and Reinhart T. Grundmann2
(1)
Department of Vascular Medicine, University Heart and Vascular Center at University Clinics Hamburg–Eppendorf, Hamburg, Germany
(2)
Former Medical Director, Community Hospital Altoetting-Burghausen, Burghausen, Germany
8.1 Treatment Indications/Guidelines
8.1.1 American College of Cardiology Foundation/American Heart Association
Recommendations (Anderson et al. 2013):
Exercise training
Class I
A program of supervised exercise training is recommended as an initial treatment modality for patients with intermittent claudication (IC). (Level of Evidence: A)
Supervised exercise training should be performed for a minimum of 30–45 min, in sessions performed at least 3 times per week for a minimum of 12 weeks. (Level of Evidence: A)
Class IIb
The usefulness of unsupervised exercise programs is not well established as an effective initial treatment modality for patients with IC. (Level of Evidence: B)
Endovascular treatment for claudication
Class I
Endovascular procedures are indicated for individuals with a vocational or lifestyle-limiting disability due to IC when clinical features suggest a reasonable likelihood of symptomatic improvement with endovascular intervention and (a) there has been an inadequate response to exercise or pharmacological therapy and/or (b) there is a very favorable risk-benefit ratio (e.g., focal aortoiliac occlusive disease). (Level of Evidence: A)
Endovascular intervention is recommended as the preferred revascularization technique for TASC type A and femoropopliteal arterial lesions. (Level of Evidence: B)
Provisional stent placement is indicated for use in the iliac arteries as salvage therapy for a suboptimal or failed result from balloon dilation. (Level of Evidence: B)
Stenting is effective as primary therapy for common iliac artery stenosis and occlusions. (Level of Evidence: B)
Stenting is effective as primary therapy in external iliac artery stenoses and occlusions. (Level of Evidence: C)
Class IIa
Stents (and other adjunctive techniques such as lasers, cutting balloons, atherectomy devices, and thermal devices) can be useful in the femoral, popliteal, and tibial arteries as salvage therapy for a suboptimal or failed result from balloon dilation (e.g, persistent translesional gradient, residual diameter stenosis >50%, or flow-limiting dissection). (Level of Evidence: C)
Class IIb
The effectiveness of stents, atherectomy, cutting balloons, thermal devices, and lasers for the treatment of femoral-popliteal arterial lesions (except to salvage a suboptimal result from balloon dilation) is not well-established. (Level of Evidence: A)
The effectiveness of uncoated/uncovered stents, atherectomy, cutting balloons, thermal devices, and lasers for the treatment of infrapopliteal lesions (except to salvage a suboptimal result from balloon dilation) is not well established. (Level of Evidence: C)
Class III
Primary stent placement is not recommended in the femoral, popliteal, or tibial arteries. (Level of Evidence: C)
Endovascular intervention is not indicated as prophylactic therapy in an asymptomatic patient with lower extremity PAD. (Level of Evidence: C)
Surgical Interventions
Class I
Surgical interventions are indicated for individuals with claudication symptoms who have a significant functional disability that is vocational or lifestyle limiting, who are unresponsive to exercise or pharmacotherapy, and who have a reasonable likelihood of symptomatic improvement. (Level of Evidence: B)
Class IIb
Because the presence of more aggressive atherosclerotic occlusive disease is associated with less durable results in patients younger than 50 years of age, the effectiveness of surgical intervention in this population for IC is unclear. (Level of Evidence: B)
Class III
Surgical intervention is not indicated to prevent progression to limb-threatening ischemia in patients with IC. (Level of Evidence: B)
Inflow procedures: aortoiliac occlusive disease:
Class I
Aortobifemoral bypass is beneficial for patients with vocational- or lifestyle-disabling symptoms and hemodynamically significant aortoiliac disease who are acceptable surgical candidates and who are unresponsive to or unsuitable for exercise, pharmacotherapy, or endovascular repair. (Level of Evidence: B)
