Authors
- Soerensen, Ulla Milther PT, MR
- Pedersen, Preben Ulrich RN, PhD
- Uhrenfeldt, Lisbeth RN, BA, MScN, PhD
Abstract
Review question: The objective of this systematic review is to identify, appraise and synthesize the best available evidence on the effectiveness of any mode of exercise program on improvement of physical functioning in persons with peripheral arterial disease and symptoms of moderate to severe intermittent claudication.
More specifically, the objective is to identify:
The effectiveness of any mode of exercise program on the physical functioning of people with moderate to severe intermittent claudication.
Background: Inactivity and lifestyle diseases have become an increasingly prevalent health problem and are now the fourth leading risk factor for global mortality.1 In response to this, the World Health Organization (WHO) has developed Global Recommendations on Physical Activity for Health, and the National Health Authorities, guidelines for physical activity.1,2 These recommendations aim to strengthen public health as well as to prevent and control non-communicable diseases (NCDs) such as cardiovascular disease, cancer and metabolic disease. Non-communicable diseases are rapidly becoming rampant and have been referred to as a global pandemic, with major health and economic challenges.3
Physical activity is shown to reduce the risk of specific NCDs.1 Peripheral arterial disease (PAD) is a cardiovascular condition which can have symptoms of intermittent claudication (IC). In this systematic review, the effect of physical activity in terms of exercise will be investigated in people with moderate to severe IC.
Peripheral arterial disease
Peripheral arterial disease is primarily caused by atherosclerosis resulting in stenosis or occlusion of the arteries which affects the circulation and blood flow in peripheral arteries.4,5 Epidemiological studies identify PAD as a serious health problem with prevalence in the adult population of approximately 12%. A current estimate of the global burden of PAD is 202 million persons worldwide, and it is increasing in particularly low-income and middle-income countries.3 Peripheral arterial disease is more prevalent in the older populations, and in people over 70 years the prevalence is almost 20%.5,6,7 In clinics, the manifestation of PAD can be symptomatic with claudication, atypical leg pain or critical limb ischemia (CLI) but in 20-50% of cases, PAD is asymptomatic.6 The diagnosis of lower extremity PAD can be established using different non-invasive techniques, and the ankle-brachial index (ABI) is widely used and recommended.4,6,8 The common definition of PAD is ABI < 0.90; also a very high ABI > 1.40 indicates PAD but with non-compressible arteries.6,8,9 Measuring the ABI after an exercise test, typically a treadmill test, increases the sensitivity of the test.8,10 The nature of PAD as a systemic and progressive disease leaves the patients with a high risk of cardiovascular and cerebrovascular events and other co-morbidities11,12 as well as further deterioration and developing critical limb ischemia with the risk of limb amputation.6,13
Intermittent claudication
Intermittent Claudication (IC) is a symptom common in about one third of the PAD population and the prevalence of IC in the general population is strongly related to age, e.g. in a Swedish study 7% in a group of people aged 60 years and over had IC.14,15 People with IC experience symptoms produced by exercise and relieved by rest.16 Ischemia and symptoms are a result of the increased energy and metabolic demand on muscles during exercise, and due to reduced blood flow to the lower extremities, the claudication cannot meet this demand.4 The severity of IC can be identified in the clinic using a classification of PAD by the Fontaine's Stages or the Rutherford Categories.4,6 The classification by Fontaine has two stages of IC whereas the Rutherford classification is the most differentiated according to the intermittent claudication with three categories of IC: mild, moderate and severe, related to the objective criteria due to treadmill walking and ankle pressure after exercise.17
Physical functioning
Physical functioning is defined as the ability to perform activities required in a person's daily life and is therefore dependent on many factors including physical fitness, and environmental and behavioral factors.18 Walking ability is particularly affected in patients with symptoms of IC and impaired lower extremity function.19,20,21 Physical function is particularly associated with the severity of PAD measured by the ABI.19,22 Individuals with PAD are significantly less physically active than people without PAD and they have a faster decline in physical functioning.23,24 It has been demonstrated that both the baseline physical function and the decline in physical function measured after two years predict the risk for later mobility loss and mortality in persons with PAD.11 Functional decline is less when people with PAD are physically active in daily life.25 In fact, due to IC, some people with PAD become inactive to avoid leg pain and this further affects their disease, resulting in loss of lower extremity muscle mass, strength and endurance.26
