Combined Aerobic and Resistance Exercise in Walking Performance of Patients With Intermittent Claudication: Systematic Review

Background: The short-term benefits of aerobic and resistance exercise in subjects affected by Peripheral Arterial Disease (PAD) are scarcely examined in interaction. This study aimed to identify the effects of combined aerobic and resistance exercise programs on walking performance compared with isolated aerobic exercise or with the usual care in patients with intermittent claudication. Methods: A systematic review was conducted following the PRISMA statement. A total of five electronic databases were searched (until October 2019) for randomized and non-randomized controlled trials. The focus comprised PAD patients with intermittent claudication who performed a combined aerobic and resistance exercise program that assessed the walking performance. Results: Seven studies include combined aerobic and resistance exercise vs. isolated aerobic or vs. usual care. The studies represented a sample size of 337 participants. The follow-up ranged from 4 to 12 weeks, 2 to 5 times-per-week. The risk of bias in the trials was a deemed moderate-to-high risk. After the interventions, the percent change in walking performance outcomes had a large variation. In the combined and isolated aerobic programs, the walking performance always improved, while in the usual care group oscillates between the deterioration and the improvement in all outcomes. Combined exercise and isolated aerobic exercise improved the claudication onset distance from 11 to 396%, and 30 to 422%, the absolute claudication distance from 81 to 197%, and 53 to 121%, and the maximal walking distance around 23 and 10%, respectively. Conclusions: Currently, there is insufficient evidence about the effects of combined aerobic and resistance exercise compared to isolated aerobic exercise or usual care on walking performance. However, despite the low quality of evidence, the combined aerobic and resistance exercise seems to be an effective strategy to improve walking performance in patients with intermittent claudication. These combined exercise modes or isolated aerobic exercise produce positive and significant results on walking performance. The usual care approach has a trend to deteriorate the walking performance. Thus, given the scarcity of data, new randomized controlled trial studies that include assessments of cardiovascular risk factors are urgently required to better determine the effect of this exercise combination.

Background: The short-term benefits of aerobic and resistance exercise in subjects affected by Peripheral Arterial Disease (PAD) are scarcely examined in interaction. This study aimed to identify the effects of combined aerobic and resistance exercise programs on walking performance compared with isolated aerobic exercise or with the usual care in patients with intermittent claudication.
Methods: A systematic review was conducted following the PRISMA statement. A total of five electronic databases were searched (until October 2019) for randomized and non-randomized controlled trials. The focus comprised PAD patients with intermittent claudication who performed a combined aerobic and resistance exercise program that assessed the walking performance.
Results: Seven studies include combined aerobic and resistance exercise vs. isolated aerobic or vs. usual care. The studies represented a sample size of 337 participants. The follow-up ranged from 4 to 12 weeks, 2 to 5 times-per-week. The risk of bias in the trials was a deemed moderate-to-high risk. After the interventions, the percent change in walking performance outcomes had a large variation. In the combined and isolated aerobic programs, the walking performance always improved, while in the usual care group oscillates between the deterioration and the improvement in all outcomes. Combined exercise and isolated aerobic exercise improved the claudication onset distance from 11 to 396%, and 30 to 422%, the absolute claudication distance from 81 to 197%, and 53 to 121%, and the maximal walking distance around 23 and 10%, respectively.
Conclusions: Currently, there is insufficient evidence about the effects of combined aerobic and resistance exercise compared to isolated aerobic exercise or usual care on walking performance. However, despite the low quality of evidence, the combined aerobic and resistance exercise seems to be an effective strategy to