Iliac endarterectomy and aortoiliac or iliofemoral bypass in the setting of acceptable aortic inflow should be used for the surgical treatment of unilateral disease or in conjunction with femoral-femoral bypass for the treatment of a patient with bilateral iliac artery occlusive disease if the patient is not a suitable candidate for aortobifemoral bypass grafting. (Level of Evidence: B)
Class IIb
Axillofemoral-femoral bypass may be considered for the surgical treatment of patients with IC in very limited settings, such as chronic infrarenal aortic occlusion associated with symptoms of severe claudication in patients who are not candidates for aortobifemoral bypass. (Level of Evidence: B)
Class III
Axillofemoral-femoral bypass should not be used for the surgical treatment of patients with IC except in very limited settings. (Level of Evidence: B)
Outflow procedures – Infrainguinal disease:
Class I
Bypasses to the popliteal artery above the knee should be constructed with autogenous vein when possible. (Level of Evidence: A)
Bypasses to the popliteal artery below the knee should be constructed with autogenous vein when possible. (Level of Evidence: B)
Class IIa
The use of synthetic grafts to the popliteal artery below the knee is reasonable only when no autogenous vein from ipsilateral or contralateral leg or arms is available. (Level of Evidence: A)
Class IIb
Femoral-tibial artery bypasses constructed with autogenous vein may be considered for the treatment of claudication in rare instances for certain patients. (Level of Evidence: B)
Because their use is associated with reduced patency rates, the effectiveness of the use of synthetic grafts to the popliteal artery above the knee is not well-established. (Level of Evidence: B)
Class III
Femoral-tibial artery bypasses with synthetic graft material should not be used for the treatment of claudication. (Level of Evidence: C)
8.1.2 National Institute for Health and Care Excellence (NICE)
The British NICE (NICE 2012) has the following recommendations identified as priorities for implementation:
Offer all people with peripheral arterial disease information, advice, support and treatment regarding the secondary prevention of cardiovascular disease on:
Smoking cessation
Diet, weight management and exercise
Lipid modification and statin therapy
Prevention, diagnosis and treatment of diabetes
Prevention, diagnosis and treatment of high blood pressure
Antiplatelet therapy
Supervised exercise programme
Offer a supervised exercise programme to all people with intermittent claudication.
Consider providing a supervised exercise programme for people with IC which involves:
2 h of supervised exercise a week for a 3-month period
Encouraging patients to exercise to the point of maximal pain.
Angioplasty and stenting
Offer angioplasty for treating people with IC only when:
advice on the benefits of modifying risk factors has been reinforced and
a supervised exercise programme has not led to a satisfactory improvement in symptoms and
imaging has confirmed that angioplasty is suitable for the person.
Do not offer primary stent placement for treating people with IC caused by aorto-iliac disease (except complete occlusion) or femoro-popliteal disease.
Consider primary stent placement for treating people with IC caused by complete aorto-iliac occlusion (rather than stenosis).
Use bare metal stents when stenting is used for treating people with IC.
Bypass surgery and graft types
Offer bypass surgery for treating people with severe lifestyle-limiting intermittent claudication only when:
angioplasty has been unsuccessful or is unsuitable and
imaging has confirmed that bypass surgery is appropriate for the person.
Use an autologous vein whenever possible for people with IC having infra-inguinal bypass surgery.
Naftidrofuryl oxalate
Consider naftidrofuryl oxalate for treating people with IC, starting with the least costly preparation, only when:
supervised exercise has not led to satisfactory improvement and
the person prefers not to be referred for consideration of angioplasty or bypass surgery.
Review progress after 3–6 months and discontinue naftidrofuryl oxalate if there has been no symptomatic benefit.
