Improving Functional Outcomes in Patients with Intermittent Claudication

In summary, while some drugs have been shown to improve walking performance in patients with intermittent claudication, the effect has tended to be modest at best and smaller than that observed with supervised exercise training. Momsen et al concluded that statins probably have the greatest functional benefits [55], and clinical guidelines recommend that all patients with PAD should receive statin therapy [3,7,8], irrespective of its effect on functional status. The UK clinical guidelines recommend considering using naftidrofuryl oxalate for the treatment of claudication, but only when supervised exercise has not worked and revascularization is not feasible or declined by the patient [8]. The ACC/AHA guidelines state that a therapeutic trial of cilostazol should be considered in all patients with lifestyle-limiting claudication in the absence of heart failure [7].

Lower-Limb Revascularization

Intermittent claudication can also be treated using endovascular procedures (angioplasty ± stent placement) or bypass surgery, both of which constitute a relatively more direct means of addressing the problem since they target the arterial lesions causing claudication. Trials of revascularization in PAD have typically focused on vessel/graft patency as the primary outcome, with less emphasis placed on functional endpoints [59]. Despite this, it is clear that successful revascularization rapidly improves walking performance [60,61], whereas noticeable improvements with supervised exercise training can take several weeks to occur (assuming good adherence) [62]. Long-term comparisons of lower-limb revascularization with alternative treatment modalities for people with intermittent claudication are scarce. Recently, Fakhry et al [63] reported the long-term clinical effectiveness of supervised exercise therapy and endovascular revascularization from a randomized trial of 151 patients. After 7 years, the treatment strategies were similarly effective in improving functional performance and quality of life; however, the total number of endovascular and surgical interventions (primary and secondary) was substantially higher in the revascularization group, which will have resulted in significantly higher health care costs in this group. Furthermore, given that supervised exercise training costs substantially less than any revascularization procedure, it is not surprising that economic analyses indicate supervised exercise training as being more cost-effective [64,65]. This is reflected in clinical guidelines, which promote supervised exercise training as the first-line therapy [3,7,8]. In the UK, NICE recommends that clinicians should only offer angioplasty for treating people with intermittent claudication when advice on the benefits of modifying risk factors has been reinforced, a supervised exercise program has not led to a satisfactory improvement in symptoms, and imaging has confirmed that angioplasty is suitable for the person [8]. Bypass surgery for treating people with severe lifestyle-limiting intermittent claudication is only recommended when angioplasty has been unsuccessful or is unsuitable, and imaging has confirmed that bypass surgery is appropriate for the person. Overall, from a technical point of view during revascularization, there is no strong evidence to support that differences in clinical outcomes are observed as a function of technical choices of anastomoses in aortobifemoral bypasses [66] or kind of angioplasty in femoropopliteal lesions [67].

Potential Alternative Therapeutic Approaches

Several non-drug, non-exercise, and non-revascularization approaches have been investigated for their impact on claudication-related functional impairment, including (but not limited to) acupuncture, biofeedback, chelation therapy, CO ₂-applications, and the dietary supplements Allium sativum (garlic), Ginkgo biloba, omega-3 fatty acids, Padma 28, Vitamin E, and carnitine supplementation. In a recent systematic review, Delaney et al highlighted that most of the 8 parallel-group randomized controlled trials of propionyl-L-carnitine supplementation (600 to 3000 mg administered orally) demonstrated improvements in walking performance between 31 and 54 m greater than placebo for pain-free walking distance and between 9 and 86 m greater than placebo for maximum walking distance [68]. Propionyl-L-carnitine has been postulated to improve walking distance by improving endothelial function, and increasing total carnitine content in the ischemic muscle, which improves muscle metabolism and stimulates oxidative phosphorylation resulting in a decrease in plasma lactate concentration on exercise [68]. In a systematic review of these complementary therapies for PAD from 2005 [69], Pittler and Ernst concluded that there was some evidence for a beneficial effect of Ginkgo biloba and Padma 28 in claudication patients; however, recent meta-analyses have concluded that there is no evidence that Ginkgo biloba produces clinically meaningful improvements in walking distances [70], and that further well-designed research is required to determine the true effects of Padma 28 [71]. None of the other complementary treatment options have sufficient supporting evidence for them to be proposed as a routine approach [72–75]. Last, a few small studies have indicated that intermittent pneumatic compression (IPC) interventions can improve walking distances in people with intermittent claudication [76–78]. To date, IPC has received limited use in the clinical setting due to issues of cost and constraint; however, modern technology has permitted the development of portable systems to be made readily available for affordable at-home use. Adequately powered randomized controlled trials and economic evaluations are required to clarify the role of IPC for improving functional outcomes in intermittent claudication.