INTRODUCTION
Peripheral arterial disease (PAD) is an occlusive atherosclerotic disease that affects blood vessels, reducing the blood flow of the lower limbs (Vascular Disease Foundation, 2012). The most common symptom is intermittent claudication (IC) affecting millions of people around the world (Gardner et al., 2014). The discomfort associated with IC contributes to a further sedentary lifestyle, that decreases physical fitness, and aggravates cardiovascular risk factors (Winzer et al., 2018). Among patients with IC, a shorter distance and a lower speed walking were associated with an increased risk of cardiovascular and all-cause of mortality (Morris et al., 2014;McDermott et al., 2016), which confirms the importance of an adequate level of physical fitness in this population (Leeper et al., 2013). Indeed, as PAD severity increases, the walking performance progressively decreases (Silva Rde et al., 2015).
Thereby, the promotion of exercise training in patients with PAD and IC is an important non-pharmacological strategy to treat and prevent this disease, which provides favorable systemic vascular effects that may reduce cardiovascular events and improve blood perfusion in PAD (McDermott et al., 2009). Supervised exercise programs have a higher efficacy in improving the physical fitness in particular the walking performance (i.e., claudication onset distance [COD], absolute claudication distance [ACD] or maximal walking distance [MWD]) and the symptomatology of this disease when compared to unsupervised exercise programs (McDermott et al., 2009;Mays and Regensteiner, 2013;McDermott, 2013). However, a recent meta-analysis found that structured home-based exercise programs are effective at improving walking performance in patients with PAD (Golledge et al., 2019). According to guidelines on the diagnosis and treatment of PAD by American Heart Association/American College of Cardiology (AHA/ACC) and European Society of Cardiology/European Society for Vascular Surgery (ESC/ESVS), patients should realize a supervised exercise walking program for a minimum of 30/45 min per session, performed at least 3 times per week for a minimum of 12 weeks (Gerhard-Herman et al., 2017;Aboyans et al., 2018). However, to reduce cardiovascular risk factors and avoid premature mortality, older adults should perform aerobic exercise and also do musclestrengthening exercises (Piercy et al., 2018;Kraus et al., 2019). A meta-analysis shows that resistance training clinically improved treadmill and flat ground walking performance in patients with PAD (Parmenter et al., 2019). However, in the available literature, the benefits of aerobic and resistance exercises in peripheral arterial disease are commonly studied alone. The combination of these two modes is more effective in the chronic modification of cardiovascular risk factors in healthy elderly men (Sousa et al., 2013), improving quality of life and lipid profiles in patients with coronary disease (Currie et al., 2015) and improving central arterial stiffness and cardiac function in patients with cardiovascular disease (Zhang et al., 2018).
Therefore, there is a clear lack of evidence about the effects of the combined exercise programs to prevent IC progression and PAD treatment. The purpose of this study was to compare the effects of combined aerobic and resistance exercise with another mode of exercise or with the usual care approach on walking performance outcomes.

Eligibility Criteria
This review included randomized controlled trials and nonrandomized controlled trials that met the following criteria: (i) contained only patients with PAD and IC; (ii) employed a combined aerobic and resistance exercise program for the treatment of IC compared to another mode of exercise program or to the usual care approach (a non-exercising control group was deemed not essential for these analyses); and (iii) contained measurements of walking performance, such as, COD, ACD, and MWD, assessed with a treadmill protocol or with the 6 min walking test (6 MWT).
The exclusion criteria for the trials were: (i) the treadmillwalking and usual care groups were prescribed medications or surgical interventions for treatment of symptoms of PAD, and the exercise/treatment group was not; (ii) only acute exercise studies (or single exercise sessions); (iii) review articles; (iv) systematic reviews; and (v) case reports.

Information Sources
Due to the lower overall sample size and the heterogeneity of protocols used, a systematic review was conducted without metaanalysis. Studies were identified by searching electronic databases and hand-searched reference lists of articles, to evaluate the effects of combined aerobic and resistance exercise programs and isolated aerobic exercise or usual care, on walking performance in patients with PAD and IC. Searches were limited to the English language, and no limits were applied to publication dates. This search was applied to Medline (Pubmed), Web of Science, B-On, Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS. The last search was run on 30 October 2019.

Study Selection
Eligibility assessment was performed independently in an unblinded standardized manner by two reviewers (IM and CA). Disagreements between reviewers were resolved by consensus. All the work of revision was oriented according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocol Moher et al., 2009). For the PRISMA checklist see Supplementary Material.

Data Collection Process
One review author extracted the data from the included studies, and the second author checked the extracted data. Disagreements were resolved by discussion between the two review authors; if no agreement could be reached, it was planned a third author would decide (NS). We contacted two authors for further information, but just one answered and provided numerical data.

