Determining the Optimal Type of Exercise for People With Symptomatic Lower Extremity Peripheral Artery Disease: Is There a One-Size-Fits-All Approach?

Lower extremity peripheral artery disease (PAD) is a progressive atherosclerotic disease that affects approximately 6% of adults worldwide and the prevalence is rising.1 Peripheral artery disease can cause cramping, aching, or pain in the muscles (calf, thigh, or buttocks) of one or both legs. The pain can occur with weight-bearing exercise that is typically relieved within 10 min of rest.2 As a result, PAD has an adverse effect on the walking capacity of an individual and is associated with significant morbidity and mortality, lower health-related quality-of-life, and functional impairment.3–5 Therefore, determining ways to improve walking capacity is an important parameter to consider when prescribing exercise to this population. In this issue of the Journal of Cardiopulmonary Rehabilitation and Prevention, Tremblay et al6 present the results of a network meta-analysis (NMA) designed to compare the effect of different modalities of supervised exercise therapy on walking capacity among people with symptomatic PAD. The authors are to be commended for this thorough analysis of the existing literature. This is the first NMA that has been conducted with the objective of determining which exercise modality is more likely to produce significant improvement in walking capacity. An NMA allows for a comparison of cohorts that may not have been included in the same randomized trial (ie, indirect comparisons). The authors conducted a search for eligible studies from January 1966 to April 18, 2021, identifying 18 studies that included a total of 1135 patients for inclusion in the NMA. The study groups were classified into seven categories based on the exercise modality intervention. In order of frequency, these included intermittent walking (n = 12 interventions), control group (n = 11 cohorts), upper or lower body resistance training (n = 5 interventions), combined aerobic and resistance training (AT+RT) (upper and/or lower body) (n = 4 interventions), standard aerobic training (n = 3 interventions), underwater exercise (n = 2 interventions), and Nordic walking (n = 1 intervention). Standard aerobic training included either arm ergometry or combined arm ergometry with intermittent treadmill walking. Underwater exercise included mostly water walking in waist-to-chest-deep water. Walking capacity (maximal walking distance) was measured in two ways and each analyzed separately. One method was by a treadmill test with a constant load or graded protocol to determine the maximal walking distance (MWD) covered when pain prevented further walking and the other was the 6-min walk test (6MWT) distance. The analysis of the MWD included 12 studies (six nodes representing five exercise interventions and control group). Of the possible 15 comparisons, 10 were direct and five were indirect. The 6MWT analysis included 10 studies with five exercise interventions and control group. Of the possible 15 comparisons, 10 were direct and five were indirect. There were no signs of inconsistency between intervention effects estimated from direct comparisons to those estimated from indirect comparisons for MWD and 6MWT outcomes. Therefore, after the comparative effectiveness of the interventions was analyzed, the authors ranked the interventions on superiority by comparing them to control groups. The results of the analyses revealed that both AT+RT in combination and intermittent aerobic walking improved the MWD greater than the control condition. Furthermore, the effect size, which is a measure of practical significance, was larger for AT+RT than intermittent walking. Both exercise strategies exceeded the minimal clinically important difference for a medium change. There was no significant effect on the MWD from aerobic training, resistance training, or Nordic walking compared with control. Further results revealed that AT+RT followed by underwater training and then intermittent walking as the most promising strategies to improve 6MWT distance. The effect size was similar for AT+RT and underwater training (both moderate) but lower for intermittent walking. WHAT CAN WE LEARN FROM THE COMBINED AT+RT EXERCISE INTERVENTIONS USED IN THESE STUDIES TO INFORM THE EXERCISE PRESCRIPTION? Tremblay et al6 reported two major limitations of these studies. First, there were only three AT+RT studies that measured the MWD and second was that the exercise prescriptions were highly variable.7–9 Indeed, an examination of the three combined AT+RT studies revealed a wide variety of aerobic exercise modalities including Nordic walking, and combinations of intermittent walking, spin, and step aerobics. In addition, the final sample sizes for the AT+RT groups were 8-28 patients, and the volume and frequency of RT was low in two of three studies. It is possible that the prescriptions in these two studies, one set of six RT exercises 1 time/wk for 6 wk, and 10 sets of two isokinetic RT exercises 1-2 times/wk for 12 wk,7,8 would provide a suboptimal stimulus to obtaining benefit. This may be owing to the investigators attempt to equalize the total duration of exercise between combined and the comparison exercise modality