8.1.3 European Society of Cardiology (Tendera et al. 2011)
Recommendations for revascularization in patients with aortoiliac lesions
When revascularization is indicated, an endovascular-first strategy is recommended in all aortoiliac TASC A—C lesions (Class I/Level of Evidence: C)
A primary endovascular approach may be considered in aortoiliac TASC D lesions in patients with severe comorbidities, if done by an experienced team. (Class IIb/ Level of Evidence: C)
Primary stent implantation rather than provisional stenting may be considered for aortoiliac lesions (Class IIb/ Level of Evidence: C)
Recommendations for the revascularization in patients with femoropopliteal lesions
When revascularization is indicated, an endovascular-first strategy is recommended in all femoropopliteal TASC A—C lesions (Class I/ Level of Evidence C)
Primary stent implantation should be considered in femoropopliteal TASC B lesions (Class IIa/ Level of Evidence: A)
A primary endovascular approach may be considered in TASC D lesions in patients with severe comorbidities and the availability of an experienced interventionist. (Class IIb/ Level of Evidence C)
Recommendations for revascularization in patients with infrapopliteal lesions
When revascularization in the infrapopliteal segment is indicated, the endovascular-first strategy should be considered (Class IIa/ Level of Evidence C)
For infrapopliteal lesions, angioplasty is the preferred technique, and stent implantation should be considered only in the case of insufficient PTA. (Class IIa/ Level of Evidence: C)
8.1.4 Society for Vascular Surgery Practice Guidelines (Conte et al. 2015)
Interventions for aortoiliac occlusive disease (AIOD) in intermittent claudication (IC)
We recommend endovascular procedures over open surgery for focal AIOD causing IC. (Grade 1/Level of Evidence: B)
We recommend endovascular interventions as first-line revascularization therapy for most patients with common iliac artery or external iliac artery occlusive disease causing IC. (Grade 1/Level of Evidence: B)
We recommend the selective use of BMS or covered stents for aortoiliac angioplasty for common iliac artery or external iliac artery occlusive disease, or both, due to improved technical success and patency. (Grade 1/Level of Evidence: B)
We recommend the use of covered stents for treatment of AIOD in the presence of severe calcification or aneurysmal changes where the risk of rupture may be increased after unprotected dilation. (Grade 1/Level of Evidence: C)
We recommend direct surgical reconstruction (bypass, endarterectomy) in patients with reasonable surgical risk and diffuse AIOD not amenable to an endovascular approach, after one or more failed attempts at EVT, or in patients with combined occlusive and aneurysmal disease. (Grade 1/Level of Evidence: B)
Interventions for femoropopliteal occlusive disease in (IC)
We recommend endovascular procedures over open surgery for focal occlusive disease of the superficial femoral artery (SFA) not involving the origin at the femoral bifurcation. (Grade 1/Level of Evidence: C)
For focal lesions (<5 cm) in the SFA that have unsatisfactory technical results with balloon angioplasty, we suggest selective stenting. (Grade 2/Level of Evidence: C)
For intermediate-length lesions (5–15 cm) in the SFA, we recommend the adjunctive use of self-expanding nitinol stents (with or without paclitaxel) to improve the midterm patency of angioplasty. (Grade 1/Level of Evidence: B)
We recommend against EVT of isolated infrapopliteal disease for IC because this treatment is of unproven benefit and possibly harmful. (Grade 1/Level of Evidence: C)
We recommend surgical bypass as an initial revascularization strategy for patients with diffuse femoropopliteal disease, small caliber (<5 mm), or extensive calcification of the SFA, if they have favorable anatomy for bypass (popliteal artery target, good runoff) and have average or low operative risk. (Grade 1/Level of Evidence: B)
We recommend using the saphenous vein as the preferred conduit for infrainguinal bypass grafts. (Grade 1/Level of Evidence: A)
In the absence of suitable vein, we suggest using prosthetic conduit for femoropopliteal bypass in claudicant patients, if the above-knee popliteal artery is the target vessel and good runoff is present. (Grade 2/Level of Evidence: C)
BMS, Bare-metal stent; EVT, Endovascular therapy; SFA, superficial femoral artery.
8.1.5 Reporting Standards of the Society for Vascular Surgery (Stoner et al. 2016)
8.1.5.1 Claudication Reporting
- 1.
An ankle-brachial index (ABI) ≤ 0.90 is the threshold for diagnosis of PAD. As stated in the recently published SVS guidelines, when the ABI is borderline or normal (>0.9) and symptoms of claudication are suggestive, we recommend exercise ABI.
- 2.
Baseline functional characterization with treadmill testing or preferably ambulatory testing by 6-min walk test.
- 3.
Quality of life assessment by validated scoring system, such as the Walking Impairment Questionnaire.
- 4.
Classification of severity based on previously published SVS guidelines.
8.1.5.2 Outcome Measures: Procedural
- 1.
Technical success is defined as successful use of a device or technique to establish vessel patency with a residual stenosis <30%. Procedural success is defined as technical success and completion of the procedure without complications.
- 2.