Data Items
The extracted outcomes data will be analyzed through a narrative synthesis. Information was extracted from each included trial on: (i) characteristics of participants (including age, gender, and stage of disease); (ii) intervention (including type, intensity, duration and week frequency of exercise) of the combined exercise program vs. the isolated aerobic exercise or vs. the usual care approach (encouraged to follow the exercise recommendations at home); (iii) walking protocol (treadmill graded protocol, treadmill constant protocol, and 6 MWT; and (iv) outcome measures (COD, ACD, MWD, and ABI).
The outcome results were reported as mean ± SD and were considered significant when p < 0.05 from the study statistical analyses. Since the treadmill-walking test was performed at a constant speed, there is a direct relationship between time and walking distance. To compare the results of the Hiatt et al. (1994) study, the data of claudication onset time and absolute claudication time originally presented in minutes was converted to seconds. The data related to COD and ACD were calculated since a constant-load exercise protocol was performed. The calculated distance results were considered statistically significant if the original results were also significant. Regarding the study by Tebbutt et al. (2011), the results were originally presented as a median, but for comparison purposes with the other studies, the COD and ACD mean values were estimated, after approval by the author. In the studies of Jakubseviciene et al. (2014) and Kropielnicka et al. (2018), since the data were presented in chart forms, the authors were contacted to provide the exact numerical data, to be able to compare with the other studies, however, they did not answer.

Quality Assessment
The methodological quality of each selected study (n = 7) used was the Physiotherapy Evidence Database (PEDro) rating scale. In the PEDro scale, points are only awarded when a quality criterion is clearly satisfied. Any disputes were resolved by consensus, or by a third author (NS) when necessary.

Study Selection
A total of 1,865 potentially relevant articles were identified through the database search, and a total of 108 studies were discarded because were duplicated. A total of 1,426 articles were removed after reading titles and 281 after reviewing the abstracts since they clearly did not meet the inclusion criteria. The full text of the remaining 50 references was examined in detail, and 43 studies did not meet the inclusion criteria. Seven studies met the inclusion criteria and were included in this systematic review (Figure 1). No unpublished relevant studies were obtained.

Participants
The total number of 337 participants were involved in the seven studies, 99 were men, 34 were female, and 204 were not reported. All patients had IC and ABI at rest ≤0.90 (except Hiatt et al., 1994 that have an ABI < 0.94 and Jakubseviciene et al., 2014 that didn't report). A total of 337 participants, 169 of whom were allocated to the combined exercise group, 132 to the isolated aerobic exercise group, and 36 to the usual care group; 43 among them were excluded from statistical analysis across all studies. The mean age among participants ranged from 57 to 82 years, and the mean body mass index, when reported, was 28.0 ± 4.3 kg/m 2 .
In the present systematic review, the majority of patients with PAD reported cardiovascular risk factors and other comorbidities conditions, at least 18% were current smokers, 15% of the patients had hypertension, 12% had hyperlipidemia, 7% had diabetes, 3% had coronary heart disease, 2% had a history of cerebrovascular disease, and 8% had other diseases ( Table 2). These values are probably higher since we only had access to 45% of the sample characterization.
The combined aerobic and resistance exercise group was compared with the isolated aerobic exercise group in 4 studies and with the usual care approach in three studies.