Exercise in relation to intermittent claudication
Exercise is a subcategory of physical activity, which according to the WHO, also includes recreational and leisure-time physical activity, transportation (e.g. walking or cycling), and occupational and household chores.1 The objective of exercise is to improve or maintain physical fitness and health.27 Depending on the purpose, exercise programs (EP) differ in terms of duration, frequency, intensity and mode of activity. Previous systematic reviews from the Cochrane Collaboration have investigated the effects of exercise on IC and found improvements in physical performance measured in maximal walking time, maximal walking distance and pain-free walking distance.28,29 In 2013, supervized exercise therapy (SET) was compared to non-supervized exercise therapy in relation to IC, concluding that SET has statistically significant benefits on treadmill maximal and pain-free walking distance.29 Different modes of SET will be compared in an upcoming study.30
Based on the evidence (Level A), SET is recommended as treatment for IC in international guidelines for management of patients with peripheral arterial disease.4,6,14 The guidelines recommend conservative therapy including exercise training, risk factor control and pharmacotherapy before other options such as endovascular therapy or by-pass surgery are considered.4,6,14 Recommendations for SET do not distinguish between different categories of intermittent claudication, and the demonstrated improvements in walking distance and pain-free walking distance seem even more relevant for persons with more severe IC as it motivates them to exercise and prevents functional decline. However, persons with moderate to severe IC are more disabled in physical functioning, are at high risk of co-morbidities, and have therefore been excluded in many studies exploring exercise for IC. This causes authors to point out that future research should include people who have more severe PAD and other co-morbidities, as they are more representative of the PAD population and some of them are not eligible for surgical intervention.29,31
Co-morbidities such as hypertension, hypercholesterolemia and diabetes mellitus are risk factors for PAD as well as for coronary artery disease.6,12,32 Exercise training provides benefits for these cardiovascular risk factors and is therefore implemented in secondary prevention of coronary artery disease.26,33 Prevention of future cardiovascular events could be a possible important side effect of exercise in PAD too, taking into consideration the common etiology.4 Some studies exploring SET for persons with more severe PAD and symptoms of moderate to severe IC have demonstrated the ability of this population to participate in the intervention.34,35 This review aims to search literature systematically to identify similar studies.
Modes of exercise
Exercise programs for treatment of IC mainly include walking modalities but other modes are explored.23,28,30,31 A systematic review of RCT found modes of aerobic exercise and walking to have equal benefits for claudication. Additionally, progressive resistance training (PRT) and upper-body exercise have also been promising: thereby providing options of SET for people with IC where they cannot tolerate walking.31 Furthermore, a pain-free walking EP appears to have a similar benefit as a walking EP with moderate claudication pain, and is therefore an effective option regarding claudications.36 The underlying mechanisms responsible for the effect of exercise are not clarified. The hypothesis is increased capillarization as there is no association with changes in post-exercise ABI but also, improved walking efficiency and a systemic cardiovascular effect are possible.6,36,37 An assessment of the effect of treatment by objective measures is recommended; in clinical trials it is usually done by a treadmill test of the peak walking time or distance as well as the time or distance for the onset of claudication.6 Patient-based questionnaires such as the Walking Impairment Questionnaire (WIQ) and the physical domain of the Medical Outcomes Short Form 36 (SF36) have also been used and are being proposed to measure physical functioning in the international guideline for the management of peripheral arterial disease (TASCII).6
Strong evidence supports that SET provides benefits for persons with intermittent claudication and SET is recommended in all international guidelines for management of peripheral arterial disease. With benefits from other modes of EP such as upper-body exercise, progressive resistance training and pain-free EP, persons with moderate to severe intermittent claudication may be able to participate in exercise.31,36,37 The aim of this systematic review is to explore current results of EP in relation to persons with moderate to severe IC.
