ReviewA systematic review of randomized controlled trials: Walking versus alternative exercise prescription as treatment for intermittent claudication
Introduction
The world-wide prevalence of peripheral arterial disease (PAD) has been estimated at 3–10%, increasing to 18–24% in persons over 70 years of age [1], [2]. The majority of patients present with classic walking-associated claudication pain. However, there is also a subset who present with atypical pain. Together, 10–20% of these patients will develop progressive claudication, with a further 1–2% developing critical limb ischemia [3]. Current management for PAD includes pharmacotherapy for coexisting disease (e.g. hypertension), risk factor management (e.g. statins for hylerlipidemia) and/or as a preventative treatment for thrombotic events associated with the underlying atherosclerosis (e.g. acetylsalicylic acid) [1]. Meta-analyses have shown that prolonged anti-platelet therapy (primarily aspirin) is effective at preventing vascular events and death from myocardial infarction and stroke in clinical cohorts [4]. Notably however, when a subset of patients with claudication were analysed further, this risk reduction after a mean of 27 months of follow-up was not statistically significant [4], [5]. In addition, whilst pharmacotherapy (e.g. pentoxyfilline) is available for reduction of symptoms and improvements in walking distance, the overall clinical benefit of pentoxyfilline is questionable and therefore it is not generally accepted for widespread use [1]. Cilostazol, though currently recommended as first-line pharmacotherapy for relief of claudication [1] is contra-indicated in patients with heart failure, thus limiting its use to a subset of individuals with PAD. There are currently no data, to our knowledge, on risk factor reduction attributable to either pentoxyfilline or cilostazol. By contrast, statin therapy may be a promising pharmaceutical alternative for obtaining symptom relief and improving exercise performance, whilst also preventing disease progression and risk factor management [1]. However, more studies are warranted to determine its clinical benefit [1]. Thus, effective pharmacotherapy for claudication is limited at present.
Treatment for PAD also includes surgical or endovascular revascularization where appropriate [1]. Surgical intervention alone, whilst effective for improving function, is reserved for severe disease or threatened loss of limb [1]. Additionally, there are a group of persons with moderate to severe disease who are ineligible for surgical intervention due to their high surgical risk related to other co-morbidities. This group of patients are often prescribed pharmacotherapy and risk factor management as primary treatment, including walking exercise advice.
The TASC-II working group [1] currently recommends walking to a moderate-high level of claudication pain as an initial treatment for intermittent claudication [1] and currently, exercise therapy guidelines differ amongst published literature reviews [3], [6]. Current recommendations include “walking to a moderate level of claudication pain, rest and repeat as often as possible” [1], or less specifically, “simple walking regimens, dynamic and static leg exercise, individualized treadmill exercise” [3]. Such exercise has been shown to significantly improve symptoms of PAD, even in those suffering with heart failure, with two independent analyses calculating significant mean improvements in overall walking ability of 150% [7] and 179% [8]. In addition, exercise is non-invasive, relatively low risk, and effective at reducing the many risk factors for atherosclerotic disease itself in patients with PAD [9] and vascular events in the general population.
However, there are a group of patients with PAD who, due to the severity of claudication pain, diabetic foot complications, calcaneal spurs, arthritis or other medical co-morbidities such as osteoporotic vertebral fractures, stroke and severe cardiorespiratory or degenerative neurological disease, are unable or unwilling to complete the current lower limb/walking exercise therapy guidelines. Unfortunately, the current exercise guidelines do not provide clinicians with an appropriate plan for these patients who are unable or unwilling to undertake lower limb or walking exercise, and unable to tolerate surgical intervention due to co-morbidities. There is a need to define the clinical utility of alternative modes of exercise for this difficult-to-treat group of patients.
Thus, the purpose of this investigation was to systematically review the literature for all randomized controlled trials (RCTs) using any form of exercise as treatment for intermittent claudication (IC), and subsequently compare any alternate forms of exercise to walking. We aimed to identify whether there is an alternative treatment option for those who are unable to adhere to the current exercise guidelines or are unsuitable for surgical or endovascular intervention. Although reviews have been conducted in the past [6], [7], [8], [10], there has been very little statistical comparison between exercising and non-exercising control groups, and walking and non-walking exercise groups. Acknowledging these significant gaps in the literature, our primary objective was to identify the role of non-walking exercise interventions compared to walking on claudication in PAD. A secondary objective was to identify whether various prescriptive elements such as supervision, duration, intensity, and/or length of exercise training programs were related to clinical benefits.
Section snippets
Data sources and searches
Due to the heterogeneity of exercise prescriptions, outcomes assessed and measurement tools used, a systematic review was conducted without meta-analysis. The electronic database search was performed, with no language restrictions, using Medline, EMBASE, AMED, SPORTDiscus, CINAHL, Pedro, Premedline, Google Scholar and Web of Knowledge. Databases were searched from earliest record to March 2011. Bibliographies of all eligible papers and reviews identified were manually searched. Search terms
Results
Results of the search strategy are presented in Fig. 1. Thirty-six intervention trials [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55] met the inclusion criteria for this claudication outcomes paper.
Discussion
In our previous review [12] we found that walking distance improves without significant changes in blood flow [25], [27], [28], [31], [34], [35], [37], [38], [40], [58] or pressure [23], [24], [26], [27], [28], [30], [31], [32], [36], [40], [41], [42], [43], [44], [47], [49], [59]. Thus, mechanisms by which exercise training generates improvements in function may be multifactorial, and remain to be elucidated. This review has shown that potentially clinically meaningful improvements in walking
Conclusion
The increasing world-wide prevalence of PAD with age [1], [2], the lack of evidence-based exercise treatment alternatives for patients with PAD who are unable to tolerate walking, and the data indicating that there may be other modes and/or intensities of exercise that may be equally, if not more effective than the current walking guidelines, emphasize the need for additional high quality research using varied exercise prescriptions in older patients with various disease severity. Modes of
Conflict of interest
The authors report no potential conflicts of interest.
Acknowledgements
This research was carried out at Exercise, Health and Performance, Faculty of Health Sciences, University of Sydney.
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