Intervention
All trials have used combined aerobic and resistance exercise, however, there are some differences between the combined For the CB group, data from the second 12 weeks of combined training were considered since in the first 12 weeks the group was a control group. For AER were considered the data of the first 12 weeks of treadmill-walking program.
exercise programs analyzed. The most common aerobic exercise mode used was treadmill-walking exercise, however, one study used a plantar flexion ergometer (Mosti et al., 2011), one study used a nordic-walking training (Kropielnicka et al., 2018), and another one used more than one mode of aerobic exercise including treadmill-walking exercise. Interval walking to moderate-maximum claudication pain was the most common prescription. The work-rest-cycle (i.e., exercise until a specific pain level, usually moderate or near maximal, followed by rest until the pain disappears, and repeat the cycle) was used due to claudication, and exercise duration raged from 20 to 50 min. The follow-up ranged from 4 to 12 weeks, and the supervised training frequency ranged from 2 to 5 days per week. For resistance exercise mode, four studies used plate loaded machines (Parr et al., 2009;Mosti et al., 2011;Delaney et al., 2014;Jakubseviciene et al., 2014), one study used a resistance pedal (Tebbutt et al., 2011), one study used a functional dynamometer under constant angular velocity (Kropielnicka et al., 2018), and another study used the body weight and an additional load resistance with a cuff weight (Hiatt et al., 1994). One study performed upper and lower body exercises, while the majority performed only lower body exercises. The number of exercises varied between 1 and 6, the sets between 1 and 4 [except Kropielnicka et al. (2018) that used 10 sets] and between 5 and 15 repetitions. Except for one study, the combined aerobic and resistance exercise program was home-based and was not supervised (Tebbutt et al., 2011).
The COD was defined as the distance on the moment in which claudication pain starts; ACD was defined as the distance that had been walked until patients were unable to continue due to the increased intensity of claudication pain, and; MWD was defined as the total walking distance reached at the end of the protocol (work-rest-cycle sum). For example, a patient walked 270 m without pain (COD) and had to stop 950 m after starting due to IC (ACD). After the pain released, he resumed his walk, and at the end of the 30-min session had walked a total of 1,600 m (MWD).

Studies Quality Assessment
The following criteria were used to classify the methodological quality: a score from PEDro equal or greater than 7 (n = 1) indicates a high methodological quality; scores between 5 and 6 (n = 2) indicate a moderate methodological quality; and scores below 5 (n = 4) indicated low methodological quality. The highest PEDro rating was   7, with an average of 5 among the included studies ( Table 3).

Combined Exercise vs. Aerobic Exercise
Statistical significant improvements were found on COD in the combined exercise group after 4 weeks (Jakubseviciene et al., 2014) and in the isolated aerobic group after 12 weeks (Hiatt et al., 1994;Delaney et al., 2014;Kropielnicka et al., 2018). Between groups, there were no significant differences. The combined exercise group showed a trend to improve the COD between 11 and 396% (+18 and +528 m), while the isolated aerobic group showed a trend to improve between 30 and 422% (+51 and +789 m) ( Table 4). Statistical significant improvements were found on ACD in the combined exercise and isolated aerobic exercise group after 12 weeks (Hiatt et al., 1994;Kropielnicka et al., 2018). Between groups, there were no significant differences. The combined exercise group showed a trend to improve the ACD between 81 and 197% (+315 and +789 m) while the isolated aerobic exercise group showed a trend to improve between 53 and 131% (+272 and +923 m) ( Table 4).
Statistical significant improvements were found in MWD in the combined group after 4 and 12 weeks (Jakubseviciene et al., 2014;Kropielnicka et al., 2018) and in the isolated aerobic group after 12 weeks (Delaney et al., 2014;Kropielnicka et al., 2018). There were no significant differences between groups. The combined exercise group showed a trend to improve the MWD around 23% (+81 m), while the isolated aerobic exercise group showed a trend to improve around 10% (+38 m) ( Table 4).

Combined Exercise vs. Usual Care Approach
Statistical significant improvements were not found in COD after 6 or 12 weeks of combined exercise and usual care approach. However, between groups, statistical differences were found in COD with improvements found only in the combined group (Parr et al., 2009). The combined exercise group showed a trend to improve the COD between 26 and 104% (+31 and +130 m), while the usual care deteriorated or improved between −40 and 24% (−76 and +27 m) ( Table 4). Statistical significant improvements were found on ACD only in the combined exercise group after 8 weeks (Mosti et al., 2011). Improvement in the combined group after 6 weeks (Parr et al., 2009) and 8 weeks (Mosti et al., 2011) compared to usual care were found in ACD, with statistical differences. The combined exercise group showed a trend to improve the ACD between 10 and 67% (+104 and +195 m), while usual care deteriorated or improved between −7 and 17% (−30 and +40 m) ( Table 4).
There were no significant improvements in MWD, along with the intervention. However, the combined exercise group showed a slight trend to improve the MWD around 14% (+53 m) while the usual care group deteriorated −2 (−7 m) ( Table 4).
These walking performance results were quite variable in all groups, and their magnitude change could be affected by the applied walking protocol test (Table 4).
Rest ABI was observed in combined exercise, isolated aerobic exercise, and usual care groups; however, no changes were found in this variable (Table 1).