group. However, this risks not meeting an adequate dose for either AT or RT in the combined group. Yet, if the duration is not equalized between groups, the effect size for combined training may be higher because of a greater total volume of exercise than single modality studies for direct or indirect comparisons. Despite this, there was still a greater effect size for increasing MWD from combined AT+RT than other modalities. Regarding the underwater exercise intervention, there were only two studies included, both with a 6MWT outcome.10,11 Walking exercise (30 min of water walking and 10 min of lower-limb movements) was carried out in waist-to-chest-deep water (28-31°C), 4 d/wk, for 12 wk at an intensity up to 70-85% of heart rate reserve in both studies. Adherence was very high and the final analysis included 35 and 28 participants. There are multiple takeaways from these results. Despite the limited number of studies and variability in training volumes and type of modality within each exercise category, this NMA brings us one step closer to determining the optimal type of exercise to increase walking capacity for people living with symptomatic PAD. Combined AT+RT and underwater exercise appear to be promising exercise strategies, but further research needs to be conducted to strengthen the evidence and determine the optimal dose of each modality. Importantly, there is emerging evidence of the underlying mechanisms that may explain why these modalities might augment walking capacity. Exercise in warmer water may improve arterial stiffness10 and the buoyancy afforded by water decreases lower limb stress, allowing longer exercise duration.12 Regarding RT, there is preliminary evidence that RT results in increased capillary density,13 and AT+RT results in greater muscular strength and power than AT alone in people with symptomatic and asymptomatic PAD.8,9,14 Furthermore, one study reported that a single AT+RT session resulted in a more favorable effect on the oxidative stress response than AT alone in patients with PAD.15 While improving walking capacity is important, the decision of what modality or combination of modalities to prescribe should also consider other factors such as coexisting conditions, musculoskeletal issues, access to exercise equipment or facility, and long-term adherence. For example, it is estimated that 20-30% of people with PAD in the United States have diabetes.16 People with PAD and coexisting diabetes are 5-15 times more likely to have an amputation than those without diabetes, and an increase in glycosylated hemoglobin is correlated with greater risk of amputation.17 The results of a meta-analysis of 14 studies that demonstrated that combined AT+RT has a greater effect on glycemic control than either modality alone in patients with type 2 diabetes strengthen the recommendation for combined training in PAD.18 Furthermore, the addition of RT is especially important for patients who are not able to sustain the recommended volume of aerobic training sufficient for improving the metabolic profile. Indeed, this is more likely to occur in people with coexisting diabetes and PAD.19,20 In the United States, the maximum number of reimbursed supervised sessions for people with PAD is 7221 and in Canada 70% of the cardiac rehabilitation programs that accept referrals for patients with PAD are 9-24 wk in duration.22 Therefore, programs should foster independent exercise so that upon graduation from supervised programs, patients will continue exercising at home or in the community. Some patients have financial constraints and may not be able to purchase equipment, join a fitness facility, or have access to a pool or isokinetic or other type of RT equipment. Walking outside or at a shopping mall and using the body weight of the patient as resistence or using low-cost equipment such as hand-held dumbbells for RT may be more accessible. There should be a transition period to sustainable types of exercise before program completion. Exercise adherence after the supervised period is an important outcome when determining the optimal type(s) of exercise to improve walking capacity and other health-related outcomes and should be measured in future studies. CONCLUSION Altogether, Tremblay et al6 present a thorough NMA comparing exercise modalities and clearly report and acknowledge the limitations. In the future, comorbid conditions and ability to exercise to target intensity and more can be applied to an algorithm that will move us closer to developing targeted exercise prescriptions for improving walking capacity and other health-related outcomes. Given the effect size of combined AT+RT on walking capacity, as well as the high rate of diabetes in PAD, evidence of underlying mechanisms for improvement, and that little specialized equipment/facility is needed, combined training appears to be an effective and feasible mode of exercise in general but more studies are needed. Underwater walking exercise is another promising modality, but also requires further investigation. Nevertheless, the exercise modality should be individualized based on patient characteristics for targeted exercise therapy as one size does not likely fit all for people living with PAD.

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