A preliminary search in The JBI Database of Systematic Reviews and Implementation Reports, The Cochrane Database of Systematic Reviews, MEDLINE, CINAHL and PEDro databases did not locate any systematic reviews or protocols for a systematic review with the same objective as this review. Previous systematic reviews retrieved23,28,29,30,31 included persons with IC; however they did not investigate the specific population of persons with moderate to severe IC and the effectiveness of an exercise program on physical functioning.
Definitions
Peripheral arterial disease (PAD): a range of non-coronary arterial syndromes that are caused by the altered structure and function of the arteries that supply blood to the brain, visceral organs and the limbs.4
Exercise: a physical activity that is planned, structured, repetitive and purposeful in the sense that improvement or maintenance of one or more components of physical fitness is an objective.27
Physical fitness: a set of attributes that people have or achieve that relates to the ability to perform physical activity.27
Exercise program (EP): any modality of physical activity with clear prescriptive instructions, whether supervized or non-supervized and in any setting.
Physical activity: any bodily movement produced by skeletal muscles that require energy expenditure.38
Intermittent claudication: extremity pain, discomfort or weakness that is consistently produced by the same amount of walking or equivalent muscular activity in a given patient and that is promptly relived by cessation of that activity.16,17
Critical limb ischemia (CLI): persons with Peripheral Arterial Disease who present lower extremity ischemic rest pain, ulceration or gangrene, classified as grade II-IV or category 4-6 on the Rutherford classification.4
Article Content
Inclusion criteria
Types of participants
This review will consider studies that include adults with moderate to severe intermittent claudication, verified by a validated or a clear classification. There will be no limitation regarding gender or ethnicity. Studies dealing with participants who have co-morbidities, who are in pharmacotherapy or who have had a previous revascularization are included on the basis that these factors are well described and not subject for interventions during the study.
Types of intervention
This review will consider studies that evaluate any mode of exercise program with clearly prescribed instructions. The exercise may be based in any setting: the hospital, community or home setting. The training may be in the form of individual or group activities, and both supervized as well as non-supervized exercise training will be considered.
Types of outcomes
This review will consider studies that include outcomes measuring the walking aspect of physical functioning. Outcome must be measured by a standardized and validated test. Both objective performance-based tests as well as self-reported questionnaires assessing walking ability are included. Performance-based tests included are: a treadmill test using a standard protocol and measuring maximal walking time, distance or onset to claudication pain, the Six-minute Walk Test (6MWT) and the Shuttle Walk Test. Included questionnaires are the physical function part of SF36 and Walking impairment Questionnaire (WIQ).
Types of studies
This review will consider both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies and case control studies.
Search strategy
The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies, and a citation search will also be done on especially relevant studies. The preliminary search resulted in very few potentially relevant studies for this review. On this basis, the search strategy will be wide and inclusive with no limitations regarding dates. Studies published in English, German, Swedish, Norwegian and Danish will be considered for inclusion in this review.
The databases to be searched include:
MEDLINE, CINAHL, Embase, AMED and PEDro.
The search for unpublished studies will include:
The MedNar and Prospero databases, as well as online search for ProQuest Dissertations and Theses.
Initial keywords to be used will be:
Assessment of methodological quality
Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review
Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.
Data extraction
Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). To minimize errors two reviewers will extract data independently before discussing and making an agreement. The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Where reported data are unclear or aggregated, particularly in relation to the severity of IC, the authors of primary studies will be contacted with requests to provide disaggregated data. S
Data synthesis
Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity regarding participants or interventions in the included studies will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.
Conflicts of interest
None.
Acknowledgements
We are grateful to Line Jensen (MA) for her work with editorial assistance.
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Appendix I: Appraisal instruments
MAStARI appraisal instrument[Context Link]
Appendix II: Data extraction instruments
MAStARI data extraction instrument[Context Link]
Keywords: Intermittent claudication; Supervised exercise; Treadmill test; Walking test; SF36; physical function; Walking Impairment Questionnaire