DISCUSSION
The overall findings of this systematic review suggest that both combined aerobic and resistance and isolated aerobic programs improve claudication onset distance, absolute claudication distance, and maximal walking distance, with no significant differences found between these strategies. However, the combined aerobic and resistance exercise programs improved claudication onset distance and absolute claudication distance when compared to the usual care approach.

Combined Exercise vs. Aerobic Exercise
The positive effects of the exercise programs in IC patients are often related to improved endothelial function, skeletal muscle metabolism, blood viscosity, pain tolerance, and inflammatory responses (Stewart et al., 2002). These mechanisms are linked to exercise benefits in PAD and can counteract the disease progression. The increase in the majority of the walking performance outcomes suggest that the key to induce improvements is a well-structured exercise program, with isolated aerobic exercise or combined with resistance exercise, that complies with the specific PAD exercise doses. Accordingly, home-based exercise programs, if structured, involving adequate supervision and aimed to motivate the patients to increase physical activity levels or other behavioral interventions, can also improve walking performance outcomes (Golledge et al., 2019). The walking performance improvements are associated with significant enhancements in functional status, quality of life (Lauret et al., 2014;Novakovic et al., 2017), and also to considerable decreases in sedentary levels that may help in the management of cardiovascular risk factors (Morris et al., 2014;McDermott et al., 2016;Novakovic et al., 2017).
Although there are no significant differences in COD, ACD, and MWD between the exercise groups, it is consensual that PAD patients have lower limb muscle strength and less calf muscle mass related to the general population, which causes functional impairment, that isolated aerobic exercise by itself cannot overtake. Isolated resistance training can attenuate agerelated changes in muscle function (Papa et al., 2017), and can be associated with improvements in balance (Gonzalez et al., 2014), muscle strength, walking performance (Ritti-Dias et al., 2010;Wang et al., 2010), psychological well-being, and quality of life (Pedersen et al., 2017). However, among patients with an increased risk of cardiovascular disease, the combined training may provide more cardiovascular benefits, when compared to time-matched aerobic or resistance training alone (Schroeder et al., 2019). A single session of combined aerobic and resistance exercise improves blood flow and leg vascular resistance similar to a single aerobic session; however, combined exercise promotes better effects on oxidative stress responses (Lima et al., 2018), regarded as morbidity and mortality marks in several populations (Yucel et al., 2015;Zhang et al., 2015). Combined aerobic and resistance exercise may induce improvements in other outcomes that were not specifically studied in this systematic review. In three studies included in this systematic review, the walking performance outcomes improved (Mosti et al., 2011;Delaney et al., 2014;Kropielnicka et al., 2018), and also positive effects were found on lower limb muscle strength parameters, such as, peak torque, total work, and average power in the combined exercise when compared to isolated aerobic exercise or to usual care approach. Combined aerobic and resistance exercise, in addition to improving walking performance, also seems to increase lower limb muscle strength, which may lead to a better quality of life. One advantage of combined exercise is the fact that patients feel it as being less painful than isolated walking exercise (Ritti-Dias et al., 2010), which could help to improve exercise adherence.
In the combined groups of this systematic review, the majority of aerobic exercise sessions consisted of supervised treadmill-walking while the resistance exercise sessions, showed heterogeneity between studies, concerning the number of sets, number of repetitions and number of total exercises. The studied variables are, as well, different from each other, and in one study, the exercise characteristics were not described (Jakubseviciene et al., 2014). The exercise programs duration, ranged from 4 to 12 weeks and the study with the shortest duration (Jakubseviciene et al., 2014) achieve significant improvements in walking performance both in combined and isolated exercise groups, which can be explained because: (i) both groups performed the exercise program with a higher exercise weekly frequency (4/5 times a week), and (ii) both groups performed the exercise program immediately after a lower limb arterial surgery. The total duration of the exercise sessions (in min) and the partial aerobic exercise duration of the combined and isolated aerobic exercise programs are relevant points to note. In fact, one study implemented a total combined session duration of 90 min and matched the same aerobic exercise duration (50 min) in both combined and isolated aerobic exercise (Hiatt et al., 1994). Also, another study promoted a slightly higher total duration (+15 min) in combined exercise (Jakubseviciene et al., 2014), and two studies implemented the same session duration (Delaney et al., 2014;Kropielnicka et al., 2018), promoting a lower training volume of each exercise mode. Thus, it may not meet the current PAD guidelines, nor achieve the minimum stimulus of the exercise duration to accomplish the same benefits of isolated aerobic or resistance exercise when combined (Gerhard-Herman et al., 2017;Aboyans et al., 2018).
Supervised exercise programs not always reveal significant improvements in COD. However, ACD has always improved, which reveals a better capacity to walk long distances. The pain during exercise does not disappear, in fact, it seems that the pain is better tolerated and/or patients perceive a lower pain level. Regarding ABI results, as expected, no changes were found in combined, isolated or usual care approach groups. Exercise does not directly eliminate systemic atherosclerosis but may increase the muscle oxygen delivery or oxygen utilization through microvascular alterations and improvement of endothelial dilatation in collateral blood vessels (Baker et al., 2017).
A wide range of different protocols are used and these present a variety of characteristics, such as, constant and graded load protocols with different speeds, grade, and stage duration, which can promote distinct results, hampering adequate comparison of studies and strategies. The treadmill-walking is the most used protocol to assess the walking performance in PAD patients. When PAD patients are tested in constant protocols, the values of COD and ACD are higher (Hiatt et al., 1994). The differences are also related to the heterogeneity of this population once the same load promotes different patterns of IC. A meta-regression analysis found the highest estimated reliability in COD assessed by constant treadmill protocols, but the graded treadmill protocol promoted the highest reliability in ACD assessments (Nicolai et al., 2009). The MWD can be adequately assessed by the 6MWT and this test better represents walking in daily life compared to treadmill-walking protocols Nordanstig et al., 2014).

