-based exercise. ¹⁰ For both home-based and community-based programs, ways to promote optimal adherence is an issue that requires further study. Structured programs that incorporate behavioral elements, such as coaching and more frequent contact with patients to promote change appear to have a higher degree of success. Thus, the area of home-based exercise is ripe for more study. It is likely that a successful home program could ultimately be more utilized than a hospital- or center-based program and would be more practical, thus enhancing the use of exercise for patients.

Gap #3: Need for greater use of these therapies in women and minorities and determination of potential sex/racial differences in the effects of training

In the 1980s, as noted previously, PAD was regarded primarily as a man’s disease. However, PAD is highly prevalent in women. ³ As with other types of therapies for a wide range of diseases, research findings from clinical trials evaluating the effects of exercise training in men have often been extrapolated to women until recently. More recent studies have included up to 40% women. However, rarely have these studies been specifically designed to evaluate sex differences or the health of women in particular. Significant gaps in our current evidence base in women have resulted. One relevant question is whether women receive the same benefits as men from exercise training. Evidence on this question is relatively sparse. Gardner and colleagues reported that both sexes improved their peak walking time but that the effect was less in women than men, especially in women with diabetes.^17,18 In contrast, McDermott et al. did not observe a sex-based difference. ¹⁹ Much more research is needed to understand the benefits of exercise training in women compared to men and to inform design of ideal therapies for women versus men because optimal therapies may differ for the sexes.

Minorities have only recently been the focus of researchers seeking to study the role of exercise training to improve symptoms in PAD. This is problematic because, for instance, Black Americans are twice as likely to have PAD as non-Hispanic White Americans ²⁰ and yet relatively little is known about whether exercise therapies should be administered using the same methodology across racial and ethnic minorities compared to non-Hispanic White groups. Most other minority groups also have a higher prevalence of PAD than non-Hispanic White individuals, and the same questions apply. Although studies are now starting to include diverse populations, with more recent studies including 50–60% minority participants,^8,10,11 much more work is needed to identify ideal treatments, and assumptions cannot be made that the same treatments work across all groups. For instance, Collins and colleagues reported that in a group of 174 Black Americans with PAD, motivational interviewing did not increase walking ability compared to patient-centered assessment and counseling for exercise or control in contrast to other studies. ²¹ Further research is needed to determine optimal treatments so that treatments are appropriately used.

Gap #4: Identification of optimal individual therapies and mode of treatment and elucidation of variability in response to exercise training to enable personalized medicine-based prescriptions

As indicated above, patients with PAD present with a wide range of disease severity, location, risk factors, functional abilities, and comorbid conditions. Despite this variability, we have approached structured exercise therapy in this population as a ‘one size fits all’ solution, assuming that one form of exercise training will benefit all equally. However, it has been reported that approximately 45% of patients do not have a meaningful improvement in walking performance following structured exercise therapy.^9,10,19,22 Disease severity may have a big impact. For example, if a patient is only able to walk on a treadmill for very short periods of time before developing moderately severe ischemic symptoms, there may be no aerobic benefit and the inflammation resulting from ischemia may prevent positive skeletal muscle adaptation. In these cases, would a nonweight-bearing form of exercise allow longer duration of exercise bouts, while inducing fewer symptoms? This challenges the paradigm that inducing moderately severe ischemia is necessary to achieve benefit, which needs further examination.

There have been several studies done comparing the impact of alternative (i.e., nonwalking) modes of exercise on improvement in walking performance in patients with PAD. ²³ Examples include arm cycling,^{24 –26} leg cycling,^25,26 and, most recently, total body recumbent stepping (TBRS). ²⁷ Many of these studies have shown patient improvement following these alternative modes of exercise. In this issue, Salisbury and colleagues report the outcomes of a randomized pilot study comparing TBRS to traditional treadmill walking within a clinical supervised exercise program, demonstrating similar walking improvements in both groups. ²⁷ However, it remains to be determined in whom nonwalking exercise is more effective compared to walking exercise. Thus, larger definitive trials testing alternative modes of exercise versus walking exercise are needed to determine best practices for different subgroups of patients with PAD. It would be helpful to measure multiple cardiovascular and skeletal muscle outcomes in addition to functional outcomes to determine the mechanism(s) of response among these different modalities.

We have highlighted several gaps in our knowledge about how, in whom, and under what conditions structured exercise therapy results in functional improvement in patients with PAD. Addressing these gaps in the years to come will improve the use of a therapy that enhances overall cardiovascular health as well as ameliorating symptoms of PAD. Dr Hiatt helped set us on this path. The journey must continue!