Hemodynamic success is defined as a pressure gradient <10 mm Hg across a lesion or corresponding increase in ABI of 0.10 or toe pressure of 0.10. Other measures of hemodynamic success (such as pulse volume recording amplitude) may be acceptable.
- 3.
Patency is evaluated by an accepted imaging technique of the specific arterial site treated that clearly shows flow through the lesion.
- 4.
Within the context of a clinical trial, duplex ultrasound should be considered the standard for patency and restenosis surveillance. A peak systolic velocity >300 cm/s or peak systolic velocity ratio >3.0 indicates restenosis.
- 5.
Target lesion revascularization can be driven by clinical, anatomic, and hemodynamic indications and as such does not always contribute to the assessment of clinical failure. It should not be used as a primary end point.
8.1.5.3 Outcome Measures: Disease Specific
- 1.
In addition to anatomic and hemodynamic measures of success, claudication trials should include disease-specific quality of life outcome measures and functional assessment.
- 2.
Critical limb ischemia trials should use the objective performance goals as measures of efficacy and safety in addition to disease-specific and overall quality of life measures.
- 3.
Lower extremity endovascular therapy for PAD should be reported at minimum for 30-day, 1-year, and 2-year follow-up, promoting standardization and hence more clinically meaningful comparisons of peripheral vascular interventions. Five-year follow-up is preferable.
8.2 Results
8.2.1 Exercise Training
8.2.1.1 Meta-analysis/Systematic Reviews
Supervised vs. unsupervised exercise therapy
A Cochrane review (Lane et al. 2014) determined whether an exercise programme in people with IC was effective in alleviating symptoms and increasing walking treadmill distances and walking times. Any exercise programme or regimen used in the treatment of IC was included, such as walking, skipping and running. Thirty trials were included in this review, involving a total of 1816 participants with stable leg pain. Exercise programmes were of significant benefit compared with placebo or usual care in improving walking time and distance in people with leg pain from IC who were considered to be fit for exercise intervention. The effect of exercise, when compared with placebo or usual care, was inconclusive on mortality, amputation and peak exercise calf blood flow due to limited data. No data were given on non-fatal cardiovascular events.
This poses the question whether exercise therapy should be conducted in a supervised or unsupervised setting. Al-Jundi et al. (2013) compiled a systematic review on this topic. The 17 included studies for home-based exercise programmes (HEPs) were mostly of low methodological quality. There was “low-level” evidence that HEPs can improve walking capacity and quality of life in patients with IC when compared with baseline or in comparison to usual care or observation only. In addition, improvements with HEPs may be inferior to those resulting from supervised exercise programmes. In conclusion, clinicians should consider using HEPs to promote walking in patients with IC, as opposed to basic “go home and walk” advice, when supervised training is unavailable or impractical.
The effects of supervised versus non-supervised exercise therapy on maximal walking time or distance on a treadmill for people with IC were analyzed in a further Cochrane review (Fokkenrood et al. 2013). According to this review, supervised exercise therapy (SET) has statistically significant benefit on treadmill walking distance (maximal and pain-free) compared with non-supervised regimens. However, the clinical relevance of this has not been demonstrated definitively. A further systematic review and meta-analysis came to a similar result: in claudication patients, supervised exercise (SE) is more effective than unsupervised exercise (UE) at improving maximal walking and claudication distances, yet there is no difference in general quality of life or patient-reported community-based walking (Vemulapalli et al. 2015).
In a fourth meta-analysis it was hypothesized that there is a positive treatment effect in relation to the intensity of supervision and improvement in walking capacity (i.e., a “dose–response” hypothesis) (Gommans et al. 2014). The authors found that SET for IC is superior to all other forms of exercise therapy. Intensity of supervision was related to improved walking distance. A 3-month SET programme appeared to be the most preferable. After 3 months of training, supervision might be replaced by a home-based programme, as this meta-analysis demonstrated an equivalent effect of SET and home-based exercise therapy after 6 months.
Parmenter et al. (2015) performed the first meta-analysis limited to RCTs to analyse perceived walking impairment, general health and quality of life outcomes for exercise interventions in PAD. In analysing the findings, it is important to take into account the quality of the trials included in the review and the limited study of exercise modes other than walking. Nevertheless, this review suggests that walking training to various levels of claudication pain improves perceived walking speed, distance and stair-climbing performance as measured by the Walking Impairment Questionnaire, and self-reported physical function (SF-36) in patients with PAD.