Combined Exercise vs. Usual Care Approach
When combined aerobic and resistance exercise are compared to usual care approaches, there are positive and significant differences in COD and ACD outcomes, except in one study, where the combined exercise program was unsupervised. The unsupervised exercise program combined walking and resistance pedal, and the outcomes presented minor improvements (Tebbutt et al., 2011). This lack of effect can be related to the early interruption of the walking exercise due to intermittent claudication, and also to the inexistence of workload progression in home-based exercises. The usual care approach, have a trend to deteriorate walking performance, considering that PAD is a progressive atherosclerotic disorder that deteriorates over time. These findings are in agreement with several randomized controlled trials and systematic reviews that compared supervised walking exercise to unsupervised exercise and usual care programs (McDermott et al., 2009;Hamburg and Balady, 2011;Vascular Disease Foundation, 2012;Mays and Regensteiner, 2013;McDermott, 2013;Lane et al., 2017).
Two studies with a short program intervention (below 2months) did not comply with the current PAD exercise guidelines (Gerhard-Herman et al., 2017;Aboyans et al., 2018) but found significant improvements in COD (Parr et al., 2009) and ACD (Parr et al., 2009;Mosti et al., 2011). The study conducted by Parr et al. (2009) promoted an exercise program that consisted to 20 min of treadmill-walking exercise combined with one of the following exercises on different days: (i) cycling for 5 min followed by a 15 min circuit training (15 repetitions of six different upper and lower body exercises) in plate load machines; (ii) floor exercises consisting of either bench-step, aerobics or core stabilization exercises; and (iii) 15 min spin (cycle) class. The study conducted by Mosti et al. (2011) used an interesting modify plantar flexion ergometer (4 sets of 4min of alternated single leg work intervals) as aerobic exercise. The results revealed positive effects on ACD only after the combined exercise program, and it might indicate an important local exercise effect related to muscle mass quantity. In PAD patients, pulmonary oxygen kinetics were found to be slower in the lower extremities compared to upper extremities (Bauer et al., 2004) and circulatory adaptations were different when dynamic single-leg exercise is compared to two-leg exercise. This is related to the large redistribution of blood to the working muscles when a single-leg is used during exercise (Klausen et al., 1982). Another fact is that in Mosti et al. (2011) study, the authors combined aerobic exercise with 4 sets of 5 reps at 85-90% 1RM of dynamic leg press strength exercise, that represents a higher intensity and dose when compared to the other studies. Also, a meta-analysis found that higher intensity resistance exercise improves both flat ground and graded treadmill-walking performance in PAD patients (Parmenter et al., 2019).
The combined aerobic and resistance exercise compared to usual care promoted significant improvements in walking performance, but to date, when compared to treadmill walking, it seems to add no extra benefit to these variables. To the best of our knowledge, this is the first systematic review to compare the effects of combined aerobic and resistance exercise with isolated aerobic exercise or with usual care approach, providing important data regarding its impact on walking performance in PAD patients with IC.

Limitations
The key limitations of this systematic review were the reduced number of Randomized Controlled Trials (the trials included in this systematic review had a moderate-to-high risk of bias), one of them was not a RCT, and there are some missing details in the protocol description.

CONCLUSION
There is insufficient evidence to compare the effects on walking performance of combined aerobic and resistance exercise compared to isolated treadmill-walking or usual care approaches. However, despite the low quality of evidence, the combined aerobic and resistance exercise and isolated aerobic exercise (treadmill-walking) may lead to improve walking performance outcomes, such as COD, ACD, and MWD. Both reveal significant and positive results on walking performance; however, the combined exercise program may induce improvements in other important variables that were not the study target of this systematic review. The usual care approach has a trend to deteriorate walking performance. Thus, given the scarcity of data, high-quality RCTs that include an assessment of cardiovascular risk factors are urgently required to determine the effect of this exercise dose combination.

Recommendations for Future Research
This systematic review combined the results of 337 participants with seven studies, indicating a small sample size and a small number of articles included. Therefore, more randomized controlled trials are needed to make a meaningful comparison between combined aerobic and resistance exercise programs and, a new review should be conducted, including a meta-analysis, where possible. Additional outcomes to quantity functional lower limb strength, cardiovascular risk factors, and qualitative data should be implemented. The exercise programs applied should carefully describe the key components of training protocols, specifying the mode of exercise, intensity, week frequency, exercise duration, and the exercise load progression, since this was not always clear.

Practice Recommendations
Compared to usual care approach, short-term combined aerobic and resistance exercise programs and isolated aerobic exercise are essential for better improvements in walking performance (e.g., claudication onset distance and absolute claudication distance) in patients with intermittent claudication and peripheral arterial disease.

DATA AVAILABILITY STATEMENT
All datasets generated for this study are included in the article/Supplementary Material.

AUTHOR CONTRIBUTIONS
The literature search and selection of studies was performed by authors IM and CA. Following an initial screen of titles and abstracts (IM), full scrutiny of potentially eligible studies was independently screened by IM and CA using the specific inclusion criteria. NS arbitrated any disagreements in the study inclusion. Study quality assessment was performed by IM. CA, NS, HP, and JF revised the manuscript. All authors contributed to the development of the final manuscript, reviewed, and approved the submitted version.

FUNDING
This work was supported by the Foundation for Science and Technology (FCT, Portugal) and European Social Fund (ESF), through a Doctoral grant endorsed to the IM (SFRH/BD/133120/2017) under the Human Potential Operating Program (POPH). This work was also supported by the ERDF-European Regional Development Fund through the Operational Programme for Competitiveness and Internationalization-COMPETE 2020 Programme and by National Funds through the Portuguese funding agency, FCT-Fundação para a Ciência e a Tecnologia within project NORTE-01-0145-FEDER-031161; PTDC/MEC-VAS/31161/2017. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.