Specific problems
In most studies, SET consists of treadmill or track walking. However, alternative modes of exercise therapy have been described. Lauret et al. (2014) assessed the effects of different modes of SET on the maximum walking distance of patients with IC in a Cochrane review. Five studies comparing supervised walking exercise and alternative modes of exercise were found. The alternative modes of exercise therapy included cycling, strength training, and upper-arm ergometry. The studies represented a sample size of 135 participants with a low risk of bias. Overall, there was no clear evidence of a difference between supervised walking exercise and alternative modes of exercise in maximum walking distance on a treadmill or in pain-free walking distance. The results indicate that alternative exercise modes may be useful when supervised walking exercise is not an option for the patient.
Occasionally, there is concern regarding the safety of performing SET because IC patients are at risk for untoward cardiovascular events. Gommans, Fokkenrood et al. (2015a) found 74 studies representing 82,725 h of training in 2876 IC patients. Eight adverse events were reported, six of cardiac and two of noncardiac origin, resulting in an all-cause complication rate of one event per 10,340 patient-hours. Thus, supervised exercise therapy can safely be prescribed in patients with IC because an exceedingly low all-cause complication rate was found. Routine cardiac screening before commencing SET is not required.
8.2.1.2 Studies
In a prospective, randomized controlled clinical trial Gardner et al. (2012) determined whether an optimal exercise program length exists to efficaciously change claudication onset time (COT) and peak walking time (PWT) in patients with peripheral arterial disease (PAD) and claudication. The primary finding of this investigation was that exercise-mediated gains in COT and PWT occur rapidly within the first 2 months of exercise rehabilitation and are maintained with further training. This finding has major implications for patients, exercise program personnel, and utilization of resources and facilities. From the patient’s viewpoint, claudication severity can be improved with relatively little effort by walking an average of 1.5 miles per week for 2 months. The clinical significance is that a relatively short 2-month exercise program may be preferred to a longer program to treat claudication because adherence is higher, costs associated with personnel and use of facilities are lower per patient, and more patients can be trained for a given amount of personnel time and resource utilization.
In a further prospective study, Gardner et al. (2014) determined whether sex and diabetes were factors associated with the response to exercise rehabilitation in patients with claudication. Eighty patients were randomized to home-based and supervised exercise programs, and 60 finished with complete exercise intervention data. The primary finding was that the only subgroup of patients with PAD and claudication who did not significantly improve their COT and PWT after 3 months of exercise rehabilitation was diabetic women, only 37% of diabetic women increased their COT. Of the two factors, sex was more closely related to the exercise response than diabetes, as the mean change scores for COT and PWT in women were less than half of those in men, and fewer women responded to exercise. Gender differences following SET in patients with IC were also observed by Gommans, Scheltinga et al. (2015b). In this study, absolute claudication distance increase was significantly lower for women than for men during the first 3 months of therapy. Moreover, absolute walking distance was significantly shorter for women compared with men after 1 year, women with IC benefit less from SET than men.
A randomized clinical trial was performed by Spafford et al. (2014) to determine whether Nordic pole walking (NPW) is more effective in improving walking distance than a standard home exercise programme in patients with IC. After 12 weeks the walking distance of patients in the NPW group was significantly longer than of patients in the control group. The efficacy of NPW has been confirmed by Bulińska et al. (2016). In a randomized trial they found NPW as effective as the standard traditional treadmill training and much less expensive. It should be the preferred method of exercise in IC patients.
Saxton et al. (2011) investigated the effects of upper- and lower-limb aerobic exercise training on disease-specific functional status and generic health-related quality of life (QOL) in patients with IC in a randomized controlled trial. Improvements in patient perceptions of disease-specific functional status and generic health-related QOL domains were observed after both the upper-limb and lower-limb exercise training regimens. Both forms of exercise training were well tolerated; however, because upper-limb exercise training avoids the ischemic pain that is experienced during lower-limb exertion, it could be used in the early stages of an exercise rehabilitation program until patients feel more able and confident to engage in lower-limb exercise. It might also be a preferred exercise option for patients with increased disease severity.
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